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Konda B, Sherman EJ, Massarelli E, Nieva J, Muzaffar J, Morris JC, Ryder M, Ho AL, Agulnik M, Wei L, Handley D, Moses C, Jacob R, Wright J, Streicher H, Carson W, Shah MH. Cabozantinib Plus Ipilimumab/Nivolumab in Patients With Previously Treated Advanced Differentiated Thyroid Cancer. J Clin Endocrinol Metab 2025; 110:830-837. [PMID: 39133806 PMCID: PMC11834700 DOI: 10.1210/clinem/dgae512] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 07/17/2024] [Accepted: 07/23/2024] [Indexed: 12/15/2024]
Abstract
BACKGROUND This investigator-initiated phase II trial aimed to evaluate the efficacy of cabozantinib in combination with nivolumab and ipilimumab (CaboNivoIpi) in previously treated patients with radioactive iodine-refractory differentiated thyroid cancer. METHODS Eligible patients with radioactive iodine-refractory differentiated thyroid cancer who progressed on 1 prior line of vascular endothelial growth factor receptor-targeted therapy received a 2-week run-in of cabozantinib monotherapy followed by CaboNivoIpi for 4 cycles (cycle length = 6 weeks), followed by cabozantinib plus nivolumab (cycle length = 4 weeks) until disease progression. The primary endpoint was objective response rate (ORR) within the first 6 months of treatment. A Simon optimal 2-stage design allowed for an interim analysis after accrual of 10 evaluable patients. At least 5 responses were needed to proceed to stage 2. RESULTS Among 11 patients enrolled, the median age was 69 years. Prior vascular endothelial growth factor receptor-targeted therapies included lenvatinib, pazopanib, and sorafenib plus everolimus. Median follow-up was 7.9 months. Among 10 evaluable patients, ORR within the first 6 months of treatment was 10% (1 partial response). Median progression-free survival was 9 months (95% CI, 3.0-not reached) and median overall survival was 19.2 months (95% CI, 4.6-not reached). Grade 3/4 treatment-related adverse events (AEs) were noted in 55% (6/11) and grade 5 AEs in 18% (2/11) of patients. The most common treatment-related AE was hypertension. The study did not reach its prespecified efficacy threshold. CONCLUSION CaboNivoIpi had low ORRs and a high rate of grade ≥3 treatment-related AEs. CLINICAL TRIAL REGISTRATION NCT03914300.
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Affiliation(s)
- Bhavana Konda
- Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Eric J Sherman
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Erminia Massarelli
- Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Jorge Nieva
- Department of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Jameel Muzaffar
- Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27710, USA
| | - John C Morris
- Departments of Endocrinology & Medical Oncology, Mayo Clinic Comprehensive Cancer Center, Rochester, MN 55905, USA
| | - Mabel Ryder
- Departments of Endocrinology & Medical Oncology, Mayo Clinic Comprehensive Cancer Center, Rochester, MN 55905, USA
| | - Alan L Ho
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Mark Agulnik
- Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
| | - Lai Wei
- Department of Biostatistics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Demond Handley
- Department of Biostatistics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Catherine Moses
- Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Rajani Jacob
- Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - John Wright
- Investigational Drug Branch, National Cancer Institute, Bethesda, MD 20892, USA
| | - Howard Streicher
- Investigational Drug Branch, National Cancer Institute, Bethesda, MD 20892, USA
| | - William Carson
- Division of Surgical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Manisha H Shah
- Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
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Nisar MF, Yan T, Cai Y, Wan C. Immuno-oncological Challenges and Chemoresistance in Veterinary Medicine: Probiotics as a New Strategic Tool. Probiotics Antimicrob Proteins 2025:10.1007/s12602-025-10468-8. [PMID: 39954194 DOI: 10.1007/s12602-025-10468-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/21/2025] [Indexed: 02/17/2025]
Abstract
Cancer has the highest death rates due to increased immuno-oncological (IO) challenges and chemoresistance caused by gut dysbiosis, whereas administration of probiotics may reverse these responses against anticancer therapies. Recently, immunotherapeutics have extensively been focused for significant advancements in pharmacological drug discovery and clinical outcomes. Mammals have intestinal epithelial cells, mucosal immune cells, and indigenous gut microbiota which may reshape immunotherapeutics efficacy. These include use of T-cell immune checkpoint inhibitors (ICPI), genetically engineered T-cells, tumor vaccines, monoclonal antibodies (mAbs), and anti-B- and T-cell antibodies. Immunotherapeutics for cancer treatment became popular in both veterinary and human health care systems due to their strong inhibitory actions against PD-1 and CTLA-4 to check tumorigenesis. IO issues in animals also need special attention, where caninized mAbs targeting CD-20 and CD-52 have been clinically used in treating canine B-cell and T-cell lymphomas, respectively. Probiotics appeared as strong immunotherapeutics that might be shaping the epigenetics of the organisms specifically in animal breeding practices for desired features, but limited literature regarding the immunomodulatory effects in humans and animals is available. In addition, considering the important role of probiotics in humans and veterinary medicine, a new perspective on the probiotic-mediated modulation of ncRNAs (miRNAs, lncRNAs, circRNAs) is also highlighted and would be a new therapeutic tool. This review provides insight into the cellular processes and pharmacological activities for treating veterinary infectious diseases and covers small drug molecules as ncRNA-modulators in veterinary medicine.
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Affiliation(s)
- Muhammad Farrukh Nisar
- Ministry of Education and Jiangxi Key Laboratory of Crop Physiology, Ecology and Genetic Breeding, Jiangxi Agricultural University, Nanchang, 330045, China
- Jiangxi Key Laboratory for Post-harvest Technology and Nondestructive Testing of Fruits & Vegetables, College of Agronomy, Jiangxi Agricultural University, Nanchang, 330045, China
- Department of Physiology and Biochemistry, Cholistan University of Veterinary and Animal Sciences (CUVAS), Bahawalpur, Pakistan
| | - Tingdong Yan
- School of Pharmacy, Nantong University, Nantong, 226001, China.
| | - Yi Cai
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Chunpeng Wan
- Jiangxi Key Laboratory for Post-harvest Technology and Nondestructive Testing of Fruits & Vegetables, College of Agronomy, Jiangxi Agricultural University, Nanchang, 330045, China.
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Zhao H, Huang S, Wu J, Lu Y, Zou Y, Zeng H, Li C, Wang J, Zhang X, Duan S, Liang W. Efficacy and safety of first-line PD-1/PD-L1 inhibitor in combination with CTLA-4 inhibitor in the treatment of patients with advanced non-small cell lung cancer: a systemic review and meta-analysis. Front Immunol 2025; 16:1515027. [PMID: 39981238 PMCID: PMC11839650 DOI: 10.3389/fimmu.2025.1515027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 01/20/2025] [Indexed: 02/22/2025] Open
Abstract
Introduction The combination of PD-1/PD-L1 inhibitor with CTLA-4 inhibitor for advanced non-small cell lung cancer(NSCLC) is presently a significant area of research, however its clinical application remains contentious. This meta-analysis aimed to assess the efficacy and safety of first-line PD-1/PD-L1 inhibitor in combination with CTLA-4 inhibitor (CP) in the treatment of patients with advanced NSCLC. Methods A systemic search was conducted in four databases (PubMed, Cochrane library, Embase, and Web of Science) from their establishment until January 17, 2024, for randomized controlled trials that investigated the use of the first-line PD-1/PD-L1 inhibitor plus CTLA-4 inhibitor in patients with advanced NSCLC. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were subjected to meta-analyses. Results Totally 7 eligible randomized controlled trials including 4682 people were included. Two comparative analyses were performed: CP versus chemotherapy, CP versus PD-1/PD-L1 inhibitor (P). Compared with the chemotherapy group, CP improved OS (HR: 0.84, 95% CI: 0.75-0.94, p<0.05) but not PFS (HR: 0.94, 95%CI: 0.73-1.20, p = 0.63) or ORR (OR: 1.16, 95% CI: 0.79-1.71, p = 0.45). In terms of toxicity, CP had slightly fewer any AEs compared to chemotherapy (RR: 0.94, 95% CI: 0.91-0.97; p<0.05). Compared to the P group, there was no significant difference in OS (MD: -0,25, 95% CI: -2.47-1.98, p = 0.83), PFS (MD: -0.91, 95% CI: -3.19-1.36, p = 0.43), and ORR (OR:1.05, 95% CI. 0.80-1.36, p = 0.73). Subgroup analysis revealed that CP provided superior OS compared with P in patients with PD-L1 expression < 1%. Conclusion CP was a feasible and safe first-line therapy for patients with advanced NSCLC. Specifically, CP may function as a therapeutic alternative for individuals with low or negative PD-L1 expression, resulting in enhanced long-term outcomes compared to chemotherapy or P. Further randomized controlled trials with prolonged follow-up periods are necessary to validate these results, particularly focusing on efficacy in patients with differing PD-L1 expression levels, to improve the stratified implementation of immunotherapy. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024621116, identifier CRD42024621116.
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Affiliation(s)
- Huimin Zhao
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Shanshan Huang
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Jianyu Wu
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Yanlan Lu
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Yue Zou
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Haijian Zeng
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Chunlan Li
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Jin Wang
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Xiaochen Zhang
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
- Medicine College, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Siliang Duan
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
- Medicine College, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Weiming Liang
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
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Zheng M, Qu J, Xiang D, Xing L. Organoids in lung cancer brain metastasis: Foundational research, clinical translation, and prospective outlooks. Biochim Biophys Acta Rev Cancer 2025; 1880:189235. [PMID: 39647672 DOI: 10.1016/j.bbcan.2024.189235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 12/01/2024] [Accepted: 12/01/2024] [Indexed: 12/10/2024]
Abstract
Brain metastasis stands as a leading contributor to mortality in lung cancer patients, yet the intricate mechanism underlying this phenomenon remains elusive. This underscores the need for robust preclinical models and effective treatment strategies. Emerging as viable in vitro models that closely replicate actual tumors, three-dimensional culture systems, particularly organoids derived from non-malignant cells or cancer organoids, have emerged as promising avenues. This review delves into the forefronts of fundamental research and clinical applications focused on lung cancer brain metastasis-derived organoids, highlighting current challenges and delineating prospects. These studies offer tremendous potential for clinical application despite being in nascent status.
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Affiliation(s)
- Mei Zheng
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Jialin Qu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China
| | - Dongxi Xiang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China; Department of Biliary-Pancreatic Surgery, the Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
| | - Ligang Xing
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China.
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Léna H, Greillier L, Cropet C, Bylicki O, Monnet I, Audigier-Valette C, Falchero L, Vergnenègre A, Demontrond P, Geier M, Guisier F, Hominal S, Locher C, Corre R, Chouaid C, Ricordel C. Nivolumab plus ipilimumab versus carboplatin-based doublet as first-line treatment for patients with advanced non-small-cell lung cancer aged ≥70 years or with an ECOG performance status of 2 (GFPC 08-2015 ENERGY): a randomised, open-label, phase 3 study. THE LANCET. RESPIRATORY MEDICINE 2025; 13:141-152. [PMID: 39486424 DOI: 10.1016/s2213-2600(24)00264-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 08/08/2024] [Accepted: 08/08/2024] [Indexed: 11/04/2024]
Abstract
BACKGROUND Combined treatment with anti-PD-1 and anti-CTLA-4 antibodies has shown superiority over chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC), but data for older patients (aged ≥70 years) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or those with an ECOG performance status of 2 are scarce. We aimed to test the superiority of the PD-1 antibody nivolumab and the CTLA-4 antibody ipilimumab over platinum-based doublet chemotherapy as first-line treatment in patients with NSCLC aged 70 years or older or with an ECOG performance status of 2. METHODS This open-label, multicentre, randomised, controlled, phase 3 trial was done at 30 hospitals and cancer centres in France. Eligible patients had stage IV histologically proven NSCLC, with no known oncogenic alterations, and were either aged 70 years or older with ECOG performance status of 0-2 or younger than 70 years with an ECOG performance status of 2. Patients were randomly assigned (1:1) centrally, using a computer-generated algorithm stratified by age (<70 vs ≥70 years), ECOG performance status (0-1 vs 2), and histology (squamous vs non-squamous) to receive nivolumab plus ipilimumab or platinum-based doublet chemotherapy (carboplatin [area under the curve ≤700 mg] plus pemetrexed [500 mg/m2 intravenous infusion every 3 weeks] or carboplatin [on day 1; area under the curve ≤700 mg] plus paclitaxel [90 mg/m2 as intravenous infusion on days 1, 5, and 15, every 4 weeks]). The primary endpoint was overall survival; secondary endpoints included progression-free survival and safety. All efficacy analyses were performed in the intention-to-treat population, which included all randomly assigned patients. Safety was analysed in the safety analysis set, which included all randomly assigned patients who received at least one dose of study treatment and who had at least one safety follow-up. The trial is registered with ClinicalTrials.gov, NCT03351361. FINDINGS The trial was stopped early for futility on the basis of a pre-planned interim analysis after 33% of the expected events had occurred. Between Feb 12, 2018, and Dec 15, 2020, 217 patients were randomly assigned, of whom 216 patients were included in the final analysis, with 109 patients in the nivolumab plus ipilimumab group and 107 in the chemotherapy group; median age was 74 years (IQR 70-78). Median overall survival was 14·7 months (95% CI 8·0-19·7) in the nivolumab plus ipilimumab group and 9·9 months (7·7-12·3) in chemotherapy group (hazard ratio [HR] 0·85 [95% CI 0·62-1·16]). Among patients aged 70 years or older with an ECOG performance status of 0-1 (median age 76 years [IQR 73-79]), median overall survival was longer in the nivolumab plus ipilimumab group than the chemotherapy group: 22·6 months (95% CI 18·1-36·0) versus 11·8 months (8·9-20·5; HR 0·64 [95% CI 0·46-0·96]). Among patients with an ECOG performance status of 2 (median age 69 years [IQR 63-75]), median overall survival was 2·9 months (95% CI 1·4-4·8) in the nivolumab plus ipilimumab group versus 6·1 months (3·5-10·4) in the chemotherapy group (HR 1·32 [95% CI 0·82-2·11]). No new safety signals were reported. The most frequent grade 3 or worse adverse events were neutropenia (28 [27%] of 103 patients) in the chemotherapy group and endocrine disorders (five [5%] of 105 patients), cardiac disorders (ten [10%] patients), and gastrointestinal disorders (11 [11%] patients) in the nivolumab plus ipilimumab group. INTERPRETATION The study showed no benefit of nivolumab plus ipilimumab combination in the overall study population. As a result of early stopping, the trial was underpowered for primary and secondary endpoints; however, the finding of better survival with nivolumab plus ipilimumab compared with platinum doublet in the subgroup of older patients with NSCLC with an ECOG performance status of 0-1 warrants further study. FUNDING Bristol-Myers Squibb.
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Affiliation(s)
- Hervé Léna
- Service de Pneumologie, Centre Hospitalier Universitaire de Rennes, Université Rennes 1, INSERM, UMR_S 1242, Centre Eugène Marquis, Rennes, France.
| | - Laurent Greillier
- Multidisciplinary Oncology and Therapeutic Innovations, Aix-Marseille University, APHM, INSERM, CNRS, CRCM, Hôpital Nord, Marseille, France
| | - Claire Cropet
- Unité de Biostatistique-Direction de la Recherche et de l'Innovation, Centre Léon Bérard, Lyon, France
| | | | - Isabelle Monnet
- Service de Pneumologie, Centre Hospitalier Intercommunal Créteil, Créteil, France
| | | | - Lionel Falchero
- Service de Pneumologie et Cancérologie Thoracique, Hôpitaux Nord-Ouest, Villefranche sur Saône, France
| | - Alain Vergnenègre
- Unité d'Oncologie Thoracique, Centre Hospitalier Universitaire Dupuytren, Limoges, France
| | | | - Margaux Geier
- Institut de Cancérologie et Imagerie, Hopital Cavale Blanche Centre Hospitalier Universitaire Brest, Brest, France
| | - Florian Guisier
- Service de Pneumologie, Centre Hospitalier Universitaire Rouen, Rouen, France
| | - Stéphane Hominal
- Service de Pneumologie, Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France
| | - Chrystèle Locher
- Service de Pneumologie, Grand Hôpital de l'Est Francilien (Meaux), Meaux, France
| | - Romain Corre
- Centre Hospitalier de Cornouaille, Service de Pneumologie, Quimper, France
| | - Christos Chouaid
- Service de Pneumologie, Centre Hospitalier Intercommunal Créteil, Créteil, France
| | - Charles Ricordel
- Service de Pneumologie, Centre Hospitalier Universitaire de Rennes, Université Rennes 1, INSERM, UMR_S 1242, Centre Eugène Marquis, Rennes, France
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Li H, Xu Y, Jiao X, Xu Q, Peng Z, Tang Y, Zhang J, Huang B, Shen Y, Chang B, Xia B, Duan W, Wang D, Zhu L, An R, Zhang G, Tang Y, Huang J, Qiu H, Wang L, Huang Y, Li G, Qian J, Sun L, Zheng H, Lou G, Zhang Y, Chen Y, Lu L, Cheng Y, Liu J, Zhao W, Ji J, He A, Wang K, Yu G, Zhu H, Ma C, Yuan J, Wang X, Zhang H, Ma X, Cai C, Yin K, Xie H, Wang Y, Wang S, Li L, Zhou H, Wang J, Zhu J, Ma D, Gao Q. IBI310 plus sintilimab vs. placebo plus sintilimab in recurrent/metastatic cervical cancer: A double-blind, randomized controlled trial. MED 2025:100573. [PMID: 39827881 DOI: 10.1016/j.medj.2024.100573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 11/27/2024] [Accepted: 12/20/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND It remains unclear whether adding CTLA-4 blockade to PD-1/PD-L1 blockade improves clinical outcomes in cervical cancer (CC). METHODS In this randomized, double-blind, placebo-controlled, phase 2 study (ClinicalTrials.gov: NCT04590599), patients with recurrent/metastatic CC (R/M CC) who experienced disease progression after or during platinum-based chemotherapy were enrolled from 37 centers across China and randomly assigned (1:1), stratified by PD-L1 expression and prior treatment lines, to receive either IBI310 plus sintilimab or placebo plus sintilimab intravenously every 3 weeks for 12 weeks, followed by sintilimab alone. The primary endpoint was the objective response rate (ORR). Pivotal secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. FINDINGS 205 patients were randomized to receive IBI310-sintilimab (n = 103) or placebo-sintilimab (n = 102). The ORR difference between the IBI310-sintilimab arm (32.3%, 95% confidence interval [CI]: 23.3%-42.5%) and the placebo-sintilimab arm (23.5%, 95% CI: 15.5%-33.1%) was not significant (p = 0.17). IBI310-sintilimab and placebo-sintilimab exhibited median PFS values of 3.6 (95% CI: 2.7-6.3) and 4.2 months (95% CI: 2.8-6.2), respectively (hazard ratio [HR] = 0.91, 95% CI: 0.65-1.27; p = 0.58). The median OSs were 13.9 months (95% CI: 11.5-25.6) in the IBI310-sintilimab arm and 17.2 months (95% CI: 13.7-25.9) in the placebo-sintilimab arm (HR = 1.12, 95% CI: 0.79-1.58; p = 0.54). Adding IBI310 to sintilimab increased the incidence of grade ≥3 treatment-related adverse events (55% versus 19%). CONCLUSIONS Compared to single-agent PD-1/PD-L1 blockade, dual blockade of CTLA-4 and PD-1/PD-L1 did not significantly improve clinical outcomes in R/M CC. FUNDING This work was funded by Innovent Biologics (Suzhou).
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Affiliation(s)
- Huayi Li
- National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Yu Xu
- National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Xiaofei Jiao
- National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Qin Xu
- Department of Gynecology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Jinan District, Fuzhou 350000, China
| | - Zikun Peng
- National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Ying Tang
- Gynecological Oncology Center, Chongqing University Cancer Hospital, Chongqing 400000, China
| | - Jieqing Zhang
- Department of Gynecologic Oncology, Guangxi Medical University Cancer Hospital, Nanning 530000, China
| | - Bowen Huang
- National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Yiyang Shen
- National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Baoping Chang
- Department of Medical Oncology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471000, China
| | - Bairong Xia
- Department of Gynecology and Oncology, Anhui Provincial Cancer Hospital, Hefei 230000, China
| | - Wei Duan
- Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100000, China
| | - Danbo Wang
- Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang 110000, China
| | - Lijing Zhu
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210000, China
| | - Ruifang An
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710000, China
| | - Guonan Zhang
- Department of Gynecologic Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu 610000, China
| | - Yaling Tang
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xiamen University, Xiamen 361000, China
| | - Jianli Huang
- Department of Oncology Radiotherapy, Zhangzhou Municipal Hospital of Fujian Province/Zhangzhou Affiliated Hospital of Fujian Medical Hospital, Zhangzhou 363000, China
| | - Hui Qiu
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430000, China
| | - Li Wang
- Department of Gynecological Oncology, Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital), Zhengzhou 450000, China
| | - Yi Huang
- Department of Gynecologic Oncology, Hubei Cancer Hospital, Wuhan 430000, China
| | - Guiling Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Jianhua Qian
- Department of Gynecology and Obstetrics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Li Sun
- Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518000, China
| | - Hong Zheng
- Department of Gynecology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital, Beijing 100000, China
| | - Ge Lou
- Department of Gynecologic Oncology, Harbin Medical University Cancer Hospital, Harbin 150000, China
| | - Youzhong Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250000, China
| | - Youguo Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou 215000, China
| | - Liqin Lu
- Department of Medical Oncology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310000, China
| | - Yan Cheng
- Department of Gynecological Radiation Oncology, Zhengzhou University First Affiliated Hospital, Zhengzhou 450000, China
| | - Jihong Liu
- Department of Gynecologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510000, China
| | - Weidong Zhao
- Department of Obstetrics and Gynecology, Anhui Provincial Hospital, Hefei 230000, China
| | - Jianghai Ji
- Department of Gynecology, Cangzhou People's Hospital, Cangzhou 061000, China
| | - Aiqin He
- Department of Gynecological Oncology, The Affiliated Tumor Hospital of Nantong University, Nantong Tumor Hospital, Nantong 226000, China
| | - Ke Wang
- Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300000, China
| | - Guohua Yu
- Department of Medical Oncology, Weifang People's Hospital, Weifang 261000, China
| | - Hong Zhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410000, China
| | - Cailing Ma
- Department of Gynecology, Xinjiang Medical University Affiliated First Hospital, Urumqi 830000, China
| | - Jianlin Yuan
- Department of Gynecology and Obstetrics, Cancer Hospital Affiliated to Xinjiang Medical University, Urumqi 830000, China
| | - Xia Wang
- Department of Oncology Radiotherapy, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China
| | - Hongfei Zhang
- National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Xinyan Ma
- National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Chujun Cai
- National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Kang Yin
- National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Han Xie
- National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Ya Wang
- National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Shuyan Wang
- Medical Science and Strategy Oncology, Innovent Biologics, Inc., Shanghai 200000, China
| | - Li Li
- Department of Biostatistics and Information, Innovent Biologics, Inc., Shanghai 200000, China
| | - Hui Zhou
- Medical Science and Strategy Oncology, Innovent Biologics, Inc., Shanghai 200000, China
| | - Jing Wang
- Department of Gynecologic Cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410000, China.
| | - Jianqing Zhu
- Department of Gynecological Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 310000, China.
| | - Ding Ma
- National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
| | - Qinglei Gao
- National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
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7
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Foffano L, Bertoli E, Bortolot M, Torresan S, De Carlo E, Stanzione B, Del Conte A, Puglisi F, Spina M, Bearz A. Immunotherapy in Oncogene-Addicted NSCLC: Evidence and Therapeutic Approaches. Int J Mol Sci 2025; 26:583. [PMID: 39859299 PMCID: PMC11765476 DOI: 10.3390/ijms26020583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/09/2025] [Accepted: 01/09/2025] [Indexed: 01/27/2025] Open
Abstract
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. The discovery of specific driver mutations has revolutionized the treatment landscape of oncogene-addicted NSCLC through targeted therapies, significantly improving patient outcomes. However, immune checkpoint inhibitors (ICIs) have demonstrated limited effectiveness in this context. Emerging evidence, though, reveals significant heterogeneity among different driver mutation subgroups, suggesting that certain patient subsets may benefit from ICIs, particularly when combined with other therapeutic modalities. In this review, we comprehensively examine the current evidence on the efficacy of immunotherapy in oncogene-addicted NSCLC. By analyzing recent clinical trials and preclinical studies, along with an overview of mechanisms that may reduce immunotherapy efficacy, we explored potential strategies to address these challenges, to provide insights that could optimize immunotherapy approaches and integrate them effectively into the treatment algorithm for oncogene-addicted NSCLC.
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Affiliation(s)
- Lorenzo Foffano
- Department of Medical Oncology, CRO di Aviano, National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (M.B.); (E.D.C.); (B.S.); (A.D.C.); (F.P.); (M.S.); (A.B.)
- Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Elisa Bertoli
- Department of Medical Oncology, CRO di Aviano, National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (M.B.); (E.D.C.); (B.S.); (A.D.C.); (F.P.); (M.S.); (A.B.)
| | - Martina Bortolot
- Department of Medical Oncology, CRO di Aviano, National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (M.B.); (E.D.C.); (B.S.); (A.D.C.); (F.P.); (M.S.); (A.B.)
- Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Sara Torresan
- Department of Medical Oncology, CRO di Aviano, National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (M.B.); (E.D.C.); (B.S.); (A.D.C.); (F.P.); (M.S.); (A.B.)
- Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Elisa De Carlo
- Department of Medical Oncology, CRO di Aviano, National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (M.B.); (E.D.C.); (B.S.); (A.D.C.); (F.P.); (M.S.); (A.B.)
| | - Brigida Stanzione
- Department of Medical Oncology, CRO di Aviano, National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (M.B.); (E.D.C.); (B.S.); (A.D.C.); (F.P.); (M.S.); (A.B.)
| | - Alessandro Del Conte
- Department of Medical Oncology, CRO di Aviano, National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (M.B.); (E.D.C.); (B.S.); (A.D.C.); (F.P.); (M.S.); (A.B.)
| | - Fabio Puglisi
- Department of Medical Oncology, CRO di Aviano, National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (M.B.); (E.D.C.); (B.S.); (A.D.C.); (F.P.); (M.S.); (A.B.)
- Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Michele Spina
- Department of Medical Oncology, CRO di Aviano, National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (M.B.); (E.D.C.); (B.S.); (A.D.C.); (F.P.); (M.S.); (A.B.)
| | - Alessandra Bearz
- Department of Medical Oncology, CRO di Aviano, National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (M.B.); (E.D.C.); (B.S.); (A.D.C.); (F.P.); (M.S.); (A.B.)
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8
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Inoue T, Narukawa M. Immune-related and Common Adverse Events With Programmed Cell Death 1/Programmed Cell Death Ligand 1 inhibitors combined with other Anticancer Therapy for Solid Tumors: A Systematic Review and Meta-analysis. Clin Oncol (R Coll Radiol) 2025; 37:103662. [PMID: 39536701 DOI: 10.1016/j.clon.2024.10.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 09/01/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024]
Abstract
AIMS The combination of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors and anticancer therapies has been in the spotlight in recent years. However, the risks associated with these combination therapies are not fully elucidated. The primary objective of this study was to evaluate the relative risk of organ-specific immune-related adverse events (irAEs) and common adverse events (AEs) in patients treated with PD-1/PD-L1 inhibitor-based combination therapies compared to those treated with PD-1/PD-L1 inhibitor monotherapy for solid tumors. MATERIALS AND METHODS An electronic database search was performed using ClinicalTrials.gov, Medline, and American Society of Clinical Oncology (ASCO)/European Society for Medical Oncology (ESMO) annual meeting libraries. We included randomized controlled trials designed to assess the safety of combination therapies using PD-1/PD-L1 inhibitors and other anticancer drugs. All the selected clinical studies included solid tumors and provided information on the incidence of nonserious and serious AEs. The quality of evidence was assessed using the Cochrane risk-of-bias tool. A meta-analysis was performed using random-effect models to pool the results. RESULTS The primary analysis included 16 relevant clinical studies comprising 4232 patients, of whom 2071 and 2161 patients received PD-1/PD-L1 inhibitor--based combination therapy and PD-1/PD-L1 inhibitor monotherapy, respectively. Serious organ-specific irAEs were infrequent, even when PD-1/PD-L1 inhibitors were combined with other anticancer drugs. The incidence of serious colitis was significantly higher in the combination therapy group than in the monotherapy group. Among the common AEs associated with PD-1/PD-L1 inhibitors, the incidence of serious pyrexia/fever, nonserious pyrexia/fever, fatigue, nausea, decreased appetite, vomiting, diarrhea, dyspnea, and rash significantly increased in the combination therapy group. In the subgroup analysis based on the modes of action of concomitant anticancer drugs, the combination of PD-1/PD-L1 inhibitors and DNA synthesis inhibitors significantly increased the risk of serious colitis compared to PD-1/PD-L1 inhibitor monotherapy. CONCLUSION Organ-specific irAEs occur infrequently when combinations of PD-1/PD-L1 inhibitors and other anticancer drugs are used. However, the risk of serious colitis and certain AEs is higher than that associated with PD-1/PD-L1 inhibitor monotherapy. Vigilant monitoring of AEs and implementation of appropriate clinical management strategies guided by the mode of action of the combination drugs are essential.
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Affiliation(s)
- T Inoue
- Department of Clinical Medicine (Pharmaceutical Medicine), Graduate School of Pharmaceutical Sciences, Kitasato University, Shirokane 5-9-1, Minato-ku, Tokyo 108-8641, Japan; Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
| | - M Narukawa
- Department of Clinical Medicine (Pharmaceutical Medicine), Graduate School of Pharmaceutical Sciences, Kitasato University, Shirokane 5-9-1, Minato-ku, Tokyo 108-8641, Japan.
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9
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Zeng W, Wang J, Chen Z, Yang J, Zhu A, Zheng Y, Chen X, Liu Y, Wu L, Xie Y, Ju S, Chen J, Ding C, Li C, Tong X, Liu M, Zhao J. Efficient Predictor for Immunotherapy Efficacy: Detecting Pan-Clones Effector Tumor Antigen-Specific T Cells in Blood by Nanoparticles Loading Whole Tumor Antigens. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2409913. [PMID: 39498880 PMCID: PMC11727128 DOI: 10.1002/advs.202409913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 10/09/2024] [Indexed: 11/07/2024]
Abstract
Cancer involves tumor cells and tumor-specific immunity. The ability to accurately quantify tumor-specific immunity is limited. Most immunotherapies function by activating new effector tumor antigen-specific T cells (ETASTs) or reactivating the pre-existing ETASTs repertoire. Therefore, the amount of ETASTs can be used to characterize immunotherapy efficacy. Tumor antigens are highly heterogeneous and detecting most ETASTs is challenging. Therefore, nanoparticles loading whole-cell tumor antigens are used to activate and detect pan-clones ETASTs in the blood. The differences between ETASTs and other T cells are transformed into activated and non-activated states. By measuring markers of the activated status and cytotoxic function of ETASTs, it can distinguish ETASTs from other T cells. ETASTs in patients with lung cancer are higher than those in healthy individuals and those with benign pulmonary nodules. Therapeutic efficacy positively correlated with the number of ETASTs in the blood. ETATS levels increase only in the blood of patients who respond to immunotherapy. Single-cell sequencing studies validated these findings. This study provides a highly accurate, specific, non-invasive, and efficient biomarker for predicting immunotherapy efficacy in lung and other cancers. This method can also be applied to evaluate the efficacy of other treatments, such as radiotherapy, oncolytic viruses, and nanomedicine-based therapies.
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Affiliation(s)
- Weibiao Zeng
- Institute of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Department of PharmaceuticsCollege of Pharmaceutical SciencesSoochow UniversitySuzhouJiangsu215123P. R. China
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Department of Thoracic SurgeryShanghai General HospitalShanghai Jiaotong University School of MedicineShanghai200080P. R. China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational ResearchSoochow UniversitySuzhouJiangsu215123P. R. China
| | - Jin Wang
- Department of PharmaceuticsCollege of Pharmaceutical SciencesSoochow UniversitySuzhouJiangsu215123P. R. China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational ResearchSoochow UniversitySuzhouJiangsu215123P. R. China
| | - Zhike Chen
- Institute of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational ResearchSoochow UniversitySuzhouJiangsu215123P. R. China
| | - Jian Yang
- Institute of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational ResearchSoochow UniversitySuzhouJiangsu215123P. R. China
| | - Ao Zhu
- Department of PharmaceuticsCollege of Pharmaceutical SciencesSoochow UniversitySuzhouJiangsu215123P. R. China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational ResearchSoochow UniversitySuzhouJiangsu215123P. R. China
| | - Yan Zheng
- Department of PharmaceuticsCollege of Pharmaceutical SciencesSoochow UniversitySuzhouJiangsu215123P. R. China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational ResearchSoochow UniversitySuzhouJiangsu215123P. R. China
| | - Xianlan Chen
- Department of PharmaceuticsCollege of Pharmaceutical SciencesSoochow UniversitySuzhouJiangsu215123P. R. China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational ResearchSoochow UniversitySuzhouJiangsu215123P. R. China
| | - Yuhan Liu
- Department of PharmaceuticsCollege of Pharmaceutical SciencesSoochow UniversitySuzhouJiangsu215123P. R. China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational ResearchSoochow UniversitySuzhouJiangsu215123P. R. China
| | - Leilei Wu
- Department of RadiotherapyShanghai Pulmonary Hospital of Tongji UniversityShanghai200000P. R. China
| | - Yufeng Xie
- Institute of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational ResearchSoochow UniversitySuzhouJiangsu215123P. R. China
| | - Sheng Ju
- Institute of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational ResearchSoochow UniversitySuzhouJiangsu215123P. R. China
| | - Jun Chen
- Institute of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational ResearchSoochow UniversitySuzhouJiangsu215123P. R. China
| | - Cheng Ding
- Institute of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational ResearchSoochow UniversitySuzhouJiangsu215123P. R. China
| | - Chang Li
- Institute of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational ResearchSoochow UniversitySuzhouJiangsu215123P. R. China
| | - Xin Tong
- Institute of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational ResearchSoochow UniversitySuzhouJiangsu215123P. R. China
| | - Mi Liu
- Department of PharmaceuticsCollege of Pharmaceutical SciencesSoochow UniversitySuzhouJiangsu215123P. R. China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational ResearchSoochow UniversitySuzhouJiangsu215123P. R. China
- Suzhou Ersheng Biopharmaceutical Co., LtdSuzhou215123P. R. China
- Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics DevelopmentSoochow UniversitySuzhou215123P. R. China
- Wuxi Boston Biopharmaceutical Co., LtdWuxi214125P. R. China
| | - Jun Zhao
- Institute of Thoracic SurgeryThe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123P. R. China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational ResearchSoochow UniversitySuzhouJiangsu215123P. R. China
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10
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Kesari S, Wojcinski A, Pabla S, Seager RJ, Gill JM, Carrillo JA, Wagle N, Park DJ, Nguyen M, Truong J, Takasumi Y, Chaiken L, Chang SC, Barkhoudarian G, Kelly DF, Juarez TM. Pre-radiation Nivolumab plus ipilimumab in patients with newly diagnosed high-grade gliomas. Oncoimmunology 2024; 13:2432728. [PMID: 39572979 PMCID: PMC11587836 DOI: 10.1080/2162402x.2024.2432728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 10/28/2024] [Accepted: 11/18/2024] [Indexed: 11/24/2024] Open
Abstract
The limited success of immune checkpoint inhibitors (ICIs) in the adjuvant setting for glioblastoma highlights the need to explore administering ICIs prior to immunosuppressive radiation. To address the feasibility and safety of this approach, we conducted a phase I study in patients with newly diagnosed Grade 3 and Grade 4 gliomas. Patients received nivolumab 300 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity. Fifteen patients were treated, with four patients on dexamethasone at treatment initiation and five tumors having MGMT promoter methylated. Treatment began a median of 38 days post-surgery. The most common treatment-related adverse events (AEs) were rash, pruritus, fatigue, nausea, and anorexia. Grade 3 AEs were lipase increased (n = 2), anorexia (n = 1), pruritus (n = 1), and rash (n = 3), and one Grade 4 cerebral edema occurred. Median progression-free survival (mPFS) was 1.3 months and median overall survival (mOS) was 19.3 months (95% CI, 12.9-NA). Three patients deferred conventional radiochemotherapy for over seven months while ten eventually received it. Progressing tumors tended to exhibit higher LAG-3 levels at baseline compared to shrinking tumors. Analysis of paired pre-treatment and post-progression tissue (n = 5) showed trends of up-regulated TGF-β, ERBB2, ERBB3, and ERBB4 signaling pathways, downregulated PPAR signaling, decreased B cell proportions, and increased monocytes proportions in tumors post-treatment. We show nivolumab plus ipilimumab can be safely administered prior to standard radiotherapy for newly diagnosed gliomas and is operationally feasible. Clinicaltrials.gov NCT03425292 registered February 7, 2018.
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Affiliation(s)
- Santosh Kesari
- Pacific Neuroscience Institute, Neuro-Oncology, Santa Monica, CA, USA
| | | | | | | | - Jaya M. Gill
- Pacific Neuroscience Institute, Neuro-Oncology, Santa Monica, CA, USA
| | - Jose A. Carrillo
- Pacific Neuroscience Institute, Neuro-Oncology, Santa Monica, CA, USA
| | - Naveed Wagle
- Pacific Neuroscience Institute, Neuro-Oncology, Santa Monica, CA, USA
| | - David J. Park
- Providence St. Jude Medical Center, Department of Hematology and Oncology, Fullerton, CA, USA
| | - Minhdan Nguyen
- Pacific Neuroscience Institute, Neuro-Oncology, Santa Monica, CA, USA
| | - Judy Truong
- Pacific Neuroscience Institute, Neuro-Oncology, Santa Monica, CA, USA
| | - Yuki Takasumi
- Pacific Neuroscience Institute, Neuro-Oncology, Santa Monica, CA, USA
- Providence Saint John’s Health Center, Department of Pathology, Santa Monica, CA, USA
| | - Lisa Chaiken
- Pacific Neuroscience Institute, Neuro-Oncology, Santa Monica, CA, USA
- Providence Saint John’s Health Center, Department of Radiology, Santa Monica, CA, USA
| | - Shu-Ching Chang
- Providence St. Vincent Medical Center, Clinical Research Program Services, Portland, OR, USA
| | | | - Daniel F. Kelly
- Pacific Neuroscience Institute, Neuro-Oncology, Santa Monica, CA, USA
| | - Tiffany M. Juarez
- Pacific Neuroscience Institute, Neuro-Oncology, Santa Monica, CA, USA
- Saint John’s Cancer Institute, Translational Neurosciences, Santa Monica, CA, USA
- CureScience Institute, San Diego, CA, USA
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11
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He X, Liu Y, Gao X, Tang F, Tian Y, Gong S, Shen J, Wang A, Sun L, Wei W, Weng L. N-terminal acetylation of transcription factor LIP induces immune therapy resistance via suppression of PD-L1 expression in non-small cell lung cancer. J Immunother Cancer 2024; 12:e009905. [PMID: 39615895 PMCID: PMC11624798 DOI: 10.1136/jitc-2024-009905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 11/05/2024] [Indexed: 12/09/2024] Open
Abstract
BACKGROUND Programmed death-1 (PD-1) checkpoint blockade has revolutionized cancer therapy, yet its clinical success is confined to a subset of patients, underscoring the urgent need to understand the molecular underpinnings of programmed cell death ligand 1 (PD-L1) expression to combat immunotherapy resistance. METHODS Employing CRISPR/Cas9 screening, we identified key regulators of PD-L1 in non-small cell lung cancer (NSCLC) cells, focusing on the transcription factor CEBPB and its isoform liver-enriched inhibitory protein (LIP). Through chromatin immunoprecipitation (ChIP) and luciferase reporter assays, we explored the interaction between LIP and basic-helix-loop-helix E22 (BHLHE22) in controlling PD-L1 transcription. We also used immunofluorescence and NBD-CI assays to examine how N-terminal acetylation affects LIP's subcellular localization. The impact of LIP on tumor growth was assessed via subcutaneous tumorigenicity assays, while immunohistochemistry and immunofluorescence were used to analyze LIP-induced alterations in the tumor immune microenvironment. RESULTS Our research indicates that CEBPB, particularly its LIP isoform, significantly suppresses PD-L1 expression in NSCLC cells. This suppression is contingent on LIP's N-terminal acetylation by the N-terminal acetyltransferase A complex, which facilitates LIP's nuclear entry and interaction with BHLHE22. This interaction leads to the formation of a co-repressor complex at the PD-L1 promoter, effectively reducing PD-L1 expression and enhancing the tumor immune response. CONCLUSIONS Identifying CEBPB, especially the LIP isoform, as a pivotal regulator of PD-L1 expression sheds light on the mechanisms behind PD-1 blockade resistance in NSCLC. Our findings suggest that modulating LIP's function or its molecular interactions might offer a novel approach to boosting the efficacy of immunotherapies.
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Affiliation(s)
- Xiang He
- Key Laboratory of Molecular Radiation Oncology Hunan Province, Xiangya Cancer Center, Xiangya Hospital Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, China
| | - Yongshuo Liu
- Department of Pathology and Lab Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Xing Gao
- Department of Stomatology, Xiangya Hospital Central South University, Changsha, Hunan, China
- Center of Oral and Maxillofacial Cancer (COMAC), Xiangya Hospital Central South University, Changsha, Hunan, China
| | - Feiyu Tang
- Center for Biotherapy, Sun Yat-Sen University, Guangzhou, China
| | - Yuxi Tian
- Department of Geriatric Respiratory and Critical Care Medicine, Xiangya Hospital Central South University, Changsha, Hunan, China
| | - Siyuan Gong
- Key Laboratory of Molecular Radiation Oncology Hunan Province, Xiangya Cancer Center, Xiangya Hospital Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, China
| | - Jia Shen
- Key Laboratory of Molecular Radiation Oncology Hunan Province, Xiangya Cancer Center, Xiangya Hospital Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, China
| | - Aimin Wang
- Department of Emergency, Xiangya Hospital Central South University, Changsha, China
| | - Lunquan Sun
- Key Laboratory of Molecular Radiation Oncology Hunan Province, Xiangya Cancer Center, Xiangya Hospital Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, China
| | - Wensheng Wei
- Biomedical Pioneering Innovation Center, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, Peking University School of Life Sciences, Beijing, China
- Changping Laboratory, Beijing, China
| | - Liang Weng
- Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing, China
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12
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Marchetti M, Ferrari J, Vezzaro T, Masatti L, Tasca G, Maggino T, Tozzi R, Saccardi C, Noventa M, Spagnol G. The Role of Immunotherapy in MMR-Deficient Endometrial Carcinoma: State of the Art and Future Perspectives. J Clin Med 2024; 13:7041. [PMID: 39685500 DOI: 10.3390/jcm13237041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/12/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024] Open
Abstract
This study provides a comprehensive overview of the role of immunotherapy in the treatment of mismatch repair-deficient (MMRd) endometrial carcinomas. Immunotherapy has emerged as a transformative approach in the treatment of MMRd due to the high mutation rate and subsequent PD-1/PD-L1 overexpression seen in these tumors. This review analyzes the current landscape of existing randomized clinical trials, highlighting the efficacy of immune checkpoint inhibitors (ICIs) like pembrolizumab, avelumab, and dostarlimab. Additionally, the focus extends to the potential of combined therapeutic strategies, such as the integration of ICIs with targeted agents, while also exploring the application of immunotherapy in non-traditional settings beyond advanced or recurrent disease. This includes emerging roles in the adjuvant and neoadjuvant contexts to prevent recurrence and target early-stage disease. These findings underscore the importance of tailoring treatments based on the molecular characteristics of each tumor and paving the way for future advancements in the field of gynecologic oncology. Despite promising results, this article acknowledges the necessity of further research to refine patient selection criteria and explore combination strategies that can overcome resistance mechanisms.
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Affiliation(s)
- Matteo Marchetti
- Unit of Gynecology and Obstetrics, Department of Women and Children's Health, University of Padua, 35100 Padua, Italy
| | - Jacopo Ferrari
- Unit of Gynecology and Obstetrics, Department of Women and Children's Health, University of Padua, 35100 Padua, Italy
| | - Tommaso Vezzaro
- Unit of Gynecology and Obstetrics, Department of Women and Children's Health, University of Padua, 35100 Padua, Italy
| | - Laura Masatti
- Department of Biology, University of Padua, 35100 Padua, Italy
| | - Giulia Tasca
- Medical Oncology 2 Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Tiziano Maggino
- Unit of Gynecology and Obstetrics, Department of Women and Children's Health, University of Padua, 35100 Padua, Italy
| | - Roberto Tozzi
- Unit of Gynecology and Obstetrics, Department of Women and Children's Health, University of Padua, 35100 Padua, Italy
| | - Carlo Saccardi
- Unit of Gynecology and Obstetrics, Department of Women and Children's Health, University of Padua, 35100 Padua, Italy
| | - Marco Noventa
- Unit of Gynecology and Obstetrics, Department of Women and Children's Health, University of Padua, 35100 Padua, Italy
| | - Giulia Spagnol
- Unit of Gynecology and Obstetrics, Department of Women and Children's Health, University of Padua, 35100 Padua, Italy
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13
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Wang J, Zeng W, Xue J, Zhu A, Chen X, Zheng Y, Liu Y, Qin S, Zhao J, Liu M. Efficient Biomarker for Immunotherapy: Measuring Broad Clones Effector Tumor Antigen-Specific T Cells in the Blood of Esophageal Cancer Patients. Anal Chem 2024. [PMID: 39561375 DOI: 10.1021/acs.analchem.4c04049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2024]
Abstract
Cancer is the result of the interactions between tumor cells and tumor-specific immune responses. The current biomarkers detect tumor cells' properties, but accurate measurement of tumor-specific immunity is lacking. Most immunotherapies work by activating new effector tumor antigen-specific T cells (ETASTs) or reactivating pre-existing ETASTs' repertoire. The responses to immunotherapy depend on the increase of ETASTs. The amount of ETASTs, especially in blood, is critical for therapeutic efficacy. Distinguishing ETASTs from other T cells by their structural characteristics is difficult. Therefore, nanoparticles loading whole tumor antigens are utilized to activate broad clones ETASTs pre-existing in peripheral blood, followed by detecting them. Thus, the differences between ETASTs and other T cells are transformed to the differences between activated states and unactivated states. By measuring the markers of activated states and cytotoxic functions, we can distinguish ETASTs from other T cells. Nanoparticles loading mixed multiple allogeneic tumor tissue lysates or mixed multiple tumor cell lines can be utilized as universal nanoparticles to replace nanoparticles loading personalized tumor tissue. ETASTs (TATAN-activated CD8+IFN-γ+) in esophageal cancer patients are more than those in healthy people. Measurement of the ETASTs in the blood of esophageal cancer patients before and after ongoing therapy showed that ETATSs increased in the blood of patients who were responsive to immunotherapy but did not increase in the blood of nonresponders. These illustrated that therapeutic efficacy was positively correlated with the level of ETASTs in PBMC. Altogether, this study provides us a highly accurate and specific biomarker for predicting the therapeutic efficacy of cancer immunotherapy and potentially other therapies, such as radiotherapy.
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Affiliation(s)
- Jin Wang
- Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational Research, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
| | - Weibiao Zeng
- Institute of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
| | - Jiao Xue
- Department of Radiotherapy, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
| | - Ao Zhu
- Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational Research, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
| | - Xianlan Chen
- Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational Research, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
| | - Yan Zheng
- Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational Research, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
| | - Yuhan Liu
- Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational Research, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
| | - Songbing Qin
- Department of Radiotherapy, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
| | - Jun Zhao
- Institute of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational Research, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
| | - Mi Liu
- Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
- Institute of Minimally Invasive Thoracic Cancer Therapy and Translational Research, Soochow University, Suzhou, Jiangsu 215123, People's Republic of China
- Suzhou Ersheng Biopharmaceutical Co., Ltd., Suzhou 215123, People's Republic of China
- Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou 215123, China
- Wuxi Boston Biopharmaceutical Co., Ltd., Wuxi 214125, People's Republic of China
- Kunshan Hospital of Traditional Chinese Medicine, Kunshan 215300, People's Republic of China
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14
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Long B, Zhou H, Yu Z, Zhu J, Yang H, Huang Z, Wei D, Chen S, Yang X, Zhao X, Zhang W, Yan H, Guan X, Li L, Zhang G, Yu H, Che S, Gao Z, Jiang X, Luo C, Mao J, Zhao D, Li Y, Jiang Z, Jiao Z. Neoadjuvant cadonilimab plus FLOT chemotherapy in locally advanced gastric/gastroesophageal junction adenocarcinoma: A multicenter, phase 2 study. MED 2024:100531. [PMID: 39536755 DOI: 10.1016/j.medj.2024.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 08/06/2024] [Accepted: 10/10/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Treatment with cadonilimab and chemotherapy has shown promise as a first-line treatment for gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. However, its application in neoadjuvant settings has not yet been documented. METHODS This multicenter, phase 2 trial (ChiCTR2200066893) was conducted at four hospitals across China. Treatment-naive patients with locally advanced G/GEJ adenocarcinoma (cT3/4, N+, M0) and who were human epidermal growth factor receptor 2 negative received 3-cycle or 4-cycle neoadjuvant treatment of cadonilimab plus FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) chemotherapy, followed by gastrectomy and 4-cycle adjuvant FLOT chemotherapy. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included major pathological response (MPR), overall response rate (ORR), disease control rate (DCR), R0 resection rate, downstaging rate, and safety. FINDINGS Between December 23, 2022, and December 15, 2023, 32 of 38 patients completed the scheduled treatment, achieving an R0 resection rate of 100% (32/32). The pCR rate was 21.1% (8/38, 90% confidence interval [CI]: 9.7-32.4), and the MPR rate was 44.7% (17/38, 90% CI: 30.9-58.5). Radiological evaluations were available for 28 of 38 patients by blinded independent central review. The ORR was 60.7% (17/28, 90% CI: 44.7-76.7), and the DCR was 100.0% (28/28, 90% CI: 100.0-100.0). Tumor downstaging occurred in 71.9% of patients (23/32), with consistent efficacy across all populations observed in the subgroup analysis. Grade 3 adverse events occurred in 31.6% of patients without severe safety issues. CONCLUSIONS Neoadjuvant cadonilimab plus FLOT chemotherapy treatment exhibits promising efficacy with manageable toxicities in locally advanced G/GEJ adenocarcinoma, providing preliminary evidence for further investigation. FUNDING This study was funded by Akeso Biopharma.
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Affiliation(s)
- Bo Long
- Lanzhou University Second Hospital, The General Surgery Department, Lanzhou, China
| | - Huinian Zhou
- Lanzhou University Second Hospital, The General Surgery Department, Lanzhou, China
| | - Zeyuan Yu
- Lanzhou University Second Hospital, The General Surgery Department, Lanzhou, China
| | - Junmin Zhu
- Lanzhou University Second Hospital, The General Surgery Department, Lanzhou, China
| | - Hanteng Yang
- Lanzhou University Second Hospital, The General Surgery Department, Lanzhou, China
| | - Zeping Huang
- Lanzhou University Second Hospital, The Oncological Surgery Department, Lanzhou, China
| | - Dengwen Wei
- Sun Yat-sen University Cancer Center Gansu Provincial Cancer Hospital, The Gastrointestinal Surgery Department, Lanzhou, China
| | - Shigong Chen
- Lanzhou University Second Hospital, The General Surgery Department, Lanzhou, China
| | - Xiaojun Yang
- Gansu Provincial Hospital, The General Surgery Department, Lanzhou, China
| | - Xiaoning Zhao
- Sun Yat-sen University Cancer Center Gansu Provincial Cancer Hospital, The Gastrointestinal Surgery Department, Lanzhou, China
| | - Wenjuan Zhang
- Lanzhou University Second Hospital, The Radiology Department, Lanzhou, China
| | - Hong Yan
- Lanzhou University Second Hospital, The Pathology Department, Lanzhou, China
| | - Xiaoying Guan
- Lanzhou University Second Hospital, The Pathology Department, Lanzhou, China
| | - Long Li
- Lanzhou University Second Hospital, The General Surgery Department, Lanzhou, China
| | - Gengyuan Zhang
- Lanzhou University Second Hospital, The General Surgery Department, Lanzhou, China
| | - Hongwei Yu
- Lanzhou University Second Hospital, The General Surgery Department, Lanzhou, China
| | - Shengfu Che
- Lanzhou University Second Hospital, The General Surgery Department, Lanzhou, China
| | - Zhongti Gao
- Lanzhou University Second Hospital, The General Surgery Department, Lanzhou, China
| | - Xiangyan Jiang
- Lanzhou University Second Hospital, The General Surgery Department, Lanzhou, China
| | - Changjiang Luo
- Lanzhou University Second Hospital, The General Surgery Department, Lanzhou, China
| | - Jie Mao
- Lanzhou University Second Hospital, The General Surgery Department, Lanzhou, China
| | - Da Zhao
- The First Hospital of Lanzhou University, The Oncology Department, Lanzhou, China
| | - Yumin Li
- Lanzhou University Second Hospital, The Oncological Surgery Department, Lanzhou, China
| | - Zebin Jiang
- Gansu Provincial Hospital, The General Surgery Department, Lanzhou, China
| | - Zuoyi Jiao
- Lanzhou University Second Hospital, The General Surgery Department, Lanzhou, China; Biobank of Tumors from Plateau of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China.
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15
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Weller M, Remon J, Rieken S, Vollmuth P, Ahn MJ, Minniti G, Le Rhun E, Westphal M, Brastianos PK, Soo RA, Kirkpatrick JP, Goldberg SB, Öhrling K, Hegi-Johnson F, Hendriks LEL. Central nervous system metastases in advanced non-small cell lung cancer: A review of the therapeutic landscape. Cancer Treat Rev 2024; 130:102807. [PMID: 39151281 DOI: 10.1016/j.ctrv.2024.102807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 07/19/2024] [Accepted: 07/29/2024] [Indexed: 08/19/2024]
Abstract
Up to 40% of patients with non-small cell lung cancer (NSCLC) develop central nervous system (CNS) metastases. Current treatments for this subgroup of patients with advanced NSCLC include local therapies (surgery, stereotactic radiosurgery, and, less frequently, whole-brain radiotherapy), targeted therapies for oncogene-addicted NSCLC (small molecules, such as tyrosine kinase inhibitors, and antibody-drug conjugates), and immune checkpoint inhibitors (as monotherapy or combination therapy), with multiple new drugs in development. However, confirming the intracranial activity of these treatments has proven to be challenging, given that most lung cancer clinical trials exclude patients with untreated and/or progressing CNS metastases, or do not include prespecified CNS-related endpoints. Here we review progress in the treatment of patients with CNS metastases originating from NSCLC, examining local treatment options, systemic therapies, and multimodal therapeutic strategies. We also consider challenges regarding assessment of treatment response and provide thoughts around future directions for managing CNS disease in patients with advanced NSCLC.
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Affiliation(s)
- Michael Weller
- Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
| | - Jordi Remon
- Paris-Saclay University, Department of Cancer Medicine, Gustave Roussy, Villejuif, France.
| | - Stefan Rieken
- Department of Radiation Oncology, University Hospital Göttingen (UMG), Göttingen, Germany; Comprehensive Cancer Center Lower Saxony (CCC-N), University Hospital Göttingen (UMG), Göttingen, Germany.
| | - Philipp Vollmuth
- Division for Computational Radiology & Clinical AI, Clinic for Neuroradiology, University Hospital Bonn, Bonn, Germany; Division for Medical Image Computing, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Myung-Ju Ahn
- Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
| | - Giuseppe Minniti
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza University of Rome, Rome, Italy; IRCCS Neuromed, Pozzilli, Italy.
| | - Emilie Le Rhun
- Departments of Neurosurgery and Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
| | - Manfred Westphal
- Department of Neurosurgery and Institute for Tumor Biology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
| | | | - Ross A Soo
- Department of Hematology-Oncology, National University Hospital, Singapore, Singapore.
| | - John P Kirkpatrick
- Departments of Radiation Oncology and Neurosurgery, Duke University, Durham, NC, USA.
| | - Sarah B Goldberg
- Department of Medicine (Medical Oncology), Yale School of Medicine, Yale Cancer Center, New Haven, CT, USA.
| | | | - Fiona Hegi-Johnson
- Department of Radiation Oncology, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Australia; Sir Peter MacCallum Department of Clinical Oncology, University of Melbourne, Melbourne, Australia.
| | - Lizza E L Hendriks
- Department of Respiratory Medicine, Maastricht University Medical Centre, GROW School for Oncology and Reproduction, Maastricht, Netherlands.
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16
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Li H, Zhao W, Li C, Shen H, Li M, Wang C, Han C, Yi C, Wang J, Meng X, Liu L, Yu S, Li J. The efficacy and safety of a novel PD-1/CTLA-4 bispecific antibody cadonilimab (AK104) in advanced non-small cell lung cancer: A multicenter retrospective observational study. Thorac Cancer 2024; 15:2327-2338. [PMID: 39390972 PMCID: PMC11554550 DOI: 10.1111/1759-7714.15455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/10/2024] [Accepted: 09/05/2024] [Indexed: 10/12/2024] Open
Abstract
BACKGROUND For patients with advanced non-small cell lung cancer (NSCLC) who have received frontline immunochemotherapy, subsequent treatment options are limited. As the first dual programmed cell death-1 (PD-1)/cytotoxic T lymphocyte-associated antigen-4 bispecific antibody approved globally, cadonilimab demonstrated potential antitumor activity in advanced NSCLC patients resistant to anti-PD-1/PD-L1 antibodies. METHODS We retrospectively collected efficacy and safety data from advanced NSCLC patients treated with cadonilimab-based regimens in later therapy lines. RESULTS A total of 41 advanced NSCLC patients refractory to anti-PD-1/PD-L1 therapy were enrolled. More than half of the patients received cadonilimab-based regimen as a fourth or later line of treatment. At the data cutoff date, treatment efficacy could be evaluated in 23 patients. One patient (4.3%) achieved partial response, eight patients (34.8%) experienced stable disease, and 14 patients (60.9%) progressed. The objective response rate and disease control rate were 4.3% and 39.1%, respectively. The median progression-free survival for all evaluated patients was 108.0 days. Due to the short follow-up period, the median overall survival has not yet been reached. Treatment-related adverse events (TRAEs) and immune-related AEs occurred in 63.4% and 22% patients, respectively. The most common TRAEs included gamma-glutamyl transferase elevation (17.1%), coughing (14.6%), and fatigue (12.2%). Five patients (12.2%) experienced grade ≥3 TRAEs. CONCLUSIONS In this heavily pretreated cohort of advanced NSCLC patients, cadonilimab-based regimens showed moderate antitumor efficacy with a generally tolerable and manageable safety profile. However, more evidence is needed to support the administration of cadonilimab in NSCLC patients refractory to previous anti-PD-1/PD-L1 therapy.
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Affiliation(s)
- Hongxin Li
- School of Pharmaceutical Sciences, Cheeloo College of MedicineShandong UniversityJinanChina
| | - Wen Zhao
- Department of Medical OncologyQilu Hospital, Cheeloo College of Medicine, Shandong UniversityJinanChina
| | - Chengming Li
- Department of Radiation OncologyShandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical SciencesJinanChina
| | - Hongchang Shen
- Department of OncologyShandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanChina
| | - Meiying Li
- Clinical Trial CenterShandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanChina
| | - Chengjun Wang
- Department of Medical OncologyQilu Hospital, Cheeloo College of Medicine, Shandong UniversityJinanChina
| | - Chunyan Han
- Department of OncologyShandong Provincial Third Hospital, Shandong UniversityJinanChina
- Department of RadiotherapyThe Third Affiliated Hospital of Shandong First Medical University (Affiliated Hospital of Shandong Academy of Medical Sciences)JinanChina
| | - Cuihua Yi
- Department of Medical OncologyQilu Hospital, Cheeloo College of Medicine, Shandong UniversityJinanChina
| | - Jun Wang
- Department of OncologyThe First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan HospitalJinanChina
- Shandong Lung Cancer InstituteJinanChina
| | - Xue Meng
- Department of Radiation OncologyShandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical SciencesJinanChina
| | - Lian Liu
- Department of Medical OncologyQilu Hospital, Cheeloo College of Medicine, Shandong UniversityJinanChina
| | - Shuwen Yu
- Department of PharmacyQilu Hospital, Cheeloo College of Medicine, Shandong UniversityJinanChina
- Clinical Trial CenterNMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, Shandong UniversityJinanChina
| | - Jisheng Li
- Department of Medical OncologyQilu Hospital, Cheeloo College of Medicine, Shandong UniversityJinanChina
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17
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Wu B, Zhang B, Li B, Wu H, Jiang M. Cold and hot tumors: from molecular mechanisms to targeted therapy. Signal Transduct Target Ther 2024; 9:274. [PMID: 39420203 PMCID: PMC11491057 DOI: 10.1038/s41392-024-01979-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 08/20/2024] [Accepted: 09/12/2024] [Indexed: 10/19/2024] Open
Abstract
Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which has shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment in cancer therapy, only a minority of patients exhibit a positive response to it. In patients with solid tumors, those who respond well to ICB treatment typically demonstrate an active immune profile referred to as the "hot" (immune-inflamed) phenotype. On the other hand, non-responsive patients may exhibit a distinct "cold" (immune-desert) phenotype, differing from the features of "hot" tumors. Additionally, there is a more nuanced "excluded" immune phenotype, positioned between the "cold" and "hot" categories, known as the immune "excluded" type. Effective differentiation between "cold" and "hot" tumors, and understanding tumor intrinsic factors, immune characteristics, TME, and external factors are critical for predicting tumor response and treatment results. It is widely accepted that ICB therapy exerts a more profound effect on "hot" tumors, with limited efficacy against "cold" or "altered" tumors, necessitating combinations with other therapeutic modalities to enhance immune cell infiltration into tumor tissue and convert "cold" or "altered" tumors into "hot" ones. Therefore, aligning with the traits of "cold" and "hot" tumors, this review systematically delineates the respective immune characteristics, influencing factors, and extensively discusses varied treatment approaches and drug targets based on "cold" and "hot" tumors to assess clinical efficacy.
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Affiliation(s)
- Bo Wu
- Department of Neurology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Bo Zhang
- Department of Youth League Committee, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Bowen Li
- Department of Pancreatic and Gastrointestinal Surgery, Ningbo No. 2 Hospital, Ningbo, China
| | - Haoqi Wu
- Department of Gynaecology and Obstetrics, The Second Hospital of Dalian Medical University, Dalian, China
| | - Meixi Jiang
- Department of Neurology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China.
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18
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Chen J, Liu S, Ruan Z, Wang K, Xi X, Mao J. Thrombotic events associated with immune checkpoint inhibitors and novel antithrombotic strategies to mitigate bleeding risk. Blood Rev 2024; 67:101220. [PMID: 38876840 DOI: 10.1016/j.blre.2024.101220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/23/2024] [Accepted: 06/05/2024] [Indexed: 06/16/2024]
Abstract
Although immunotherapy is expanding treatment options for cancer patients, the prognosis of advanced cancer remains poor, and these patients must contend with both cancers and cancer-related thrombotic events. In particular, immune checkpoint inhibitors are associated with an increased risk of atherosclerotic thrombotic events. Given the fundamental role of platelets in atherothrombosis, co-administration of antiplatelet agents is always indicated. Platelets are also involved in all steps of cancer progression. Classical antithrombotic drugs can cause inevitable hemorrhagic side effects due to blocking integrin β3 bidirectional signaling, which regulates simultaneously thrombosis and hemostasis. Meanwhile, many promising new targets are emerging with minimal bleeding risk and desirable anti-tumor effects. This review will focus on the issue of thrombosis during immune checkpoint inhibitor treatment and the role of platelet activation in cancer progression as well as explore the mechanisms by which novel antiplatelet therapies may exert both antithrombotic and antitumor effects without excessive bleeding risk.
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Affiliation(s)
- Jiayi Chen
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Shuang Liu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zheng Ruan
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Kankan Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Xiaodong Xi
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Jianhua Mao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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19
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Algazi A, Papadopoulos KP, Tsai F, Hansen AR, Angra N, Das M, Sheth S, Siu LL. Safety and clinical activity of durvalumab combined with tremelimumab in recurrent/metastatic head and neck squamous cell carcinoma: a multicenter phase I study. ESMO Open 2024; 9:103646. [PMID: 39043009 PMCID: PMC11325272 DOI: 10.1016/j.esmoop.2024.103646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 06/14/2024] [Accepted: 06/17/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND Programmed cell death protein 1 (PD-1) inhibitors prolong survival versus chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), which often expresses cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-ligand 1 (PD-L1), providing a rationale for combined PD-(L)1 and CTLA-4 blockade. We report a phase I, open-label study of the PD-L1 inhibitor durvalumab plus the CTLA-4 inhibitor tremelimumab (NCT02262741). METHODS In dose exploration, two cohorts of previously treated patients received durvalumab 10 mg/kg plus tremelimumab 3 mg/kg, or durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, for up to 12 months. Dose expansion comprised two cohorts of previously untreated patients with R/M HNSCC having baseline PD-L1 tumor cell (TC) expression ≥25% and <25% and one cohort of immunotherapy-pretreated patients with any PD-L1 level. All received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, then durvalumab 10 mg/kg, for up to 12 months. The primary endpoint was safety. The secondary endpoints were objective response rate (ORR) by RECIST version 1.1, pharmacokinetics, pharmacodynamics, and immunogenicity. RESULTS A total of 71 patients were treated. The median duration of exposure was 13.6 weeks for durvalumab and 13.1 weeks for tremelimumab. In dose exploration, no dose-limiting toxicities occurred. No maximum tolerated dose was identified. Treatment-related adverse events (TRAEs) occurred in 69.0% of patients; grade 3/4 and serious TRAEs occurred in 31.0% and 18.3%, respectively. TRAEs led to discontinuation in 9.9%. There were no treatment-related deaths. The ORR was 5.6% (95% confidence interval 1.6-13.8), including one complete response and three partial responses, all patients were in dose expansion with PD-L1 TC ≥25% and no prior immunotherapy exposure; three had ongoing responses ≥12 months. The median overall survival in the total population was 8.6 months. Soluble PD-L1 suppression was almost complete in all cohorts, suggesting target engagement. CD4+Ki67+ T cells were significantly elevated in all dose-expansion cohorts. CONCLUSIONS Treatment was well tolerated. However, response rates were low despite target engagement, no drug-drug interactions, and no drug-neutralizing antibodies to durvalumab.
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Affiliation(s)
- A Algazi
- Head and Neck Medical Oncology Program, University of California, San Francisco.
| | - K P Papadopoulos
- Clinical Research, South Texas Accelerated Research Therapeutics (START), San Antonio
| | - F Tsai
- Medical Oncology, HonorHealth Research and Innovation Institute, Scottsdale, USA
| | - A R Hansen
- Medical Oncology, Princess Margaret Cancer Centre, Toronto, Canada
| | - N Angra
- Oncology R&D, AstraZeneca, Gaithersburg
| | - M Das
- Oncology R&D, AstraZeneca, Gaithersburg
| | - S Sheth
- Division of Oncology, University of North Carolina Lineberger Cancer Center, Chapel Hill, USA
| | - L L Siu
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, Toronto, Canada
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20
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Cheng W, Kang K, Zhao A, Wu Y. Dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in lung cancer. J Hematol Oncol 2024; 17:54. [PMID: 39068460 PMCID: PMC11283714 DOI: 10.1186/s13045-024-01581-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 07/22/2024] [Indexed: 07/30/2024] Open
Abstract
Cancer immunotherapies, represented by immune checkpoint inhibitors (ICIs), have reshaped the treatment paradigm for both advanced non-small cell lung cancer and small cell lung cancer. Programmed death receptor-1/programmed death receptor ligand-1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are some of the most common and promising targets in ICIs. Compared to ICI monotherapy, which occasionally demonstrates treatment resistance and limited efficacy, the dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 operates at different stages of T cell activation with synergistically enhancing immune responses against cancer cells. This emerging dual therapy heralds a new direction for cancer immunotherapy, which, however, may increase the risk of drug-related adverse reactions while improving efficacy. Previous clinical trials have explored combination therapy strategy of anti-PD-1/PD-L1 and anti-CTLA-4 agents in lung cancer, yet its efficacy remains to be unclear with the inevitable incidence of immune-related adverse events. The recent advent of bispecific antibodies has made this sort of dual targeting more feasible, aiming to alleviate toxicity without compromising efficacy. Thus, this review highlights the role of dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in treating lung cancer, and further elucidates its pre-clinical mechanisms and current advancements in clinical trials. Besides, we also provide novel insights into the potential combinations of dual blockade therapies with other strategies to optimize the future treatment mode for lung cancer.
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Affiliation(s)
- Weishi Cheng
- Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Kai Kang
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ailin Zhao
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Yijun Wu
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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21
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Liu HM, Yu ZL, Xia HF, Zhang LZ, Fu QY, Wang Y, Gong HY, Chen G. EGFR Mutation and TKI Treatment Promote Secretion of Small Extracellular Vesicle PD-L1 and Contribute to Immunosuppression in NSCLC. Biomolecules 2024; 14:820. [PMID: 39062533 PMCID: PMC11274907 DOI: 10.3390/biom14070820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/21/2024] [Accepted: 06/29/2024] [Indexed: 07/28/2024] Open
Abstract
In Asian populations with non-small-cell lung cancer (NSCLC), EGFR mutations are highly prevalent, occurring in roughly half of these patients. Studies have revealed that individuals with EGFR mutation typically fare worse with immunotherapy. In patients who received EGFR tyrosine kinase inhibitor (TKI) treatment followed by anti-PD-1 therapy, poor results were observed. The underlying mechanism remains unclear. We used high-resolution flow cytometry and ELISA to detect the circulating level of small extracellular vesicle (sEV) PD-L1 in NSCLC individuals with EGFR mutations before and after receiving TKIs. The secretion amount of sEV PD-L1 of lung cancer cell lines with EGFR mutations under TKI treatment or not were detected using high-resolution flow cytometry and Western blotting. The results revealed that patients harboring EGFR mutations exhibit increased levels of sEV PD-L1 in circulation, which inversely correlated with the presence of CD8+ T cells in tumor tissues. Furthermore, tumor cells carrying EGFR mutations secrete a higher quantity of PD-L1-positive sEVs. TKI treatment appeared to amplify the levels of PD-L1-positive sEVs in the bloodstream. Mutation-induced and TKI-induced sEVs substantially impaired the functionality of CD8+ T cells. Importantly, our findings indicated that EGFR mutations and TKI therapies promote secretion of PD-L1-positive sEVs via distinct molecular mechanisms, namely the HRS and ALIX pathways, respectively. In conclusion, the increased secretion of PD-L1-positive sEVs, prompted by genetic alterations and TKI administration, may contribute to the limited efficacy of immunotherapy observed in EGFR-mutant patients and patients who have received TKI treatment.
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Affiliation(s)
- Hai-Ming Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Zi-Li Yu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Hou-Fu Xia
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Lin-Zhou Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Qiu-Yun Fu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
| | - Yi Wang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Hong-Yun Gong
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Gang Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
- TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China
- Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, China
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22
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Wang C, Fu H, Wang F. Durvalumab supplementation for non-small-cell lung cancer: a meta-analysis study. J Cardiothorac Surg 2024; 19:421. [PMID: 38965530 PMCID: PMC11223428 DOI: 10.1186/s13019-024-02940-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 06/17/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND Durvalumab supplementation may have some potential in improving the efficacy in patients with non-small-cell lung cancer (NSCLC), and this meta-analysis aims to explore the impact of durvalumab supplementation on efficacy for NSCLC. METHODS PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched, and we included randomized controlled trials (RCTs) assessing the effect of durvalumab supplementation on efficacy in patients with NSCLC. Overall survival and progression-free survival were included for this meta-analysis. RESULTS Four RCTs were finally included in the meta-analysis. Overall, compared with control group for NSCLC, durvalumab supplementation showed significantly improved survival rate (odd ratio [OR] = 1.64; 95% confidence interval [CI] = 1.31 to 2.06; P < 0.0001), overall survival ( hazard ratio [HR] = 0.73; 95% CI = 0.61 to 0.87; P = 0.0003), progression-free survival rate (OR = 2.31; 95% CI = 1.78 to 3.01; P < 0.00001) and progression-free survival (HR = 0.71; 95% CI = 0.54 to 0.95; P = 0.02), and had the capability to reduce the incidence of grade ≥ 3 adverse events (OR = 0.26; 95% CI = 0.16 to 0.42; P < 0.00001). CONCLUSIONS Durvalumab supplementation is effective to improve the efficacy for NSCLC.
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Affiliation(s)
- Chengchen Wang
- Department of Oncology Radiotherapy Center, Chongqing University Cancer Hospital, Chongqing, 400030, China.
- Chongqing University Cancer Hospital, No. 181 Hanyu Road, Chongqing, 400030, China.
| | - Hongyi Fu
- Department of Nursing, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, China
| | - Feng Wang
- Department of Oncology Radiotherapy Center, Chongqing University Cancer Hospital, Chongqing, 400030, China
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23
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Gao X, Ji K, Jia Y, Shan F, Chen Y, Xu N, Jia Z, Liu T, Yang N, Zhong H, Li C, Guo Z, Fan Q, Lin X, Zhang Y, Ren H, Yang H, Yao Z, Liu W, Wang ZM, Li B, Xia M, Shen L, Li Z, Ji J. Cadonilimab with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma: the phase 1b/2 COMPASSION-04 trial. Nat Med 2024; 30:1943-1951. [PMID: 38778212 DOI: 10.1038/s41591-024-03007-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 04/17/2024] [Indexed: 05/25/2024]
Abstract
Treatment with anti-programmed cell death protein 1 (PD-1) therapy and chemotherapy prolongs the survival of patients with unresectable advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The benefit from anti-PD-1 therapy is enriched in patients with programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS)-positive or CPS-high tumors compared with patients with PD-L1 CPS-negative or CPS-low tumors. In this phase 1b/2 study, we evaluated the efficacy and safety of cadonilimab, a bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen-4, plus chemotherapy as first-line treatment in patients with human epidermal growth factor receptor 2-negative unresectable advanced or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was the recommended phase 2 dose (RP2D) for phase 1b and the objective response rate for phase 2. Secondary endpoints included disease control rate, duration of response, time to response, progression-free survival, overall survival (OS) and safety. The primary endpoint was met. No dose-limiting toxicities were observed during dose escalation in phase 1b; the recommended phase 2 dose was determined as 6 mg kg-1 every 2 weeks. The objective response rate was 52.1% (95% confidence interval (CI) = 41.6-62.5), consisting of complete and partial responses in 4.3% and 47.9% of patients, respectively. The median duration of response, progression-free survival and OS were 13.73 months (95% CI = 7.79-19.12), 8.18 months (95% CI = 6.67-10.48) and 17.48 months (95% CI = 12.35-26.55), respectively. The median OS in patients with a PD-L1 CPS ≥ 5 was 20.32 months (95% CI = 4.67-not estimable); in patients with a PD-L1 CPS < 1, the median OS reached 17.64 months (95% CI = 11.63-31.70). The most common treatment-related grade 3 or higher adverse events were decreased neutrophil count (19.1%), decreased platelet count (16.0%), anemia (12.8%) and decreased leukocyte count (8.5%). No new safety signal was identified. The current regimen showed promising clinical activity and manageable safety in patients with gastric or GEJ adenocarcinoma regardless of PD-L1 expression. Chinadrugtrials.org.cn registration: CTR20182027.
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MESH Headings
- Humans
- Stomach Neoplasms/drug therapy
- Stomach Neoplasms/pathology
- Middle Aged
- Male
- Female
- Esophagogastric Junction/pathology
- Adenocarcinoma/drug therapy
- Adenocarcinoma/pathology
- Aged
- Receptor, ErbB-2/metabolism
- Adult
- Esophageal Neoplasms/drug therapy
- Esophageal Neoplasms/pathology
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Bispecific/therapeutic use
- Antibodies, Bispecific/adverse effects
- Antibodies, Bispecific/administration & dosage
- B7-H1 Antigen/antagonists & inhibitors
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Affiliation(s)
- Xiangyu Gao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Ke Ji
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yongning Jia
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Fei Shan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Ye Chen
- The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, China
| | - Nong Xu
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ziyu Jia
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | | | - Nong Yang
- Hunan Cancer Hospital, Changsha, China
| | | | | | | | - Qingxia Fan
- The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Xiaoyan Lin
- Fujian Medical University Union Hospital, Fuzhou, China
| | - Yan Zhang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Hui Ren
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Hongxia Yang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | | | - Wei Liu
- Akeso Biopharma, Inc, Zhongshan, China
| | | | | | | | - Lin Shen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China.
| | - Ziyu Li
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China.
| | - Jiafu Ji
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China.
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24
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Zhang C, Shao J, Tang X, Wu J, Li P, Li W, Wang C. The real-world treatment characteristic and efficacy of immune checkpoint inhibitors in non-small cell lung cancer: Data from a retrospective cohort study. Int Immunopharmacol 2024; 134:112152. [PMID: 38761777 DOI: 10.1016/j.intimp.2024.112152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 04/21/2024] [Accepted: 04/22/2024] [Indexed: 05/20/2024]
Abstract
BACKGROUND The efficacy and prognosis of immune checkpoint inhibitors (ICIs) remain unresolved issues. Here, we assessed the treatment characteristics and efficacy of ICIs in non-small cell lung cancer (NSCLC) using real-world data and evaluated the predictive value of factors, including programmed death-ligand 1 (PD-L1) expression, for the clinical outcome of ICIs in NSCLC. METHODS Analyzed data was collected from hospitalized patients in the West China Hospital of Sichuan University between January 2017 and March 2023. The Kaplan-Meier method was utilized for analyzing real-world progression-free survival (rwPFS), while Cox regression models was employed to access the correlation between the efficacy of immunotherapy and sociodemographic characteristics, disease information, and characteristics of ICI treatment. RESULTS A total of 545 patients were included in the retrospective study and characteristics of immunotherapy varied significantly among PD-L1 expression groups. The median rwPFS for the entire population was 9.76 months. Subgroup analyses revealed that patients with high PD-L1 expression, early TNM stage, first-line immunotherapy, EGFR wild-type and those who have not received radiotherapy and targeted therapy previously were more likely to have better rwPFS. Furthermore, multivariate Cox regression analyses identified PD-L1 expression, EGFR mutation status and previous radiotherapy as the most influential predictors of the response to ICI treatment. CONCLUSIONS This study presents the real-world experience of Chinese NSCLC patients undergoing ICI treatment, offering guidance for clinical decision-making based on various patient conditions, preferences, and indications for ICIs, through the evaluation of immunotherapy efficacy and predictors in NSCLC patients.
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Affiliation(s)
- Chenyang Zhang
- Institute of Hospital Management, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Jun Shao
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Targeted Tracer Research and Development Laboratory, Med-X Center for Manufacturing, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Xiaolong Tang
- Health Management Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jiayang Wu
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Targeted Tracer Research and Development Laboratory, Med-X Center for Manufacturing, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Peiyi Li
- Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, The Research Units of West China (2018RU012)-Chinese Academy of Medical Sciences, West China Hospital, Sichuan University, Chengdu, China.
| | - Weimin Li
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Targeted Tracer Research and Development Laboratory, Med-X Center for Manufacturing, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China.
| | - Chengdi Wang
- Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Targeted Tracer Research and Development Laboratory, Med-X Center for Manufacturing, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China.
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25
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Melero I, Yau T, Kang YK, Kim TY, Santoro A, Sangro B, Kudo M, Hou MM, Matilla A, Tovoli F, Knox J, He AR, El-Rayes B, Acosta-Rivera M, Lim HY, Soleymani S, Yao J, Neely J, Tschaika M, Hsu C, El-Khoueiry AB. Nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma previously treated with sorafenib: 5-year results from CheckMate 040. Ann Oncol 2024; 35:537-548. [PMID: 38844309 DOI: 10.1016/j.annonc.2024.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 03/14/2024] [Accepted: 03/15/2024] [Indexed: 07/24/2024] Open
Abstract
BACKGROUND Nivolumab plus ipilimumab demonstrated promising clinical activity and durable responses in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 040 study at 30.7-month median follow-up. Here, we present 5-year results from this cohort. PATIENTS AND METHODS Patients were randomized 1 : 1 : 1 to arm A [nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W (four doses)] or arm B [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W (four doses)], each followed by nivolumab 240 mg Q2W, or arm C (nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W). The primary objectives were safety, tolerability, investigator-assessed objective response rate (ORR), and duration of response (DOR) per RECIST version 1.1. RESULTS A total of 148 patients were randomized across treatment arms. At 60-month minimum follow-up (62.6-month median follow-up), the ORR was 34% (n = 17), 27% (n = 13), and 29% (n = 14) in arms A, B, and C, respectively. The median DOR was 51.2 months [95% confidence interval (CI) 12.6 months-not estimable (NE)], 15.2 months (95% CI 7.1 months-NE), and 21.7 months (95% CI 4.2 months-NE), respectively. The median overall survival (OS) was 22.2 months (34/50; 95% CI 9.4-54.8 months) in arm A, 12.5 months (38/49; 95% CI 7.6-16.4 months) in arm B, and 12.7 months (40/49; 95% CI 7.4-30.5 months) in arm C; 60-month OS rates were 29%, 19%, and 21%, respectively. In an exploratory analysis of OS by response (6-month landmark), the median OS was meaningfully longer for responders versus nonresponders for all arms. No new safety signals were identified with longer follow-up. There were no new discontinuations due to immune-mediated adverse events since the primary analysis. CONCLUSIONS Consistent with the primary analysis, the arm A regimen of nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit, with no new safety signals in patients with advanced HCC following sorafenib treatment, further supporting its use as a second-line treatment in these patients.
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Affiliation(s)
- I Melero
- Department of Immunology, Clinica Universidad de Navarra and CIBERONC, Pamplona, Spain.
| | - T Yau
- Department of Medicine, University of Hong Kong, Hong Kong, China
| | - Y-K Kang
- Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, South Korea
| | - T-Y Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - A Santoro
- Humanitas University and IRCCS Humanitas Research Hospital - Humanitas Cancer Center, Rozzano, Italy
| | - B Sangro
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain
| | - M Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - M-M Hou
- Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan
| | - A Matilla
- Hospital General Universitario Gregorio Marañón CIBEREHD, Madrid, Spain
| | - F Tovoli
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - J Knox
- Princess Margaret Cancer Centre, Toronto, Canada
| | - A R He
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - B El-Rayes
- Department of Hematology and Medical Oncology, University of Alabama at Birmingham, Birmingham, USA
| | | | - H Y Lim
- School of Medicine, Sungkyunkwan University, Seoul, Korea
| | | | - J Yao
- Informatics and Predictive Sciences, Bristol Myers Squibb, Princeton, USA
| | - J Neely
- Translational Medicine, Bristol Myers Squibb, Princeton, USA
| | - M Tschaika
- Oncology Clinical Development, Bristol Myers Squibb, Princeton, USA
| | - C Hsu
- National Taiwan University Hospital, Taipei, Taiwan; National Taiwan University Cancer Center, Taipei, Taiwan
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26
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Khan B, Qahwaji RM, Alfaifi MS, Mobashir M. Nivolumab and Ipilimumab Acting as Tormentors of Advanced Tumors by Unleashing Immune Cells and Associated Collateral Damage. Pharmaceutics 2024; 16:732. [PMID: 38931856 PMCID: PMC11207028 DOI: 10.3390/pharmaceutics16060732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/22/2024] [Accepted: 05/01/2024] [Indexed: 06/28/2024] Open
Abstract
Combining immune checkpoint inhibitors, specifically nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4), holds substantial promise in revolutionizing cancer treatment. This review explores the transformative impact of these combinations, emphasizing their potential for enhancing therapeutic outcomes across various cancers. Immune checkpoint proteins, such as PD1 and CTLA4, play a pivotal role in modulating immune responses. Blocking these checkpoints unleashes anticancer activity, and the synergy observed when combining multiple checkpoint inhibitors underscores their potential for enhanced efficacy. Nivolumab and ipilimumab harness the host's immune system to target cancer cells, presenting a powerful approach to prevent tumor development. Despite their efficacy, immune checkpoint inhibitors are accompanied by a distinct set of adverse effects, particularly immune-related adverse effects affecting various organs. Understanding these challenges is crucial for optimizing treatment strategies and ensuring patient well-being. Ongoing clinical trials are actively exploring the combination of checkpoint inhibitory therapies, aiming to decipher their synergistic effects and efficacy against diverse cancer types. This review discusses the mechanisms, adverse effects, and various clinical trials involving nivolumab and ipilimumab across different cancers, emphasizing their transformative impact on cancer treatment.
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Affiliation(s)
- Bushra Khan
- Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India;
| | - Rowaid M. Qahwaji
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 22233, Saudi Arabia;
- Hematology Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mashael S. Alfaifi
- Department of Epidemiology, Faculty of Public Health and Health Informatics, Umm Al-Qura University, Makkah 21955, Saudi Arabia;
| | - Mohammad Mobashir
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Solnavägen 9, 171 65 Solna, Sweden
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Mao Z, Pang G, Huang X, Chen X, Wu J, Xu X, Teng Z, Tan Y, Wang P. Risk factors of immune checkpoint inhibitor-related pneumonitis after neoadjuvant immunochemotherapy for resectable NSCLC. BMC Pulm Med 2024; 24:253. [PMID: 38783253 PMCID: PMC11112843 DOI: 10.1186/s12890-024-03041-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 04/29/2024] [Indexed: 05/25/2024] Open
Abstract
BACKGROUND The incidence of checkpoint inhibitor-associated pneumonitis (CIP) in advanced non-small cell lung cancer (NSCLC) has been substantiated through large-scale clinical trials or real-world studies. However, reports on CIP incidence within the context of neoadjuvant immunotherapy for resectable NSCLC remain scarce. This study endeavors to investigate the incidence, risk factors, and outcomes of CIP in patients with resectable NSCLC receiving neoadjuvant immunochemotherapy. METHODS A retrospective, case-control study was conducted on patients diagnosed with NSCLC stages IIA-IIIB who received neoadjuvant immunochemotherapy between January 2018 and September 2022. Patients were stratified into two groups based on the presence or absence of CIP, facilitating a comparative analysis of clinical characteristics, treatment modalities, physiological indicators, and prognostic outcomes . RESULTS The study cohort comprised 245 patients, with 11.4% (28/245) experiencing CIP. The median period of CIP onset was 70 (range, 40-221) days. The incidence of severe CIP (grade 3-4) was 3.7% (9/245). Patients with CIP showed a higher all-cause mortality rate of 21.4% (6/28) compared to that of patients without CIP. Those who developed CIP exhibited elevated body mass index (BMI) values (p = 0.028) and increased fibrinogen (FIB) levels (p < 0.001), alongside a significant decrease in both diffusing capacity for carbon monoxide (DLCO)% pred (p = 0.001) and DLCO/VA% pred (p = 0.021) after neoadjuvant therapy compared to pre-indicators. Receiver operating characteristic curve (ROC) analysis showed that the area under the ROC curve of three assessed variables (FIB levels, BMI, DLCO) reached 0.806 in predicting CIP occurrence at an early stage. CONCLUSIONS This cohort demonstrated that elevated BMI, increased FIB levels, and decreased pulmonary diffusion function after neoadjuvant therapy are risk factors of CIP occurrence. Early assessment and continuous monitoring of these indicators are imperative for the predictive identification of CIP, enhancing patient management and outcomes.
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Affiliation(s)
- Zhirong Mao
- Department of Respiratory Medicine, School of Medicine, Second Affiliated Hospital of Zhejiang University, Hangzhou, 310000, Zhejiang, China
| | - Guanchao Pang
- Department of Respiratory Medicine, School of Medicine, Second Affiliated Hospital of Zhejiang University, Hangzhou, 310000, Zhejiang, China
- Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, 322000, Zhejiang, China
| | - Xiaojie Huang
- Department of Respiratory Medicine, School of Medicine, Second Affiliated Hospital of Zhejiang University, Hangzhou, 310000, Zhejiang, China
| | - Xiuxiu Chen
- Department of Respiratory Medicine, School of Medicine, Second Affiliated Hospital of Zhejiang University, Hangzhou, 310000, Zhejiang, China
| | - Jiaji Wu
- Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, 322000, Zhejiang, China
| | - Xia Xu
- Department of Pathology, School of Medicine, Second Affiliated Hospital of Zhejiang University, Hangzhou, 310000, Zhejiang, China
| | - Zhihua Teng
- Department of Thoracic Surgery, School of Medicine, Second Affiliated Hospital of Zhejiang University, Hangzhou, 310000, Zhejiang, China
| | - Yanbin Tan
- Department of Radiology, School of Medicine, Second Affiliated Hospital of Zhejiang University, Hangzhou, 310000, Zhejiang, China
| | - Pingli Wang
- Department of Respiratory Medicine, School of Medicine, Second Affiliated Hospital of Zhejiang University, Hangzhou, 310000, Zhejiang, China.
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He S, Zhao Z. Genetically engineered cell-derived nanovesicles for cancer immunotherapy. NANOSCALE 2024; 16:8317-8334. [PMID: 38592744 PMCID: PMC11075450 DOI: 10.1039/d3nr06565k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/10/2024]
Abstract
The emergence of immunotherapy has marked a new epoch in cancer treatment, presenting substantial clinical benefits. Extracellular vesicles (EVs), as natural nanocarriers, can deliver biologically active agents in cancer therapy with their inherent biocompatibility and negligible immunogenicity. However, natural EVs have limitations such as inadequate targeting capability, low loading efficacy, and unpredictable side effects. Through progress in genetic engineering, EVs have been modified for enhanced delivery of immunomodulatory agents and antigen presentation with specific cancer targeting ability, deepening the role of EVs in cancer immunotherapy. This review briefly describes typical EV sources, isolation methods, and adjustable targeting of EVs. Furthermore, this review highlights the genetic engineering strategies developed for delivering immunomodulatory agents and antigen presentation in EV-based systems. The prospects and challenges of genetically engineered EVs as cancer immunotherapy in clinical translation are also discussed.
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Affiliation(s)
- Shan He
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, IL 60612, USA.
| | - Zongmin Zhao
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, IL 60612, USA.
- Translational Oncology Program, University of Illinois Cancer Center, Chicago, IL 60612, USA
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Oaknin A, Moore K, Meyer T, López-Picazo González J, Devriese LA, Amin A, Lao CD, Boni V, Sharfman WH, Park JC, Tahara M, Topalian SL, Magallanes M, Molina Alavez A, Khan TA, Copigneaux C, Lee M, Garnett-Benson C, Wang X, Naumann RW. Nivolumab with or without ipilimumab in patients with recurrent or metastatic cervical cancer (CheckMate 358): a phase 1-2, open-label, multicohort trial. Lancet Oncol 2024; 25:588-602. [PMID: 38608691 DOI: 10.1016/s1470-2045(24)00088-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 01/31/2024] [Accepted: 02/05/2024] [Indexed: 04/14/2024]
Abstract
BACKGROUND In preliminary findings from the recurrent or metastatic cervical cancer cohort of CheckMate 358, nivolumab showed durable anti-tumour responses, and the combination of nivolumab plus ipilimumab showed promising clinical activity. Here, we report long-term outcomes from this cohort. METHODS CheckMate 358 was a phase 1-2, open-label, multicohort trial. The metastatic cervical cancer cohort enrolled patients from 30 hospitals and cancer centres across ten countries. Female patients aged 18 years or older with a histologically confirmed diagnosis of squamous cell carcinoma of the cervix with recurrent or metastatic disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and up to two previous systemic therapies were enrolled into the nivolumab 240 mg every 2 weeks group, the randomised groups (nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks [NIVO3 plus IPI1] or nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 3 weeks for four cycles then nivolumab 240 mg every 2 weeks [NIVO1 plus IPI3]), or the NIVO1 plus IPI3 expansion group. All doses were given intravenously. Patients were randomly assigned (1:1) to NIVO3 plus IPI1 or NIVO1 plus IPI3 via an interactive voice response system. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal, or for up to 24 months. The primary endpoint was investigator-assessed objective response rate. Anti-tumour activity and safety were analysed in all treated patients. This study is registered with ClinicalTrials.gov (NCT02488759) and is now completed. FINDINGS Between October, 2015, and March, 2020, 193 patients were recruited in the recurrent or metastatic cervical cancer cohort of CheckMate 358, of whom 176 were treated. 19 patients received nivolumab monotherapy, 45 received NIVO3 plus IPI1, and 112 received NIVO1 plus IPI3 (45 in the randomised group and 67 in the expansion group). Median follow-up times were 19·9 months (IQR 8·2-44·8) with nivolumab, 12·6 months (7·8-37·1) with NIVO3 plus IPI1, and 16·7 months (7·2-27·5) with pooled NIVO1 plus IPI3. Objective response rates were 26% (95% CI 9-51; five of 19 patients) with nivolumab, 31% (18-47; 14 of 45 patients) with NIVO3 plus IPI1, 40% (26-56; 18 of 45 patients) with randomised NIVO1 plus IPI3, and 38% (29-48; 43 of 112 patients) with pooled NIVO1 plus IPI3. The most common grade 3-4 treatment-related adverse events were diarrhoea, hepatic cytolysis, hyponatraemia, pneumonitis, and syncope (one [5%] patient each; nivolumab group), diarrhoea, increased gamma-glutamyl transferase, increased lipase, and vomiting (two [4%] patients each; NIVO3 plus IPI1 group), and increased lipase (nine [8%] patients) and anaemia (seven [6%] patients; pooled NIVO1 plus IPI3 group). Serious treatment-related adverse events were reported in three (16%) patients in the nivolumab group, 12 (27%) patients in the NIVO3 plus IPI1 group, and 47 (42%) patients in the pooled NIVO1 plus IPI3 group. There was one treatment-related death due to immune-mediated colitis in the NIVO1 plus IPI3 group. INTERPRETATION Nivolumab monotherapy and nivolumab plus ipilimumab combination therapy showed promise in the CheckMate 358 study as potential treatment options for recurrent or metastatic cervical cancer. Future randomised controlled trials of nivolumab plus ipilimumab or other dual immunotherapy regimens are warranted to confirm treatment benefit in this patient population. FUNDING Bristol Myers Squibb and Ono Pharmaceutical.
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Affiliation(s)
- Ana Oaknin
- Medical Oncology Service, Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
| | - Kathleen Moore
- Stephenson Cancer Center, Oklahoma City, OK, USA; Sarah Cannon Research Institute, Nashville, TN, USA
| | - Tim Meyer
- University College London, London, UK
| | | | - Lot A Devriese
- Universitair Medisch Centrum Utrecht, Utrecht, Netherlands
| | - Asim Amin
- Levine Cancer Institute, Atrium Health, Charlotte, NC, USA
| | | | - Valentina Boni
- Medical Oncology, START Madrid, Centro Integral Oncológico Clara Campal, Hospital Madrid Norte Sanchinarro, Madrid, Spain
| | - William H Sharfman
- Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center, Baltimore, MD, USA
| | | | - Makoto Tahara
- National Cancer Center Hospital East, Kashiwa, Japan
| | - Suzanne L Topalian
- Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Kimmel Cancer Center, Baltimore, MD, USA
| | | | | | | | | | - Michelle Lee
- Bristol Myers Squibb, Princeton, NJ, USA; Syneos Health, Morrisville, NC, USA
| | | | - Xuya Wang
- Bristol Myers Squibb, Princeton, NJ, USA
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Ioffe D, McSweeny M, Hall MJ. Precision Medicine in the Era of Genetic Testing: Microsatellite Instability Evolved. Clin Colon Rectal Surg 2024; 37:157-171. [PMID: 38617845 PMCID: PMC11007599 DOI: 10.1055/s-0043-1770385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
The recognized importance of microsatellite instability (MSI) in cancer has evolved considerably in the past 30 years. From its beginnings as a molecular predictor for Lynch syndrome, MSI first transitioned to a universal screening test in all colorectal and endometrial cancers, substantially increasing the identification of patients with Lynch syndrome among cancer patients. More recently, MSI has been shown to be a powerful biomarker of response to immune checkpoint blockade therapy across a diversity of tumor types, and in 2017 was granted Food and Drug Administration approval as the first tumor histology-agnostic biomarker for a cancer therapy. Focusing on colorectal cancer specifically, immune checkpoint blockade therapy has been shown to be highly effective in the treatment of both MSI-high (MSI-H) colon and rectal cancer, with data increasingly suggesting an early role for immune checkpoint blockade therapy in MSI-H colorectal tumors in the neoadjuvant setting, with the potential to avoid more toxic and morbid approaches using traditional chemotherapy, radiation therapy, and surgery. The success of MSI as an immune checkpoint blockade target has inspired ongoing vigorous research to identify new similar targets for immune checkpoint blockade therapy that may help to one day expand the reach of this revolutionary cancer therapy to a wider swath of patients and indications.
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Affiliation(s)
- Dina Ioffe
- Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Michelle McSweeny
- Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Michael J. Hall
- Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Cheng L, Chen L, Shi Y, Gu W, Ding W, Zheng X, Liu Y, Jiang J, Zheng Z. Efficacy and safety of bispecific antibodies vs. immune checkpoint blockade combination therapy in cancer: a real-world comparison. Mol Cancer 2024; 23:77. [PMID: 38627681 PMCID: PMC11020943 DOI: 10.1186/s12943-024-01956-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 02/07/2024] [Indexed: 04/19/2024] Open
Abstract
Emerging tumor immunotherapy methods encompass bispecific antibodies (BSABs), immune checkpoint inhibitors (ICIs), and adoptive cell immunotherapy. BSABs belong to the antibody family that can specifically recognize two different antigens or epitopes on the same antigen. These antibodies demonstrate superior clinical efficacy than monoclonal antibodies, indicating their role as a promising tumor immunotherapy option. Immune checkpoints are also important in tumor immunotherapy. Programmed cell death protein-1 (PD-1) is a widely acknowledged immune checkpoint target with effective anti-tumor activity. PD-1 inhibitors have demonstrated notable therapeutic efficacy in treating hematological and solid tumors; however, more than 50% of patients undergoing this treatment exhibit a poor response. However, ICI-based combination therapies (ICI combination therapies) have been demonstrated to synergistically increase anti-tumor effects and immune response rates. In this review, we compare the clinical efficacy and side effects of BSABs and ICI combination therapies in real-world tumor immunotherapy, aiming to provide evidence-based approaches for clinical research and personalized tumor diagnosis and treatment.
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Affiliation(s)
- Linyan Cheng
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Lujun Chen
- Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China
- Institute for Cell Therapy of Soochow University, Changzhou, China
| | - Yuan Shi
- Laboratory of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Weiying Gu
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Weidong Ding
- Department of Hematology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao Zheng
- Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China.
- Institute for Cell Therapy of Soochow University, Changzhou, China.
| | - Yan Liu
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
| | - Jingting Jiang
- Department of Tumor Biological Treatment, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, China.
- Institute for Cell Therapy of Soochow University, Changzhou, China.
| | - Zhuojun Zheng
- Department of Hematology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
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32
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Parra ER, Zhang J, Duose DY, Gonzalez-Kozlova E, Redman MW, Chen H, Manyam GC, Kumar G, Zhang J, Song X, Lazcano R, Marques-Piubelli ML, Laberiano-Fernandez C, Rojas F, Zhang B, Taing L, Jhaveri A, Geisberg J, Altreuter J, Michor F, Provencher J, Yu J, Cerami E, Moravec R, Kannan K, Luthra R, Alatrash G, Huang HH, Xie H, Patel M, Nie K, Harris J, Argueta K, Lindsay J, Biswas R, Van Nostrand S, Kim-Schulze S, Gray JE, Herbst RS, Wistuba II, Gettinger S, Kelly K, Bazhenova L, Gnjatic S, Lee JJ, Zhang J, Haymaker C. Multi-omics Analysis Reveals Immune Features Associated with Immunotherapy Benefit in Patients with Squamous Cell Lung Cancer from Phase III Lung-MAP S1400I Trial. Clin Cancer Res 2024; 30:1655-1668. [PMID: 38277235 PMCID: PMC11016892 DOI: 10.1158/1078-0432.ccr-23-0251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 05/06/2023] [Accepted: 01/24/2024] [Indexed: 01/28/2024]
Abstract
PURPOSE Identifying molecular and immune features to guide immune checkpoint inhibitor (ICI)-based regimens remains an unmet clinical need. EXPERIMENTAL DESIGN Tissue and longitudinal blood specimens from phase III trial S1400I in patients with metastatic squamous non-small cell carcinoma (SqNSCLC) treated with nivolumab monotherapy (nivo) or nivolumab plus ipilimumab (nivo+ipi) were subjected to multi-omics analyses including multiplex immunofluorescence (mIF), nCounter PanCancer Immune Profiling Panel, whole-exome sequencing, and Olink. RESULTS Higher immune scores from immune gene expression profiling or immune cell infiltration by mIF were associated with response to ICIs and improved survival, except regulatory T cells, which were associated with worse overall survival (OS) for patients receiving nivo+ipi. Immune cell density and closer proximity of CD8+GZB+ T cells to malignant cells were associated with superior progression-free survival and OS. The cold immune landscape of NSCLC was associated with a higher level of chromosomal copy-number variation (CNV) burden. Patients with LRP1B-mutant tumors had a shorter survival than patients with LRP1B-wild-type tumors. Olink assays revealed soluble proteins such as LAMP3 increased in responders while IL6 and CXCL13 increased in nonresponders. Upregulation of serum CXCL13, MMP12, CSF-1, and IL8 were associated with worse survival before radiologic progression. CONCLUSIONS The frequency, distribution, and clustering of immune cells relative to malignant ones can impact ICI efficacy in patients with SqNSCLC. High CNV burden may contribute to the cold immune microenvironment. Soluble inflammation/immune-related proteins in the blood have the potential to monitor therapeutic benefit from ICI treatment in patients with SqNSCLC.
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Affiliation(s)
- Edwin Roger Parra
- Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jiexin Zhang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Dzifa Yawa Duose
- Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Edgar Gonzalez-Kozlova
- Department of Oncological Sciences, Mount Sinai, New York, New York
- Tisch Cancer Institute, Mount Sinai, New York, New York
- Precision Immunology Institute, Mount Sinai, New York, New York
- Icahn School of Medicine at Mount Sinai, New York, New York
| | - Mary W. Redman
- SWOG Statistical Center, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Hong Chen
- Department of Thoracic-Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ganiraju C. Manyam
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gayatri Kumar
- Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jianhua Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xingzhi Song
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rossana Lazcano
- Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mario L. Marques-Piubelli
- Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Caddie Laberiano-Fernandez
- Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Frank Rojas
- Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Baili Zhang
- Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Len Taing
- CIMAC-CIDC Network, Pipeline Development and Portal Integration, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Aashna Jhaveri
- CIMAC-CIDC Network, Pipeline Development and Portal Integration, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jacob Geisberg
- CIMAC-CIDC Network, Pipeline Development and Portal Integration, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jennifer Altreuter
- CIMAC-CIDC Network, Pipeline Development and Portal Integration, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Franziska Michor
- CIMAC-CIDC Network, Pipeline Development and Portal Integration, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - James Provencher
- CIMAC-CIDC Network, Pipeline Development and Portal Integration, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Joyce Yu
- CIMAC-CIDC Network, Pipeline Development and Portal Integration, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Ethan Cerami
- CIMAC-CIDC Network, Pipeline Development and Portal Integration, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Radim Moravec
- Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, NCI, Bethesda, Maryland
| | - Kasthuri Kannan
- Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rajyalakshmi Luthra
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gheath Alatrash
- Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer, Houston, Texas
| | - Hsin-Hui Huang
- Precision Immunology Institute, Mount Sinai, New York, New York
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Hui Xie
- Precision Immunology Institute, Mount Sinai, New York, New York
| | | | - Kai Nie
- Precision Immunology Institute, Mount Sinai, New York, New York
| | - Jocelyn Harris
- Precision Immunology Institute, Mount Sinai, New York, New York
| | | | - James Lindsay
- Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Roshni Biswas
- Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Stephen Van Nostrand
- CIMAC-CIDC Network, Pipeline Development and Portal Integration, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Seunghee Kim-Schulze
- Department of Oncological Sciences, Mount Sinai, New York, New York
- Tisch Cancer Institute, Mount Sinai, New York, New York
- Precision Immunology Institute, Mount Sinai, New York, New York
- Icahn School of Medicine at Mount Sinai, New York, New York
| | | | - Roy S. Herbst
- Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut
| | - Ignacio I. Wistuba
- Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Karen Kelly
- International Association for the Study of Lung Cancer, Denver, Colorado
| | - Lyudmila Bazhenova
- University of California San Diego Moores Cancer Center, La Jolla, California
| | - Sacha Gnjatic
- Department of Oncological Sciences, Mount Sinai, New York, New York
- Tisch Cancer Institute, Mount Sinai, New York, New York
- Precision Immunology Institute, Mount Sinai, New York, New York
- Icahn School of Medicine at Mount Sinai, New York, New York
| | - J. Jack Lee
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jianjun Zhang
- Department of Thoracic-Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Cara Haymaker
- Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Yang M, Cao H, Wang C, Yu C, Sun P. Incidence of thromboembolic events in non-small cell lung cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis. J Cancer Res Ther 2024; 20:509-521. [PMID: 38687920 DOI: 10.4103/jcrt.jcrt_1031_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 01/08/2024] [Indexed: 05/02/2024]
Abstract
ABSTRACT The incidence of thromboembolic events (TEs) in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) has rarely been reported. The MEDLINE, EMBASE, and the Cochrane Library databases were searched. The primary outcome was the incidence of TEs, and the secondary outcome was the relationship between TEs and overall survival (OS) following ICI therapy. A subgroup analysis of TE incidents was performed according to the TE type and combination regimens. The I2 statistic was used to determine the heterogeneity, and funnel plots and Egger's test were used to assess publication bias. A total of 16,602 patients with NSCLC in 63 experimental arms were included in the analysis. The rate of TEs ranged from 0.1% to 13.8%, and the pooled overall incidence of all-grade TEs was 3% (95% confidence interval [CI], 2%-4%). The pooled rate of high-grade TEs was 1% (95% CI, 1%-2%). The venous and arterial TE rates were 3% (95% CI, 2%-4%) and 1% (95% CI, 1%-2%), respectively. Patients who received immunotherapy + chemoradiotherapy had the highest incidence of TEs (7%). The TE pooled rate was higher in patients treated with combined ICIs than in those treated with mono ICIs (4% vs. 2%). The OS was lower in patients with TEs than in those without TEs (hazard ratio, 1.4; 95% CI, 1.02%-1.92%). The incidence of TEs in NSCLC patients treated with ICIs was reasonable. Nonetheless, clinicians must be aware of potential thrombotic complications and treat them promptly.
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Affiliation(s)
- Miaomiao Yang
- Department of Oncology, Yantai Yuhuangding Hospital, Affiliated with Medical College of Qingdao University, Yantai, Shandong, P.R. China
| | - Hongxin Cao
- Department of Medical Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, P.R. China
| | - Congcong Wang
- Department of Oncology, Yantai Yuhuangding Hospital, Affiliated with Medical College of Qingdao University, Yantai, Shandong, P.R. China
| | - Caiyan Yu
- Department of Oncology, Yantai Yuhuangding Hospital, Affiliated with Medical College of Qingdao University, Yantai, Shandong, P.R. China
| | - Ping Sun
- Department of Oncology, Yantai Yuhuangding Hospital, Affiliated with Medical College of Qingdao University, Yantai, Shandong, P.R. China
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Yan X, Zhao L, Wu F, Shen B, Zhou G, Feng J, Yue C, Zhu J, Yu S. Efficacy and safety analysis of immune checkpoint inhibitor rechallenge therapy in locally advanced and advanced non-small cell lung cancer: a retrospective study. J Thorac Dis 2024; 16:1787-1803. [PMID: 38617775 PMCID: PMC11009570 DOI: 10.21037/jtd-23-1767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 01/26/2024] [Indexed: 04/16/2024]
Abstract
Background Immune checkpoint inhibitors (ICIs) have dramatically changed the first-line treatment pattern of non-small cell lung cancer (NSCLC) without driver gene alterations. However, the optimal choice for second-line treatment after initial treatment with ICIs is unclear. This study aimed to clarify the efficacy and safety of ICI rechallenge therapy in locally advanced and advanced NSCLC. Methods We retrospectively analyzed the histories of 224 patients with locally advanced or advanced NSCLC treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy and/or antiangiogenic therapy in first-line treatment. Progression-free survival 2 (PFS2) was the time from the first defined progress disease (PD) to the second disease progression or death. Efficacy evaluation was performed directly in accordance with RECIST v1.1 criteria. Adverse events (AEs) were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Survival data were estimated using the Kaplan-Meier method or Cox survival regression model and compared using the log-rank test in overall cohort and other subgroups. Results There were no significant differences in objective response rate (ORR) and median PFS2 (mPFS2) between the ICI rechallenge group and non-rechallenge group (ORR: 10.3% vs. 15.3%, P=0.308; mPFS2: 5.33 vs. 4.40 months, P=0.715). And the ICI rechallenge group showed no new safety signals compared with non-rechallenge group. In ICI rechallenge group, patients resistant to first-line immunotherapy had a lower ORR and shorter PFS2 compared with those who responded to initial ICIs treatment (ORR: 7.0% vs. 17.6%, P=0.038; mPFS2: 3.68 vs. 5.91 months, P=0.014). No significant difference in mPFS2 was observed among different second-line treatment groups (P=0.362). Radiotherapy in second-line treatment and ICI rechallenge therapy were not the main factors affecting PFS2. Conclusions ICI rechallenge therapy beyond disease progression did not improve clinical outcomes in patients with NSCLC, but no new safety signals emerged. However, patients with favorable response to initial ICIs treatment still showed significant efficacy of subsequent ICI rechallenge therapy.
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Affiliation(s)
- Xiaoqi Yan
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Luqing Zhao
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Fei Wu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Bo Shen
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Guoren Zhou
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Jifeng Feng
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Chao Yue
- Department of General Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Jingni Zhu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
| | - Shaorong Yu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China
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Barr T, Ma S, Li Z, Yu J. Recent advances and remaining challenges in lung cancer therapy. Chin Med J (Engl) 2024; 137:533-546. [PMID: 38321811 DOI: 10.1097/cm9.0000000000002991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Indexed: 02/08/2024] Open
Abstract
ABSTRACT Lung cancer remains the most common cause of cancer death. Given the continued research into new drugs and combination therapies, outcomes in lung cancer have been improved, and clinical benefits have been expanded to a broader patient population. However, the overall cure and survival rates for lung cancer patients remain low, especially in metastatic cases. Among the available lung cancer treatment options, such as surgery, radiation therapy, chemotherapy, targeted therapies, and alternative therapies, immunotherapy has shown to be the most promising. The exponential progress in immuno-oncology research and recent advancements made in the field of immunotherapy will further increase the survival and quality of life for lung cancer patients. Substantial progress has been made in targeted therapies using tyrosine kinase inhibitors and monoclonal antibody immune checkpoint inhibitors with many US Food And Drug Administration (FDA)-approved drugs targeting the programmed cell death ligand-1 protein (e.g., durvalumab, atezolizumab), the programmed cell death-1 receptor (e.g., nivolumab, pembrolizumab), and cytotoxic T-lymphocyte-associated antigen 4 (e.g., tremelimumab, ipilimumab). Cytokines, cancer vaccines, adoptive T cell therapies, and Natural killer cell mono- and combinational therapies are rapidly being studied, yet to date, there are currently none that are FDA-approved for the treatment of lung cancer. In this review, we discuss the current lung cancer therapies with an emphasis on immunotherapy, including the challenges for future research and clinical applications.
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Affiliation(s)
- Tasha Barr
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California 91010, USA
| | - Shoubao Ma
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California 91010, USA
- Comprehensive Cancer Center, City of Hope, Los Angeles, California 91010, USA
| | - Zhixin Li
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California 91010, USA
| | - Jianhua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California 91010, USA
- Comprehensive Cancer Center, City of Hope, Los Angeles, California 91010, USA
- Department of Immuno-Oncology, Beckman Research Institute, Los Angeles, California 91010, USA
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Bai Y, Yang W, Käsmann L, Sorich MJ, Tao H, Hu Y. Immunotherapy for advanced non-small cell lung cancer with negative programmed death-ligand 1 expression: a literature review. Transl Lung Cancer Res 2024; 13:398-422. [PMID: 38496691 PMCID: PMC10938091 DOI: 10.21037/tlcr-23-144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/05/2023] [Indexed: 03/19/2024]
Abstract
Background and Objective Lung cancer, mainly non-small cell lung cancer (NSCLC), is a serious threat to human life. In particular, the prognosis for advanced patients is poor, with the 5-year survival rate being exceedingly low. In recent years, immune checkpoint inhibition has changed the pattern of the treatment of a variety of cancers, including lung cancer; however, not all patients can benefit from immunotherapy, and thus finding the right biomarkers is particularly important for guiding precise treatment. Programmed death-ligand 1 (PD-L1) expression is one of the most valuable biomarkers for predicting the efficacy of lung cancer immunotherapy. Several studies have confirmed that patients with high PD-L1 expression are more likely to benefit from immunotherapy, but there is a high proportion of people with negative PD-L1 expression constituting a patient population that cannot be ignored. This article reviews the distribution of PD-L1 expression, the methods for evaluating PD-L1, and the effectiveness of immunotherapy for advanced NSCLC with negative PD-L1 expression. Methods We performed a literature review to identify relevant data published until September 2022. In order to organize related information, we searched for literature in PubMed; abstracts and reports published in the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), the World Conference on Lung Cancer (WCLC), and other congresses; and clinical trial information registered on ClinicalTrials.gov. Information on the distribution of PD-L1 expression, detection of PD-L1, and immunotherapy efficacy for NSCLC with negative PD-L1 expression was collated and reviewed. Key Content and Findings The incidence of PD-L1 expression in patients with stage IIIB/IV NSCLC is similar in all regions of the world, but PD-L1 expression level is associated with certain clinicopathological features. The expression of PD-L1 can be evaluated by various detecting methods. Some immunotherapy regimens have better efficacy than traditional chemotherapy in patients with negative PD-L1 expression. Conclusions Patients with NSCLC and negative PD-L1 expression can receive better survival benefits under some immunotherapy types, and these may represent a better treatment option for this relatively small patient population.
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Affiliation(s)
- Yibing Bai
- Medical School of Chinese PLA, Beijing, China
- Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Wenyu Yang
- Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
- School of Medicine, Nankai University, Tianjin, China
| | - Lukas Käsmann
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
- German Center for Lung Research (DZL), Partner Site Munich, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Michael J. Sorich
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Haitao Tao
- Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yi Hu
- Medical School of Chinese PLA, Beijing, China
- Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
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Chen J, Lu W, Chen M, Cai Z, Zhan P, Liu X, Zhu S, Ye M, Lv T, Lv J, Song Y, Wang D. Efficacy of immunotherapy in patients with oncogene-driven non-small-cell lung cancer: a systematic review and meta-analysis. Ther Adv Med Oncol 2024; 16:17588359231225036. [PMID: 38420602 PMCID: PMC10901068 DOI: 10.1177/17588359231225036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 12/18/2023] [Indexed: 03/02/2024] Open
Abstract
Background Immunotherapy is an emerging antitumor therapy that can improve the survival of patients with advanced non-small-cell lung cancer (NSCLC). However, only about 20% of NSCLC patients can benefit from this treatment. At present, whether patients with driving gene-positive NSCLC can benefit from immunotherapy is one of the hot issues. Therefore, we conducted a meta-analysis to evaluate the efficacy of immunotherapy in patients with oncogene-driven NSCLC and concluded the efficacy of altered subtypes. Methods A literature search was performed using PubMed, Web of Science, and Cochrane databases. The primary endpoints included the objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients with oncogene-driven NSCLC. Results In all, 86 studies involving 4524 patients with oncogene-driven NSCLC were included in this meta-analysis. The pooled ORRs in clinical trials treated with monoimmunotherapy of EGFR, ALK, and KRAS alteration were 6%, 0%, and 23%, respectively. In retrospective studies, the pooled ORRs of EGFR, ALK, KRAS, BRAF, MET, HER2, RET, and ROS1 alteration were 8%, 3%, 28%, 24%, 23%, 14%, 7%, and 8%, respectively. Among them, the pooled ORRs of KRAS non-G12C mutation, KRAS G12C mutation, BRAF V600E mutation, BRAF non-V600E mutation, MET-exon 14 skipping, and MET-amplification were 33% 40%, 20%, 34%, 17%, and 60%, respectively. In addition, the pooled mPFS rates of EGFR, KRAS, MET, HER2, and RET alteration were 2.77, 3.24, 2.48, 2.31, and 2.68 months, while the pooled mOS rates of EGFR and KRAS alteration were 9.98 and 12.29 months, respectively. In prospective data concerning EGFR mutation, the pooled ORR and mPFS treated with chemo-immunotherapy (IC) reached 38% and 6.20 months, while 58% and 8.48 months with chemo-immunotherapy plus anti-angiogenesis therapy (ICA). Moreover, the pooled mPFS and mOS of monoimmunotherapy was 2.33 months and 12.43 months. Conclusions EGFR-, ALK-, HER2-, RET-, and ROS1-altered NSCLC patients have poor reactivity to monoimmunotherapy but the efficacy of immune-based combined therapy is significantly improved. KRAS G12C mutation, BRAF non-V600E mutation, and MET amplification have better responses to immunotherapy, and more prospective studies are needed for further research.
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Affiliation(s)
- Jiayan Chen
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wanjun Lu
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Mo Chen
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zijing Cai
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ping Zhan
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Xin Liu
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Suhua Zhu
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Mingxiang Ye
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Tangfeng Lv
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Jiawen Lv
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002 China
| | - Yong Song
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210002 China
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002 China
| | - Dong Wang
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210002 China
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002 China
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Comen E, Budhu S, Elhanati Y, Page D, Rasalan-Ho T, Ritter E, Wong P, Plitas G, Patil S, Brogi E, Jochelson M, Bryce Y, Solomon SB, Norton L, Merghoub T, McArthur HL. Preoperative immune checkpoint inhibition and cryoablation in early-stage breast cancer. iScience 2024; 27:108880. [PMID: 38333710 PMCID: PMC10850740 DOI: 10.1016/j.isci.2024.108880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 07/31/2023] [Accepted: 01/08/2024] [Indexed: 02/10/2024] Open
Abstract
Local cryoablation can engender systemic immune activation/anticancer responses in tumors otherwise resistant to immune checkpoint blockade (ICB). We evaluated the safety/tolerability of preoperative cryoablation plus ipilimumab and nivolumab in 5 early-stage/resectable breast cancers. The primary endpoint was met when all 5 patients underwent standard-of-care primary breast surgery undelayedly. Three patients developed transient hyperthyroidism; one developed grade 4 liver toxicity (resolved with supportive management). We compared this strategy with cryoablation and/or ipilimumab. Dual ICB plus cryoablation induced higher expression of T cell activation markers and serum Th1 cytokines and reduced immunosuppressive serum CD4+PD-1hi T cells, improving effector-to-suppressor T cell ratio. After dual ICB and before cryoablation, T cell receptor sequencing of 4 patients showed increased T cell clonality. In this small subset of patients, we provide preliminary evidence that preoperative cryoablation plus ipilimumab and nivolumab is feasible, inducing systemic adaptive immune activation potentially more robust than cryoablation with/without ipilimumab.
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Affiliation(s)
- Elizabeth Comen
- Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sadna Budhu
- Ludwig Collaborative and Swim Across America Laboratory, Department of Pharmacology and Mayer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Yuval Elhanati
- Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David Page
- Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Cancer Institute, Portland, OR, USA
| | - Teresa Rasalan-Ho
- Immune Monitoring Core Facility, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Erika Ritter
- Immune Monitoring Core Facility, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Phillip Wong
- Immune Monitoring Core Facility, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - George Plitas
- Breast Surgery, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sujata Patil
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Edi Brogi
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maxine Jochelson
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yolanda Bryce
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Stephen B. Solomon
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Larry Norton
- Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Taha Merghoub
- Ludwig Collaborative and Swim Across America Laboratory, Department of Pharmacology and Mayer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Heather L. McArthur
- Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Division of Medical Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Lin L, Xiao L, Li L, Chen C, Zhang H, Yu C, Zhang L, Wei A, Li W. A meta-analysis of the efficacy of programmed cell death 1/its ligand inhibitors plus cytotoxic T-lymphocyte-associated antigen 4 inhibitors in non-small cell lung cancer. Front Pharmacol 2024; 15:1267763. [PMID: 38379896 PMCID: PMC10877718 DOI: 10.3389/fphar.2024.1267763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 01/23/2024] [Indexed: 02/22/2024] Open
Abstract
Background: Immune checkpoint inhibitors (ICIs), either as monotherapy or in combination with chemotherapy, have improved the therapeutic outcome for non-small cell lung cancer (NSCLC). However, the efficacy of combination therapies, such as programmed cell death 1(PD-1)/its ligand (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, in targeting different pathways remains unclear. We performed a meta-analysis to determine whether the addition of a CTLA-4 inhibitor to PD-1/PD-L1 therapy improves the efficacy of PD-1/PD-L1 monotherapy in NSCLC. Methods: We systematically searched various electronic databases for suitable trials. Only randomized controlled trials (RCTs) comparing the clinical efficacy of PD-1/PD-L1 with and without CTLA-4 were included in the analyses. The meta-analysis software RevMan 5.3 was used for statistical analyses. Results: A total of seven RCTs were retrieved. The results suggested that the combination of CTLA-4 and PD-1/PDL-1 inhibitors did not show enhanced efficacy over PD1/PDL-1 inhibitor monotherapy as determined by overall survival (OS) (HR = 0.98, 95% CI = 0.84-1.14, p = 0.79), progression-free survival (PFS) (HR = 0.92, 95% CI = 0.81-1.06, p = 0.25), and objective response rate (ORR) (HR = 1.08, 95% CI = 0.96-1.21, p = 0.19). Furthermore, the combination immunotherapy was associated increased toxicity as evidenced by increased incidence of any type adverse events (AEs) (RR = 1.06, 95% CI = 1.00-1.13, p = 0.03), grade ≥3 immune-mediated AEs (RR = 1.58, 95% CI = 1.36-1.82, p < 0.05), and treatment discontinuation (RR = 1.83, 95% CI = 1.46-2.28, p < 0.05). Conclusion: Combining anti-CTLA-4 with anti-PD-1/PD-L1 therapy did not improve the therapeutic efficacy, and was associated with greater toxicity than anti-PD-1/PD-L1 monotherapy in patients with advanced NSCLC. Further investigation of the combination immunotherapy in specific subsets of patients is warranted to identify and define the patient-specific benefits of this combination. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023435399.
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Affiliation(s)
- Li Lin
- Department of Oncology, Wuhan Asia General Hospital, Wuhan, China
| | - Lu Xiao
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lei Li
- Department of Oncology, Wuhan Asia General Hospital, Wuhan, China
| | - Chen Chen
- Department of Oncology, Wuhan Asia General Hospital, Wuhan, China
| | - Haorong Zhang
- Department of Oncology, Wuhan Asia General Hospital, Wuhan, China
| | - Changyan Yu
- Department of Oncology, Wuhan Asia General Hospital, Wuhan, China
| | - Lanfang Zhang
- Department of Oncology, Wuhan Asia General Hospital, Wuhan, China
| | - Anhua Wei
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Li
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Zhao Y, Chen X, Yao J, Long J, Mao Y, Wu D, Zang A, Zhao J, Liu Z, Meng R, Chen Y, Luo Y, Guo Q, Li L, Cui J. A phase Ib study evaluating the safety and efficacy of IBI310 plus sintilimab in patients with advanced non-small-cell lung cancer who have progressed after anti-PD-1/L1 therapy. Cancer Med 2024; 13:e6855. [PMID: 38214075 PMCID: PMC10905228 DOI: 10.1002/cam4.6855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 12/07/2023] [Accepted: 12/11/2023] [Indexed: 01/13/2024] Open
Abstract
BACKGROUND The development of immune checkpoint inhibitors has made a significant breakthrough in the treatment of non-small-cell lung cancer (NSCLC). However, there remains a huge unmet clinical need for patients with acquired resistance after initial treatment response. METHODS This study evaluated the combination of IBI310 (an anti-cytotoxic T lymphocyte-associated antigen-4 [CTLA-4] antibody) and sintilimab (an anti-programmed death 1 [PD-1]) antibody) in NSCLC patients who have previously been treated with anti-PD-1/ligand (L)1 and acquired resistance. The patients were randomly assigned to receive either a lower dose of IBI310 (1 mg/kg Q3W, cohort A) or a higher dose of IBI310 (3 mg/kg Q3W, cohort B) in combination with sintilimab (200 mg Q3W). The primary endpoints of the study were objective response rate (ORR) assessed by RECISTv1.1 and safety, while secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS As of November 2, 2023, the study had enrolled 30 patients, with 15 patients in each cohort. The ORR was 13.3% (2/15, 95% confidence interval [CI], 1.7-40.5) in cohort B. DCR were 46.7% (95% CI, 21.3-73.4) and 66.7% (95% CI, 38.4-88.2) in cohorts A and B, respectively. In cohorts A and B of this trial, the median follow-up times were 4.2 and 5.6 months, respectively. Median PFS was 1.45 (95% CI, 1.35-2.73) versus 2.73 (95% CI, 1.41-4.90) months for cohort A versus B; the median OS was 7.03 (95% CI, 3.09-not calculable [NC]) months in cohort A and 8.90 (95% CI, 5.13-NC) months in cohort B. Of the 30 patients, 86.7% in both cohorts experienced treatment-related adverse events (TRAEs) with Grade ≥3 TRAEs occurring in 40% and 53.3% of patients in cohorts A and B, respectively. CONCLUSION IBI310 3 mg/kg Q3W plus sintilimab was effective in a small number of previously treated anti-PD-1/L1-resistant NSCLC patients.
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Affiliation(s)
- Yuguang Zhao
- The First Hospital of Jilin University, Changchun, China
| | - Xiao Chen
- The First Hospital of Jilin University, Changchun, China
| | - Jun Yao
- The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
| | - Jianlin Long
- Chongqing University Affiliated Cancer Hospital, Chongqing, China
| | - Yong Mao
- Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Di Wu
- The First Hospital of Jilin University, Changchun, China
| | - Aimin Zang
- Affiliated Hospital of Hebei University, Baoding, China
| | - Jun Zhao
- Beijing Cancer Hospital, Beijing, China
| | - Ziling Liu
- The First Hospital of Jilin University, Changchun, China
| | - Rui Meng
- Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Ye Chen
- Innovent Biologics, Inc., Suzhou, China
| | - Yang Luo
- Innovent Biologics, Inc., Suzhou, China
| | - Qun Guo
- Innovent Biologics, Inc., Suzhou, China
| | - Li Li
- Innovent Biologics, Inc., Suzhou, China
| | - Jiuwei Cui
- The First Hospital of Jilin University, Changchun, China
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Vasudev NS, Ainsworth G, Brown S, Pickering L, Waddell T, Fife K, Griffiths R, Sharma A, Katona E, Howard H, Velikova G, Maraveyas A, Brown J, Pezaro C, Tuthill M, Boleti E, Bahl A, Szabados B, Banks RE, Brown J, Venugopal B, Patel P, Jain A, Symeonides SN, Nathan P, Collinson FJ, Powles T. Standard Versus Modified Ipilimumab, in Combination With Nivolumab, in Advanced Renal Cell Carcinoma: A Randomized Phase II Trial (PRISM). J Clin Oncol 2024; 42:312-323. [PMID: 37931206 PMCID: PMC10824383 DOI: 10.1200/jco.23.00236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 07/09/2023] [Accepted: 09/09/2023] [Indexed: 11/08/2023] Open
Abstract
PURPOSE Ipilimumab (IPI), in combination with nivolumab (NIVO), is an approved frontline treatment option for patients with intermediate- or poor-risk advanced renal cell carcinoma (aRCC). We conducted a randomized phase II trial to evaluate whether administering IPI once every 12 weeks (modified), instead of once every 3 weeks (standard), in combination with NIVO, is associated with a favorable toxicity profile. METHODS Treatment-naïve patients with clear-cell aRCC were randomly assigned 2:1 to receive four doses of modified or standard IPI, 1 mg/kg, in combination with NIVO (3 mg/kg). The primary end point was the proportion of patients with a grade 3-5 treatment-related adverse event (trAE) among those who received at least one dose of therapy. The key secondary end point was 12-month progression-free survival (PFS) in the modified arm compared with historical sunitinib control. The study was not designed to formally compare arms for efficacy. RESULTS Between March 2018 and January 2020, 192 patients (69.8% intermediate/poor-risk) were randomly assigned and received at least one dose of study drug. The incidence of grade 3-5 trAEs was significantly lower among participants receiving modified versus standard IPI (32.8% v 53.1%; odds ratio, 0.43 [90% CI, 0.25 to 0.72]; P = .0075). The 12-month PFS (90% CI) using modified IPI was 46.1% (38.6 to 53.2). At a median follow-up of 21 months, the overall response rate was 45.3% versus 35.9% and the median PFS was 10.8 months versus 9.8 months in the modified and standard IPI groups, respectively. CONCLUSION Rates of grade 3-5 trAEs were significantly lower in patients receiving modified versus standard IPI. Although 12-month PFS did not meet the prespecified efficacy threshold compared with historical control, informal comparison of treatment groups did not suggest any reduction in efficacy with the modified schedule.
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Affiliation(s)
- Naveen S. Vasudev
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, United Kingdom
| | - Gemma Ainsworth
- Clinical Trials Research Unit, University of Leeds, Leeds, United Kingdom
| | - Sarah Brown
- Clinical Trials Research Unit, University of Leeds, Leeds, United Kingdom
| | | | - Tom Waddell
- Department of Medical Oncology, Christie Hospital, Manchester, United Kingdom
| | - Kate Fife
- Addenbrooke's Hospital, Cambridge, United Kingdom
| | | | - Anand Sharma
- Mount Vernon Cancer Centre, Middlesex, United Kingdom
| | - Eszter Katona
- Clinical Trials Research Unit, University of Leeds, Leeds, United Kingdom
| | - Helen Howard
- Clinical Trials Research Unit, University of Leeds, Leeds, United Kingdom
| | - Galina Velikova
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, United Kingdom
| | | | - Janet Brown
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
| | - Carmel Pezaro
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Mark Tuthill
- Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | | | - Amit Bahl
- Bristol Haematology and Oncology Centre, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United Kingdom
| | - Bernadett Szabados
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Rosamonde E. Banks
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, United Kingdom
| | - Joanne Brown
- Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, United Kingdom
| | - Balaji Venugopal
- Institute of Cancer Sciences, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
| | - Poulam Patel
- Division of Cancer & Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Ankit Jain
- The Royal Wolverhampton NHS Trust, Wolverhampton, United Kingdom
| | - Stefan N. Symeonides
- Edinburgh Cancer Centre, Western General Hospital, NHS Lothian, Edinburgh, United Kingdom
| | - Paul Nathan
- Mount Vernon Cancer Centre, Middlesex, United Kingdom
| | - Fiona J. Collinson
- Clinical Trials Research Unit, University of Leeds, Leeds, United Kingdom
| | - Thomas Powles
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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42
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Andresen NK, Røssevold AH, Quaghebeur C, Gilje B, Boge B, Gombos A, Falk RS, Mathiesen RR, Julsrud L, Garred Ø, Russnes HG, Lereim RR, Chauhan SK, Lingjærde OC, Dunn C, Naume B, Kyte JA. Ipilimumab and nivolumab combined with anthracycline-based chemotherapy in metastatic hormone receptor-positive breast cancer: a randomized phase 2b trial. J Immunother Cancer 2024; 12:e007990. [PMID: 38242720 PMCID: PMC10806573 DOI: 10.1136/jitc-2023-007990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/27/2023] [Indexed: 01/21/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitors have shown minimal clinical activity in hormone receptor-positive metastatic breast cancer (HR+mBC). Doxorubicin and low-dose cyclophosphamide are reported to induce immune responses and counter regulatory T cells (Tregs). Here, we report the efficacy and safety of combined programmed cell death protein-1/cytotoxic T-lymphocyte-associated protein 4 blockade concomitant with or after immunomodulatory chemotherapy for HR+mBC. METHODS Patients with HR+mBC starting first-/second- line chemotherapy (chemo) were randomized 2:3 to chemotherapy (pegylated liposomal doxorubicin 20 mg/m2 every second week plus cyclophosphamide 50 mg by mouth/day in every other 2-week cycle) with or without concomitant ipilimumab (ipi; 1 mg/kg every sixth week) and nivolumab (nivo; 240 mg every second week). Patients in the chemo-only arm were offered cross-over to ipi/nivo without chemotherapy. Co-primary endpoints were safety in all patients starting therapy and progression-free survival (PFS) in the per-protocol (PP) population, defined as all patients evaluated for response and receiving at least two treatment cycles. Secondary endpoints included objective response rate, clinical benefit rate, Treg changes during therapy and assessment of programmed death-ligand 1 (PD-L1), mutational burden and immune gene signatures as biomarkers. RESULTS Eighty-two patients were randomized and received immune-chemo (N=49) or chemo-only (N=33), 16 patients continued to the ipi/nivo-only cross-over arm. Median follow-up was 41.4 months. Serious adverse events occurred in 63% in the immune-chemo arm, 39% in the chemo-only arm and 31% in the cross-over-arm. In the PP population (N=78) median PFS in the immune-chemo arm was 5.1 months, compared with 3.6 months in the chemo-only arm, with HR 0.94 (95% CI 0.59 to 1.51). Clinical benefit rates were 55% (26/47) and 48% (15/31) in the immune-chemo and chemo-only arms, respectively. In the cross-over-arm (ipi/nivo-only), objective responses were observed in 19% of patients (3/16) and clinical benefit in 25% (4/16). Treg levels in blood decreased after study chemotherapy. High-grade immune-related adverse events were associated with prolonged PFS. PD-L1 status and mutational burden were not associated with ipi/nivo benefit, whereas a numerical PFS advantage was observed for patients with a high Treg gene signature in tumor. CONCLUSION The addition of ipi/nivo to chemotherapy increased toxicity without improving efficacy. Ipi/nivo administered sequentially to chemotherapy was tolerable and induced clinical responses. TRIAL REGISTRATION NUMBER ClinicalTrials.gov Identifier: NCT03409198.
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Affiliation(s)
- Nikolai Kragøe Andresen
- Department of Clinical Cancer Research and Department of Cancer Immunology, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Andreas Hagen Røssevold
- Department of Clinical Cancer Research and Department of Cancer Immunology, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Claire Quaghebeur
- Department of Oncology, CHU UCL Namur - Site Sainte-Elisabeth, Namur, Belgium
| | - Bjørnar Gilje
- Department of Hematology and Oncology, Stavanger University Hospital, Stavanger, Norway
| | - Beate Boge
- Center for Cancer Treatment, Sørlandet Hospital Kristiansand, Kristiansand, Norway
| | - Andrea Gombos
- Department of Medical Oncology, Institut Jules Bordet, Bruxelles, Belgium
| | - Ragnhild Sørum Falk
- Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway
| | | | - Lars Julsrud
- Department of Radiology and Nuclear medicine, Oslo University Hospital, Oslo, Norway
| | - Øystein Garred
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Hege G Russnes
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Pathology and Department of Cancer Genetics, Oslo University Hospital, Oslo, Norway
| | - Ragnhild Reehorst Lereim
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Sudhir Kumar Chauhan
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Ole Christian Lingjærde
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway
| | - Claire Dunn
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Bjørn Naume
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Jon Amund Kyte
- Department of Clinical Cancer Research and Department of Cancer Immunology, Oslo University Hospital, Oslo, Norway
- Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway
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Curkovic NB, Bai K, Ye F, Johnson DB. Incidence of Cutaneous Immune-Related Adverse Events and Outcomes in Immune Checkpoint Inhibitor-Containing Regimens: A Systematic Review and Meta-Analysis. Cancers (Basel) 2024; 16:340. [PMID: 38254829 PMCID: PMC10814132 DOI: 10.3390/cancers16020340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/19/2023] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) are used to treat many cancers, and cutaneous immune-related adverse events (cirAEs) are among the most frequently encountered toxic effects. Understanding the incidence and prognostic associations of cirAEs is of importance as their uses in different settings, combinations, and tumor types expand. To evaluate the incidence of cirAEs and their association with outcome measures across a variety of ICI regimens and cancers, we performed a systematic review and meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) ICIs, both alone and in combination with chemotherapy, antiangiogenic agents, or other ICIs in patients with melanoma, renal cell carcinoma, non-small cell lung cancer, and urothelial carcinoma. Key findings of our study include variable cirAE incidence among tumors and ICI regimens, positive association with increased cirAE incidence and response rate, as well as significant association between increased vitiligo incidence and overall survival. Across 174 studies, rash, pruritis, and vitiligo were the most reported cirAEs, with incidences of 16.7%, 18.0%, and 6.6%, respectively. Higher incidence of cirAEs was associated with ICI combination regimens and with CTLA-4-containing regimens, particularly with higher doses of ipilimumab, as compared to PD-1/L1 monotherapies. Outcome measures including response rate and progression-free survival were positively correlated with incidence of cirAEs. The response rate and incidence of pruritis, vitiligo, and rash were associated with expected rises in incidence of 0.17% (p = 0.0238), 0.40% (p = 0.0010), and 0.18% (p = 0.0413), respectively. Overall survival was positively correlated with the incidence of pruritis, vitiligo, and rash; this association was significant for vitiligo (p = 0.0483). Our analysis provides benchmark incidence rates for cirAEs and links cirAEs with favorable treatment outcomes at a study level across diverse solid tumors and multiple ICI regimens.
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Affiliation(s)
- Nina B. Curkovic
- School of Medicine, Vanderbilt University, Nashville, TN 37232, USA
| | - Kun Bai
- Vanderbilt Ingram Cancer Center, Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Fei Ye
- Vanderbilt Ingram Cancer Center, Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Vanderbilt Ingram Cancer Center, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
| | - Douglas B. Johnson
- Vanderbilt Ingram Cancer Center, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
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44
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LIU Y, MIAO J. [Progress of Immunotherapy in EGFR-mutated Advanced Non-small Cell Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2024; 26:934-942. [PMID: 38163979 PMCID: PMC10767652 DOI: 10.3779/j.issn.1009-3419.2023.106.26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Indexed: 01/03/2024]
Abstract
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are currently the first-line standard of care for patients with non-small cell lung cancer (NSCLC) that harbor EGFR mutations. Nevertheless, resistance to EGFR-TKIs is inevitable. In recent years, although immune checkpoint inhibitors (ICIs) have significantly shifted the treatment paradigm in advanced NSCLC without driver mutation, clinical benefits of these agents are limited in patients with EGFR-mutated NSCLC. Compared with wild-type tumors, tumors with EGFR mutations show more heterogeneity in the expression level of programmed cell death ligand 1 (PD-L1), tumor mutational burden (TMB), and other tumor microenvironment (TME) characteristics. Whether ICIs are suitable for NSCLC patients with EGFR mutations is still worth exploring. In this review, we summarized the clinical data with regard to the efficacy of ICIs in patients with EGFR-mutated NSCLC and deciphered the unique TME in EGFR-mutated NSCLC.
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Chen JJ, Lee TH, Kuo G, Yen CL, Lee CC, Chang CH, Tu KH, Chen YC, Fang JT, Hung CC, Yang CW, Chou WC, Chi CC, Tu YK, Yu Yang H. All-cause and immune checkpoint inhibitor-associated acute kidney injury in immune checkpoint inhibitor users: a meta-analysis of occurrence rate, risk factors and mortality. Clin Kidney J 2024; 17:sfad292. [PMID: 38186874 PMCID: PMC10768773 DOI: 10.1093/ckj/sfad292] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Indexed: 01/09/2024] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) have been associated with acute kidney injury (AKI). However, the occurrence rate of ICI-related AKI has not been systematically examined. Additionally, exposure to proton pump inhibitors (PPIs) and non-steroidal anti-inflammatory drugs (NSAIDs) were considered as risk factors for AKI, but with inconclusive results in ICI-related AKI. Our aim was to analyse the occurrence rate of all-cause AKI and ICI-related AKI and the occurrence rates of severe AKI and dialysis-requiring AKI, and to determine whether exposure to PPIs and NSAIDs poses a risk for all-cause and ICI-related AKI. Methods This study population was adult ICI recipients. A systematic review was conducted by searching MEDLINE, Embase and PubMed through October 2023. We included prospective trials and observational studies that reported any of the following outcomes: the occurrence rate of all-cause or ICI-related AKI, the relationship between PPI or NSAID exposure and AKI development or the mortality rate in the AKI or non-AKI group. Proportional meta-analysis and pairwise meta-analysis were performed. The evidence certainty was assessed using the Grading of Recommendations Assessment, Development and Evaluation framework. Results A total of 120 studies comprising 46 417 patients were included. The occurrence rates of all-cause AKI were 7.4% (14.6% from retrospective studies and 1.2% from prospective clinical trials). The occurrence rate of ICI-related AKI was 3.2%. The use of PPIs was associated with an odds ratio (OR) of 1.77 [95% confidence interval (CI) 1.43-2.18] for all-cause AKI and an OR of 2.42 (95% CI 1.96-2.97) for ICI-related AKI. The use of NSAIDs was associated with an OR of 1.77 (95% CI 1.10-2.83) for all-cause AKI and an OR of 2.57 (95% CI 1.68-3.93) for ICI-related AKI. Conclusions Our analysis revealed that approximately 1 in 13 adult ICI recipients may experience all-cause AKI, while 1 in 33 adult ICI recipients may experience ICI-related AKI. Exposure to PPIs and NSAIDs was associated with an increased OR risk for AKI in the current meta-analysis.
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Affiliation(s)
- Jia-Jin Chen
- Kidney Research Center, Nephrology Department, Chang Gung Memorial Hospital in Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Tao-Han Lee
- Nephrology Department, Chansn Hospital, Taoyuan City, Taiwan
| | - George Kuo
- Kidney Research Center, Nephrology Department, Chang Gung Memorial Hospital in Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chieh-Li Yen
- Kidney Research Center, Nephrology Department, Chang Gung Memorial Hospital in Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Cheng-Chia Lee
- Kidney Research Center, Nephrology Department, Chang Gung Memorial Hospital in Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chih-Hsiang Chang
- Kidney Research Center, Nephrology Department, Chang Gung Memorial Hospital in Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Kun-Hua Tu
- Kidney Research Center, Nephrology Department, Chang Gung Memorial Hospital in Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Yung-Chang Chen
- Kidney Research Center, Nephrology Department, Chang Gung Memorial Hospital in Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Ji-Tseng Fang
- Kidney Research Center, Nephrology Department, Chang Gung Memorial Hospital in Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Cheng-Chieh Hung
- Kidney Research Center, Nephrology Department, Chang Gung Memorial Hospital in Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chih-Wei Yang
- Kidney Research Center, Nephrology Department, Chang Gung Memorial Hospital in Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Wen-Chi Chou
- Department of Hematology and Oncology, Chang Gung Memorial Hospital in Linkou and College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ching-Chi Chi
- School of Medicine, College of Medicine, Chang Gung University; Department of Dermatology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
| | - Yu-Kang Tu
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Huang- Yu Yang
- Kidney Research Center, Nephrology Department, Chang Gung Memorial Hospital in Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
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Nishi W, Wakamatsu E, Machiyama H, Matsushima R, Yoshida Y, Nishikawa T, Toyota H, Furuhata M, Nishijima H, Takeuchi A, Suzuki M, Yokosuka T. Molecular Imaging of PD-1 Unveils Unknown Characteristics of PD-1 Itself by Visualizing "PD-1 Microclusters". ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1444:197-205. [PMID: 38467981 DOI: 10.1007/978-981-99-9781-7_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Abstract
Programmed cell death-1 (PD-1) is one of the most famous coinhibitory receptors that are expressed on effector T cells to regulate their function. The PD-1 ligands, PD-L1 and PD-L2, are expressed by various cells throughout the body at steady state and their expression was further regulated within different pathological conditions such as tumor-bearing and chronic inflammatory diseases. In recent years, immune checkpoint inhibitor (ICI) therapies with anti-PD-1 or anti-PD-L1 has become a standard treatment for various malignancies and has shown remarkable antitumor effects. Since the discovery of PD-1 in 1992, a huge number of studies have been conducted to elucidate the function of PD-1. Herein, this paper provides an overview of PD-1 biological findings and sheds some light on the current technology for molecular imaging of PD-1.
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Affiliation(s)
- Wataru Nishi
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Department of Immunology, Tokyo Medical University, Tokyo, Japan
| | - Ei Wakamatsu
- Department of Immunology, Tokyo Medical University, Tokyo, Japan
| | | | - Ryohei Matsushima
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
- Department of Immunology, Tokyo Medical University, Tokyo, Japan
| | - Yosuke Yoshida
- Department of Immunology, Tokyo Medical University, Tokyo, Japan
- Department of Nephrology, Tokyo Medical University, Tokyo, Japan
| | - Tetsushi Nishikawa
- Department of Immunology, Tokyo Medical University, Tokyo, Japan
- Department of Dermatology, Tokyo Medical University, Tokyo, Japan
| | - Hiroko Toyota
- Department of Immunology, Tokyo Medical University, Tokyo, Japan
| | - Masae Furuhata
- Department of Immunology, Tokyo Medical University, Tokyo, Japan
| | | | - Arata Takeuchi
- Department of Immunology, Tokyo Medical University, Tokyo, Japan
| | - Makoto Suzuki
- Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Tadashi Yokosuka
- Department of Immunology, Tokyo Medical University, Tokyo, Japan.
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47
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Harrington KJ, Haddad R. Assessing Response for Nivolumab Plus Ipilimumab in Squamous Cell Carcinoma of the Head and Neck-Reply. JAMA Oncol 2024; 10:144-145. [PMID: 37991775 DOI: 10.1001/jamaoncol.2023.5407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2023]
Affiliation(s)
- Kevin J Harrington
- Royal Marsden Hospital/The Institute of Cancer Research NIHR Biomedical Research Centre, London, United Kingdom
| | - Robert Haddad
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
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48
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Gupta MK, Vadde R. Delivery strategies of immunotherapies in the treatment of pancreatic cancer. IMMUNE LANDSCAPE OF PANCREATIC CANCER DEVELOPMENT AND DRUG RESISTANCE 2024:173-202. [DOI: 10.1016/b978-0-443-23523-8.00004-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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49
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Stockem CF, Galsky MD, van der Heijden MS. Turning up the heat: CTLA4 blockade in urothelial cancer. Nat Rev Urol 2024; 21:22-34. [PMID: 37608154 DOI: 10.1038/s41585-023-00801-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/07/2023] [Indexed: 08/24/2023]
Abstract
Anti-PD1 and anti-PDL1 monotherapies have shown clinical efficacy in stage IV urothelial cancer and are integrated into current clinical practice. However, only a small number of the patients treated with single-agent checkpoint blockade experience an antitumour response. Insufficient priming or inhibitory factors in the tumour immune microenvironment might have a role in the lack of response. CTLA4 is an inhibitory checkpoint on activated T cells that is being studied as a therapeutic target in combination with anti-PD1 or anti-PDL1 therapies in advanced urothelial cancer. In locally advanced urothelial cancer, this combination approach has shown encouraging antitumour effects when administered pre-operatively. We believe that the presence of pre-existing intratumoural T cell immunity is not a prerequisite for response to combination therapy and that the additional value of CTLA4 blockade might involve the broadening of peripheral T cell priming, thereby transforming immunologically cold tumours into hot tumours.
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Affiliation(s)
- Chantal F Stockem
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Matthew D Galsky
- Department of Genitourinary Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
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50
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Ying K, Zou L, Wang D, Wang R, Qian J. Co-mutation of TP53 and TTN is Correlated with the Efficacy of Immunotherapy in Lung Squamous Cell Carcinoma. Comb Chem High Throughput Screen 2024; 27:2699-2711. [PMID: 37904553 DOI: 10.2174/0113862073246841230922052004] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 08/18/2023] [Accepted: 08/23/2023] [Indexed: 11/01/2023]
Abstract
BACKGROUND Immunotherapy has been a promising treatment in advanced lung cancer. However, only a few patients could benefit from it. Herein, we aimed to explore mutationrelated predictive biomarkers in lung squamous cell carcinoma (LUSC), which could help develop clinical immunotherapy strategies and screen beneficial populations. METHODS Co-occurrence and mutually exclusive analysis was conducted on the TCGA-LUSC cohort. Correlations between the gene mutation status and tumor mutation burden (TMB) levels, and neo-antigen levels were analyzed by Wilcoxon test. Kaplan-Meier method was employed to analyze the progression-free survival (PFS) of lung cancer patients with immunotherapy. Gene set enrichment analysis (GSEA) was used to investigate the functional changes affected by TP53mut/TTNmut. The immune cell infiltration landscape in co-mutation subgroups was analyzed using CIBERSORT. RESULTS 1) TP53, TTN, CSMD3, MUC16, RYR2, LRP1B, USH2A, SYNE1, ZFHX4, FAM135B, KMT2D, and NAV3 were frequently mutated in LUSC patients. 2) TMB levels in highly mutated groups were higher than that in wild type groups. 3) There were higher neoantigen levels in mutation group compared to the wild-type group, and LUSC patients in mutation group had longer PFS. 4) TP53mut/TTNmut co-mutation group exhibited higher TMB levels and better response to immunotherapy. 5) A host of immune-related signaling pathways was inhibited in TP53mut/TTNmut subgroup. 6) There were more T follicular helper cells and NK cells were in TP53mut/TTNmut subgroup than in the WT subgroup. CONCLUSION The LUSC patients with TP53 and TTN co-mutation had higher TMB levels and better response to immunotherapy. The TP53 and TTN co-mutation is a promising novel biomarker to assist LUSC immunotherapy evaluation.
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Affiliation(s)
- Kaijun Ying
- Department of Thoracic Surgery, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, Jiangsu Province, 224005, China
| | - Li Zou
- Department of Oncology, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, Jiangsu Province, 224005, China
| | - Daquan Wang
- Department of Thoracic Surgery, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, Jiangsu Province, 224005, China
| | - Rao Wang
- Department of Thoracic Surgery, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, Jiangsu Province, 224005, China
| | - Jun Qian
- Department of Thoracic Surgery, The Yancheng Clinical College of Xuzhou Medical University, The First People's Hospital of Yancheng, Yancheng, Jiangsu Province, 224005, China
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