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Li G, Che X, Wang S, Liu D, Xie D, Jiang B, Zheng Z, Zheng X, Wu G. The role of cisplatin in modulating the tumor immune microenvironment and its combination therapy strategies: a new approach to enhance anti-tumor efficacy. Ann Med 2025; 57:2447403. [PMID: 39757995 PMCID: PMC11705547 DOI: 10.1080/07853890.2024.2447403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 05/27/2024] [Accepted: 11/23/2024] [Indexed: 01/07/2025] Open
Abstract
Cisplatin is a platinum-based drug that is frequently used to treat multiple tumors. The anti-tumor effect of cisplatin is closely related to the tumor immune microenvironment (TIME), which includes several immune cell types, such as the tumor-associated macrophages (TAMs), cytotoxic T-lymphocytes (CTLs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and natural killer (NK) cells. The interaction between these immune cells can promote tumor survival and chemoresistance, and decrease the efficacy of cisplatin monotherapy. Therefore, various combination treatment strategies have been devised to enhance patient responsiveness to cisplatin therapy. Cisplatin can augment anti-tumor immune responses in combination with immune checkpoint blockers (such as PD-1/PD-L1 or CTLA4 inhibitors), lipid metabolism disruptors (like FASN inhibitors and SCD inhibitors) and nanoparticles (NPs), resulting in better outcomes. Exploring the interaction between cisplatin and the TIME will help identify potential therapeutic targets for improving the treatment outcomes in cancer patients.
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Affiliation(s)
- Guandu Li
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Xiangyu Che
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Shijin Wang
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Dequan Liu
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Deqian Xie
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Bowen Jiang
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Zunwen Zheng
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Xu Zheng
- Department of Cell Biology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, China
| | - Guangzhen Wu
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
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2
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Hashimoto K, Nishimura S, Goto K. PD‑1/PD‑L1 immune checkpoint in bone and soft tissue tumors (Review). Mol Clin Oncol 2025; 22:31. [PMID: 39989606 PMCID: PMC11843085 DOI: 10.3892/mco.2025.2826] [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: 12/08/2024] [Accepted: 01/22/2025] [Indexed: 02/25/2025] Open
Abstract
Anti-programmed cell death 1 (PD-1)/PD-1 ligand-1 (PD-L1) drugs have been used clinically, including those for skin cancer, with reasonable efficacy. Despite extensive ongoing research on bone and soft tissue sarcomas, there is a paucity of reviews that present a coherent picture. The present article is a comprehensive narrative review on the role of the PD-1/PD-L1 immune checkpoint in bone and soft tissue tumors. The review outlines the biological functions and mechanisms of action of PD-1/PD-L1 and its expression and clinical significance in various tumor types, including osteosarcoma and soft tissue sarcoma. Clinical trial results of immune checkpoint inhibitors, their association with prognosis, mechanisms of resistance to therapy, immune-related adverse events, and their potential in combination therapies, were also discussed.
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Affiliation(s)
- Kazuhiko Hashimoto
- Department of Orthopedic Surgery, Kindai University Hospital, Osaka-Sayama, Osaka 589-8511, Japan
| | - Shunji Nishimura
- Department of Orthopedic Surgery, Kindai University Hospital, Osaka-Sayama, Osaka 589-8511, Japan
| | - Koji Goto
- Department of Orthopedic Surgery, Kindai University Hospital, Osaka-Sayama, Osaka 589-8511, Japan
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Chen J, Ma N, Chen B, Huang Y, Li J, Li J, Chen Z, Wang P, Ran B, Yang J, Bai J, Ning S, Ai J, Wei Q, Liu L, Cao D. Synergistic effects of immunotherapy and adjunctive therapies in prostate cancer management. Crit Rev Oncol Hematol 2025; 207:104604. [PMID: 39732304 DOI: 10.1016/j.critrevonc.2024.104604] [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: 11/15/2024] [Revised: 12/14/2024] [Accepted: 12/20/2024] [Indexed: 12/30/2024] Open
Abstract
In recent years, cancer immunotherapy has received widespread attention due to significant tumor clearance in some malignancies. Various immunotherapy approaches, including vaccines, immune checkpoint inhibitors, oncolytic virotherapy, bispecific T cell engagers, and adoptive T cell transfer, have completed or are undergoing clinical trials for prostate cancer. Despite immune checkpoint blockade's extraordinary effectiveness in treating a variety of cancers, targeted prostate cancer treatment using the immune system is still in its infancy. Multiple factors including the heterogeneity of prostate cancer, the cold tumor microenvironment, and a low level of neoantigens, contribute to the poor immunotherapy response. Significant effort is being devoted to improving immune-based prostate cancer therapy. Recently, several key discoveries demonstrate that prostate cancer immunotherapy agents may be used to promise better prognosis for patients as part of combination strategies with other agents targeting tumor-associated immune mechanism of resistance. Here, this review comprehensively examines the recent advancements in immunotherapy for prostate cancer, exploring its potential synergistic effects when combined with other treatment modalities to enhance clinical efficacy.
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Affiliation(s)
- Jie Chen
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Na Ma
- Department of Pediatrics, West China Second University Hospital, Sichuan University, No. 20, 3rd section, South Renmin Road, Chengdu 610041, China
| | - Bo Chen
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yin Huang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jinze Li
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jin Li
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zeyu Chen
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Puze Wang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Biao Ran
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jiahao Yang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jingxing Bai
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Shu Ning
- Department of Urologic Surgery, University of California Davis, Davis, CA, USA
| | - Jianzhong Ai
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qiang Wei
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Liangren Liu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Dehong Cao
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China.
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Gaillard S, Verma N, Berg M, Harrison J, Huang P, Leatherman JM, Doucet M, Sen R, Suru A, Cai H, Durham J, Jelovac D, Cimino-Mathews A, Cherry C, Ganguly S, Emens LA. A clinical study of tremelimumab, alone or in combination with olaparib, for recurrent epithelial ovarian cancer. Gynecol Oncol 2025; 194:41-47. [PMID: 39951918 DOI: 10.1016/j.ygyno.2025.01.015] [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: 12/17/2024] [Revised: 01/30/2025] [Accepted: 01/31/2025] [Indexed: 02/17/2025]
Abstract
OBJECTIVE PARP inhibitors may work synergistically to improve the efficacy of immunotherapy in patients with epithelial ovarian cancer (EOC). We performed a parallel-arm study of tremelimumab, alone or with olaparib, in patients with recurrent EOC. METHODS Eligibility criteria included measurable disease and progression <12 months from last platinum. Participants were randomized to Arm A (tremelimumab monotherapy, 10 mg/kg/dose intravenously [IV]) or Arm B (dose level 1 [DL1] olaparib orally 150 mg twice daily with tremelimumab IV 3 mg/kg/dose and DL2 olaparib orally 150 mg twice daily with tremelimumab IV 10 mg/kg/dose). Primary objectives were safety, change in peripheral ICOS+ T cells, and identification of optimal dose combination. RESULTS Among 24 total patients (12 on Arm A, 6 on Arm B-DL1, 6 on Arm B-DL2), the most common grade 3 toxicities were rash (13 %), immune-mediated hepatitis (8 %), and colitis (8 %). No grade ≥ 4 toxicities were identified. No dose-limiting toxicities were identified. One patient (Arm B-DL2) experienced a partial response; no complete responses were observed. Ten patients (7 on Arm A, 2 on Arm B-DL2, and 1 on Arm B-DL1) had a best response of stable disease. There was a significant increase in CD4+ICOS+ and CD8+ICOS+ T cells at both C1D15 and C1D22 in groups treated with tremelimumab IV 10 mg/kg/dose, but not in those treated with tremelimumab 3 mg/kg/dose. CONCLUSIONS Tremelimumab IV 10 mg/kg/dose with olaparib 150 mg orally twice daily was safe and feasible. Tremelimumab 10 mg/kg/dose (as opposed to 3 mg/kg/dose) was required for immune activation, although this did not translate into clinical responses.
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Affiliation(s)
- Stéphanie Gaillard
- Department of Oncology Johns Hopkins School of Medicine, Baltimore, MD, United States of America; Department of Gynecology and Obstetrics Division of Gynecologic Oncology, Johns Hopkins School of Medicine, Baltimore, MD, United States of America.
| | - Neha Verma
- Department of Oncology Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Maureen Berg
- Department of Oncology Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Jeanne Harrison
- Department of Oncology Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Peng Huang
- Department of Oncology Division of Biostatistics and Bioinformatics, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - James M Leatherman
- Department of Oncology Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Michele Doucet
- Department of Oncology Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Rupashree Sen
- Department of Oncology Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Aditya Suru
- Department of Oncology Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Hongyan Cai
- Department of Oncology Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Jennifer Durham
- Department of Oncology Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Danijela Jelovac
- Department of Oncology Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Ashley Cimino-Mathews
- Department of Oncology Johns Hopkins School of Medicine, Baltimore, MD, United States of America; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Christopher Cherry
- Department of Oncology Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Sudipto Ganguly
- Department of Oncology Johns Hopkins School of Medicine, Baltimore, MD, United States of America
| | - Leisha A Emens
- Department of Oncology Johns Hopkins School of Medicine, Baltimore, MD, United States of America
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5
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Boehm DT, Landreth KM, Kilic ES, Lee KS, Misra B, Bobbala S, Damron FH, Liu TW. Intratumoral administration of mRNA COVID-19 vaccine delays melanoma growth in mice. Sci Rep 2025; 15:5337. [PMID: 39948424 PMCID: PMC11825918 DOI: 10.1038/s41598-025-89930-0] [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: 08/29/2024] [Accepted: 02/10/2025] [Indexed: 02/16/2025] Open
Abstract
Immunotherapies are effective for cancer treatment but are limited in 'cold' tumor microenvironments due to a lack of infiltrating CD8+ T cells, key players in the anti-cancer immune response. The onset of the COVID-19 pandemic sparked the widespread use of mRNA-formulated vaccines and is well documented that vaccination induces a Th1-skewed immune response. Here, we evaluated the effects of an intratumoral injection of the mRNA COVID-19 vaccine in subcutaneous melanoma tumor mouse models. Tumor growth and survival studies following a single intratumoral injection of the COVID-19 vaccine showed significant tumor suppression and prolonged survival in established B16F10 subcutaneous tumor-bearing mice. mRNA vaccine treatment resulted in a significant increase in CD8+ T cell infiltration into the tumor microenvironment, as observed using intravital imaging and flow cytometry. Further tumor growth suppression was achieved using additional mRNA vaccine treatments. Combination administration of mRNA vaccine with immune checkpoint therapies demonstrated enhanced effects, further delaying tumor growth and improving the survival time of tumor-bearing mice. This study demonstrates that mRNA vaccines may be used as adjuvants for immunotherapies.
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Affiliation(s)
- Dylan T Boehm
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, 64 Medical Center Drive, Morgantown, WV, 26506, USA
- Vaccine Development Center at West Virginia University Health Sciences Center, Morgantown, WV, USA
| | - Kaitlyn M Landreth
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, 64 Medical Center Drive, Morgantown, WV, 26506, USA
| | - Emel Sen Kilic
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, 64 Medical Center Drive, Morgantown, WV, 26506, USA
- Vaccine Development Center at West Virginia University Health Sciences Center, Morgantown, WV, USA
| | - Katherine S Lee
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, 64 Medical Center Drive, Morgantown, WV, 26506, USA
- Vaccine Development Center at West Virginia University Health Sciences Center, Morgantown, WV, USA
| | - Bishal Misra
- Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, 26506, USA
| | - Sharan Bobbala
- Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, 26506, USA
| | - F Heath Damron
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, 64 Medical Center Drive, Morgantown, WV, 26506, USA
- Vaccine Development Center at West Virginia University Health Sciences Center, Morgantown, WV, USA
| | - Tracy W Liu
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University, 64 Medical Center Drive, Morgantown, WV, 26506, USA.
- WVU Cancer Institute, West Virginia University, Morgantown, WV, 26506, USA.
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Kanayama M, Manabe T, Yoshimatsu K, Oyama R, Matsumiya H, Mori M, Takenaka M, Kuroda K, Tanaka F. Immune checkpoint inhibitors in the treatment of pleural mesothelioma: insights from real-world data. Int J Clin Oncol 2025:10.1007/s10147-025-02706-4. [PMID: 39937425 DOI: 10.1007/s10147-025-02706-4] [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: 08/31/2024] [Accepted: 01/09/2025] [Indexed: 02/13/2025]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have recently emerged as a promising strategy for the treatment of pleural mesothelioma (PM). METHODS This retrospective study evaluated treatment efficacy and safety in Japanese patients with PM treated with nivolumab and ipilimumab (N + I group: 41 patients) as first-line therapy and nivolumab monotherapy (N group: 33 patients) as second- or later-line treatment. RESULTS The median overall survival (OS) and progression-free survival (PFS) were not reached and 10.4 months in the N + I group, and 8.6 months and 3.5 months in the N group, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 68.3% of the N + I group and 72.7% of the N group, with grade 3-4 TRAEs in 19.5% and 12.1% of patients, respectively. Patients with an ECOG PS 0-1 had significantly better OS and PFS in both treatment groups (p < 0.001). In the N + I group, OS was significantly better in patients with TRAEs (p = 0.020) and in those with the epithelioid subtype (p = 0.047), although PFS was not significantly different (p = 0.138 and p = 0.154, respectively). In the N group, both OS (p = 0.007) and PFS (p = 0.048) were significantly longer in patients with TRAEs. CONCLUSION This study provides valuable real-world clinical evidence of the efficacy and safety of nivolumab plus ipilimumab and nivolumab monotherapy in Japanese patients with PM. These results support the use of ICIs as a viable treatment option for advanced or relapsed disease.
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Affiliation(s)
- Masatoshi Kanayama
- Second Department of Surgery, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
| | - Takehiko Manabe
- Second Department of Surgery, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Katsuma Yoshimatsu
- Second Department of Surgery, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Rintaro Oyama
- Second Department of Surgery, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Hiroki Matsumiya
- Second Department of Surgery, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Masataka Mori
- Second Department of Surgery, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Masaru Takenaka
- Second Department of Surgery, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Koji Kuroda
- Second Department of Surgery, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Fumihiro Tanaka
- Second Department of Surgery, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
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7
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Guan P, Jin F, Zhang A, Gao S, Liu Z. Rationally Engineered Bispecific Nanoimmunoblocker Restores Anticancer Immunity via Dual Immune Checkpoint Blockade. ACS NANO 2025; 19:5392-5405. [PMID: 39887132 DOI: 10.1021/acsnano.4c13463] [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: 02/01/2025]
Abstract
Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment. However, the outcomes of mainstay antibody inhibitors against solid tumors remain poor, facing tremendous challenges including manufacturing complexities, serious toxicities, and crosstalk among multiple checkpoints. Herein, we present a bispecific molecularly imprinted nanoimmunoblocker (bsMINIB) designed to boost potent antitumor immunity via synchronously blocking innate and adaptive immune checkpoints. Two epitopes for PD-L1 and SIRPα are selected as templates through structural analysis, and thereafter, bsMINIB capable of bridging tumor cells and macrophages is rationally engineered via an advanced imprinting approach. The bsMINIB exhibits high affinity and specificity toward PD-L1 on solid tumor cells and SIRPα on macrophages, allowing effective disruption of both PD-L1/PD-1 and CD47/SIRPα signaling. These signal disruptions restore macrophage-mediated tumor phagocytosis, promote tumor-associated antigen presentation, and reinvigorate T cell-mediated tumor killing. Using refractory triple-negative breast cancer as a solid tumor model, the bsMINIB demonstrates extended retention at the tumor site, amplified infiltration of active T cells, and reactivated antitumor macrophages, thereby effectively inhibiting tumor growth. This biomimetic nanoimmunoblocker not only presents an effective multipronged ICB therapeutic against solid tumors but also showcases a compelling paradigm for the rational engineering of bispecific nanoplatforms for synergistic immunotherapy through molecular imprinting.
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Affiliation(s)
- Peixin Guan
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China
| | - Fang Jin
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China
| | - Anqi Zhang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China
| | - Song Gao
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China
| | - Zhen Liu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China
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8
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Wu Z, Sun W, He B, Wang C. Clinical characteristics, treatment, and outcomes of nivolumab-induced uveitis. Immunopharmacol Immunotoxicol 2025:1-6. [PMID: 39885372 DOI: 10.1080/08923973.2025.2461056] [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: 11/01/2024] [Accepted: 01/26/2025] [Indexed: 02/01/2025]
Abstract
BACKGROUND Nivolumab has been linked to occurrences of uveitis, yet the clinical features associated with these episodes remain unclear. This study aimed to explore the clinical characteristics of uveitis induced by nivolumab and to offer guidance for its prevention, diagnosis, and treatment. METHODS We conducted a retrospective analysis by gathering case reports related to nivolumab-induced uveitis from both Chinese and English databases, covering the period from inception until 30 September 2024. RESULTS A total of 38 patients with uveitis were included, with a median age of 63 years (range 35 and 92). The onset of uveitis occurred between 1 week and 24 months post-administration, with a median onset time of 1.4 months. Blurred vision was the primary complaint among patients. Sixteen patients (42.1%) exhibited uveitis resembling Vogt-Koyanagi-Harada (VKH) disease. Bilateral uveitis was the most prevalent form (89.2%), followed by unilateral uveitis (8.1%). Anterior uveitis was the most frequently observed type (52.6%), succeeded by posterior uveitis (23.7%), panuveitis (21.1%), and intermediate uveitis (2.6%). Uveitis showed significant improvement or resolution following treatment with topical or systemic corticosteroids, with a median improvement time of 4 weeks post-therapy. CONCLUSIONS Uveitis is a relatively uncommon adverse effect of nivolumab, typically manifesting within 5 months of treatment. Prompt recognition of nivolumab-induced uveitis and appropriate management are crucial, as most cases are treatable.
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Affiliation(s)
- Zhaoquan Wu
- College of Pharmacy, Changsha Medical University, Changsha, Hunan, China
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, Hunan, China
| | - Wei Sun
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Binsheng He
- College of Pharmacy, Changsha Medical University, Changsha, Hunan, China
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, Hunan, China
| | - Chunjiang Wang
- College of Pharmacy, Changsha Medical University, Changsha, Hunan, China
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, Hunan, China
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9
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Chen G, Sun DC, Ba Y, Zhang YX, Zhou T, Zhao YY, Zhao HY, Fang WF, Huang Y, Wang Z, Deng C, Hu DS, Wang W, Lin JG, Li GL, Luo SX, Fu ZC, Zhu HS, Wang HL, Cai SL, Kang XQ, Zhang L, Yang YP. Anti-LAG-3 antibody LBL-007 plus anti-PD-1 antibody toripalimab in advanced nasopharyngeal carcinoma and other solid tumors: an open-label, multicenter, phase Ib/II trial. J Hematol Oncol 2025; 18:15. [PMID: 39920751 PMCID: PMC11806529 DOI: 10.1186/s13045-025-01666-6] [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: 11/10/2024] [Accepted: 01/25/2025] [Indexed: 02/09/2025] Open
Abstract
PURPOSE Open-label phase Ib/II study to investigate the safety and efficacy of LBL-007, an anti-LAG-3 antibody, plus toripalimab, an anti-PD-1 antibody, in patients with previously treated advanced nasopharyngeal carcinoma (NPC) and other solid tumors. METHODS Patients with advanced tumors refractory to prior standard therapies were enrolled. In phase Ib, patients received LBL-007 200 mg or 400 mg and toripalimab 240 mg intravenously once every 3 weeks. In phase II, all patients received LBL-007 at the recommended phase II dose (RP2D) and toripalimab 240 mg intravenously once every 3 weeks. The primary end points were safety in phase Ib and objective response rate (ORR) in phase II. The exploratory end point was the predictive capability of LAG-3 and PD-L1 expression for efficacy. RESULTS Between November 30, 2021, and December 1, 2023, 80 patients were enrolled, including 30 (37.5%) with NPC and 50 (62.5%) with other tumors. Median follow-up was 26.0 months. In Phase Ib, LBL-007 was administered at 200 mg to four patients and 400 mg to six patients, with no dose-limiting toxicities observed. Therefore, the 400 mg dose of LBL-007 was established as the RP2D and administered to 70 patients in phase II. Nine (11.3%) of 80 patients had grade 3 or 4 treatment-related adverse events, the most common of which included anemia (2.5%), hyponatremia (2.5%), increased alanine aminotransferase (2.5%), increased aspartate aminotransferase (1.3%), and fatigue (1.3%). Eight patients (10.0%) had treatment-related serious adverse events. No treatment-related deaths were reported. In immunotherapy-naive NPC patients (n = 12), ORR was 33.3%, disease control rate (DCR) was 75%, and median progression-free survival (PFS) was 10.8 months (95% CI, 1.3 to not estimated). In IO-treated NPC patients (n = 17), ORR was 11.8%, DCR was 64.7%, and median PFS was 2.7 months (95% CI, 1.4 to 4.9). For other tumors, ORRs were 15.8% in immunotherapy-naive patients and 3.7% in immunotherapy-treated patients. Patients with ≥ 2 + LAG-3 expression had a higher ORR of 28.0%, compared to 7.7% in those with < 2 + LAG-3 expression. CONCLUSION LBL-007 plus toripalimab exhibited a manageable safety profile in patients with advanced solid tumors and demonstrated promising antitumor activity in NPC, especially in immunotherapy-naive patients. These findings warrant further validation in future studies.
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Affiliation(s)
- Gang Chen
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Dongfeng East Road 651, Guangzhou, 510060, Guangdong, P.R. China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Dong-Chen Sun
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Dongfeng East Road 651, Guangzhou, 510060, Guangdong, P.R. China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Yi Ba
- Department of Gastrointestinal Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, P.R. China
| | - Ya-Xiong Zhang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Dongfeng East Road 651, Guangzhou, 510060, Guangdong, P.R. China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Ting Zhou
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Dongfeng East Road 651, Guangzhou, 510060, Guangdong, P.R. China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Yuan-Yuan Zhao
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Dongfeng East Road 651, Guangzhou, 510060, Guangdong, P.R. China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Hong-Yun Zhao
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Department of Clinical Research, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Wen-Feng Fang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Dongfeng East Road 651, Guangzhou, 510060, Guangdong, P.R. China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Yan Huang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Dongfeng East Road 651, Guangzhou, 510060, Guangdong, P.R. China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Zhen Wang
- Department of Oncology, Linyi Cancer Hospital, Linyi, P.R. China
| | - Chao Deng
- Cancer Center, Chong Qing University Three Gorges Hospital, Chongqing, P.R. China
| | - De-Sheng Hu
- Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, P.R. China
| | - Wei Wang
- Hunan Cancer Hospital, Changsha, P.R. China
| | | | - Gui-Ling Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Su-Xia Luo
- Department of Oncology, Henan Cancer Hospital, Zhengzhou, P.R. China
| | - Zhi-Chao Fu
- Department of Radiotherapy, No. 900 Hospital of the PLA Joint Logistics Support Force, Fuzhou, P.R. China
| | - Hai-Sheng Zhu
- Department of Oncology, The First People's Hospital of Yulin, Yulin, P.R. China
| | - Hui-Li Wang
- Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, China
| | - Sheng-Li Cai
- Nanjing Leads Biolabs Co., Ltd., Nanjing, P.R. China
| | | | - Li Zhang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Dongfeng East Road 651, Guangzhou, 510060, Guangdong, P.R. China
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Yun-Peng Yang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Dongfeng East Road 651, Guangzhou, 510060, Guangdong, P.R. China.
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China.
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10
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Xu J, Zhang H, Nie Z, He W, Zhao Y, Huang Z, Jia L, Du Z, Zhang B, Xia S. Cancer stem-like cells stay in a plastic state ready for tumor evolution. Neoplasia 2025; 61:101134. [PMID: 39919692 DOI: 10.1016/j.neo.2025.101134] [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: 08/01/2024] [Accepted: 01/31/2025] [Indexed: 02/09/2025]
Abstract
Cell plasticity emerges as a novel cancer hallmark and is pivotal in driving tumor heterogeneity and adaptive resistance to different therapies. Cancer stem-like cells (CSCs) are considered the root of cancer. While first defined as tumor-initiating cells with the potential to develop a heterogeneous tumor, CSCs further demonstrate their roles in cancer metastasis and adaptive therapeutic resistance. Generally, CSCs come from the malignant transformation of somatic stem cells or the de-differentiation of other cancer cells. The resultant cells gain more plasticity and are ready to differentiate into different cell states, enabling them to adapt to therapies and metastatic ecosystems. Therefore, CSCs are likely the nature of tumor cells that gain cell plasticity. However, the phenotypic plasticity of CSCs has never been systematically discussed. Here, we review the distinct intrinsic signaling pathways and unique microenvironmental niches that endow CSC plasticity in solid tumors to adapt to stressful conditions, as well as emerging opportunities for CSC-targeted therapy.
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Affiliation(s)
- Jiali Xu
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
| | - Houde Zhang
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
| | - Zhihao Nie
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
| | - Wenyou He
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
| | - Yichao Zhao
- Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Zhenhui Huang
- College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, Guangdong, China
| | - Lin Jia
- College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, Guangdong, China.
| | - Zhiye Du
- Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, China.
| | - Baotong Zhang
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
| | - Siyuan Xia
- Department of Human Cell Biology and Genetics, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China.
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11
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Viramontes KM, Thone MN, De La Torre JJ, Neubert EN, DeRogatis JM, Garcia C, Henriquez ML, Tinoco R. Contrasting roles of PSGL-1 and PD-1 in regulating T-cell exhaustion and function during chronic viral infection. J Virol 2025:e0224224. [PMID: 39912665 DOI: 10.1128/jvi.02242-24] [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: 12/16/2024] [Accepted: 01/19/2025] [Indexed: 02/07/2025] Open
Abstract
Immune checkpoints are critical regulators of T-cell exhaustion, impairing their ability to eliminate antigens present during chronic viral infections. Current immune checkpoint inhibitors (ICIs) used in the clinic aim to reinvigorate exhausted T cells; yet, most patients fail to respond or develop resistance to these therapies, underscoring the need to better understand these immunosuppressive pathways. PSGL-1 (Selplg), a recently discovered immune checkpoint, negatively regulates T-cell function. We investigated the cell-intrinsic effects of PSGL-1, PD-1, and combined deletion on CD8+ T cells during chronic viral infection. We found that combined PSGL-1 and PD-1 (Selplg-/-Pdcd1-/-) deficiency in CD8+ T cells increased their frequencies and numbers throughout chronic infection compared to the wild type. This phenotype was primarily driven by PD-1 deficiency. Furthermore, while PD-1 deletion increased virus-specific T-cell frequencies, it was detrimental to their function. Conversely, PSGL-1 deletion improved T-cell function but resulted in lower frequencies and numbers. The primary mechanism behind these differences in cell maintenance was driven by proliferation rather than survival. Combined PSGL-1 and PD-1 deletion resulted in defective T-cell differentiation, driving cells from a progenitor self-renewal state to a more terminal dysfunctional state. These findings suggest that PD-1 and PSGL-1 have distinct, yet complementary, roles in regulating T-cell exhaustion and differentiation during chronic viral infection. Overall, this study provides novel insights into the individual and combined roles of PSGL-1 and PD-1 in CD8+ T-cell exhaustion. It underscores the potential of targeting these checkpoints in a more dynamic and sequential manner to optimize virus-specific T-cell responses, offering critical perspectives for improving therapeutic strategies aimed at reinvigorating exhausted CD8+ T cells.IMPORTANCEOur findings provide a comprehensive analysis of how the dual deletion of PD-1 and PSGL-1 impacts the response and function of virus-specific CD8+ T cells, revealing novel insights into their roles in chronic infection. Notably, our findings show that while PD-1 deletion enhances T-cell frequencies, it paradoxically reduces T-cell functionality. Conversely, PSGL-1 deletion improves T-cell function but reduces their survival. Whereas the combined deletion of PSGL-1 and PD-1 in CD8+ T cells improved their survival but decreased their function and progenitor-exhausted phenotypes during infection. We believe our study advances the understanding of immune checkpoint regulation in chronic infections and has significant implications for developing more effective immune checkpoint inhibitor (ICI) therapies.
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Affiliation(s)
- Karla M Viramontes
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California Irvine, Irvine, California, USA
| | - Melissa N Thone
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California Irvine, Irvine, California, USA
| | - Jamie-Jean De La Torre
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California Irvine, Irvine, California, USA
| | - Emily N Neubert
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California Irvine, Irvine, California, USA
| | - Julia M DeRogatis
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California Irvine, Irvine, California, USA
| | - Chris Garcia
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California Irvine, Irvine, California, USA
| | - Monique L Henriquez
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California Irvine, Irvine, California, USA
| | - Roberto Tinoco
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California Irvine, Irvine, California, USA
- Center for Virus Research, University of California Irvine, Irvine, California, USA
- Institute for Immunology, University of California Irvine, Irvine, California, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, California, USA
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12
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Ahmed J, Janku F, Karp DD, Piha-Paul SA, Tsimberidou AM, Yap TA, Stephen B, Yang Y, Gurses S, Liu Q, Song J, Meric-Bernstam F, Naing A. A phase 2 basket study of talabostat, a small-molecule inhibitor of dipeptidyl peptidases, administered in combination with pembrolizumab in patients with advanced solid cancers. Cancer 2025; 131:e35728. [PMID: 39853679 DOI: 10.1002/cncr.35728] [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: 08/09/2024] [Revised: 10/17/2024] [Accepted: 10/28/2024] [Indexed: 01/26/2025]
Abstract
BACKGROUND Talabostat, an oral small molecule inhibitor of dipeptidyl peptidases (DPP4 and DPP8/9), has shown synergistic activity with immune checkpoint inhibitors in preclinical studies. This open label, phase 2 basket trial assessed the antitumor activity of combining talabostat and pembrolizumab (anti-programmed death-1 antibody) in advanced solid tumor patients. METHODS The primary objective was assessment of dose-limiting toxicity (DLT) rates in the first six patients (lead-in stage) and response rate (efficacy stage; included cohort A [checkpoint inhibitor (ICI) naive] and cohort B [ICI pretreated]) for the study treatment using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune RECIST (iRECIST). Efficacy was assessed using a Bayesian optimal phase 2 design. RESULTS A total of 31 patients enrolled in this trial (14 in cohort A, 17 in cohort B). The median age was 61 years; 17 (55%) patients were male and 21 (68%) patients were White. Among 19 (61%) patients evaluable for response, the best response was stable disease in nine patients, unconfirmed progressive disease in seven patients, and clinical progressive disease in three patients based on iRECIST. Disease control rate was 47%. One patient with programmed death-ligand 1 negative, microsatellite stable endometrial cancer had unconfirmed partial response. Median progression-free survival was 2.7 months; median overall survival was 20.5 months. One patient (cohort A) experienced a grade 4 hypotension as a DLT and treatment discontinuation. The most common toxicities were hypotension (22.6%), fatigue (9.7%), diarrhea, rash, thrombocytopenia, vomiting, syncope, general disorders and administration site conditions-other, and skin and subcutaneous tissue disorders-other, each in 6.5% of patients. CONCLUSIONS This study of the combination of talabostat and pembrolizumab in patients with advanced solid tumors demonstrated predictable adverse events and limited activity. The combination was shown to be safe. Efficacy data shows immune stable disease in nine of 19 evaluable patients, and an unconfirmed immune partial response in a patient with endometrial cancer.
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Affiliation(s)
- Jibran Ahmed
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Filip Janku
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Daniel D Karp
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sarina A Piha-Paul
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Apostolia M Tsimberidou
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Timothy Anthony Yap
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Bettzy Stephen
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yali Yang
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Serdar Gurses
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Qian Liu
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Juhee Song
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Aung Naing
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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13
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Hung Y, Lee P, Chang Y, Yang M, Chiu C, Chen M, Lan K, Lee I, Hou M, Chao Y, Huang Y. Hepatic Events During Immune Checkpoint Inhibitor Treatment Between Liver and Non-Liver Malignancies in Hepatitis B Endemic Areas. Aliment Pharmacol Ther 2025; 61:501-512. [PMID: 39582238 PMCID: PMC11707645 DOI: 10.1111/apt.18403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 07/29/2024] [Accepted: 11/07/2024] [Indexed: 11/26/2024]
Abstract
BACKGROUND Notable advances have been made in immune checkpoint inhibitors (ICIs) for cancer treatment. However, the adverse effects of ICIs, especially hepatotoxicity, remain a challenging problem. Whether patients in hepatitis B virus (HBV)-endemic areas are prone to developing hepatic adverse events during ICI treatment warrants further exploration. METHODS From 2014 to 2020, the data of all patients with cancer who received ICI treatment at Taipei Veterans General Hospital were retrospectively reviewed. The incidence of and risk factors for hepatic adverse events, including hepatitis flare, immune-related hepatitis (irHepatitis) and HBV reactivation (HBVr), were analysed through a Cox proportional hazard regression model. RESULTS A total of 1283 patients with cancer (190 hepatocellular carcinoma [HCC] patients and 1093 patients with non-HCC malignancies) were eligible for analysis, of whom 283 (22.1%) were HBsAg-positive. The incidence of hepatitis flare events of any grade was significantly higher in HCC patients than in non-HCC patients (45.8% vs. 25.6%, p < 0.001). HCC and baseline alanine aminotransferase (ALT) > 40 U/L were independent risk factors for ≥ grade 3 hepatitis flare events. No difference was observed in irHepatitis risk between HCC patients and non-HCC patients. ALT > 40 U/L was an independent risk factor for irHepatitis. Among 283 HBsAg-positive patients, six patients (2.1%) experienced HBVr. HCC patients had a higher risk of HBVr than non-HCC patients (4.4% vs. 0.6%). No specific risk factor for HBVr could be identified. However, none of the patients under nucleos/tide analogue (NUC) prophylaxis experienced HBVr in this study. CONCLUSIONS Under ICI treatment, HCC patients had a higher risk of hepatitis flare events than non-HCC patients. Abnormal baseline ALT levels are a risk factor for hepatic adverse events. NUC prophylaxis can minimise the risk of HBVr.
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Affiliation(s)
- Yi‐Ping Hung
- Department of OncologyTaipei Veterans General HospitalTaipeiTaiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung UniversityTaipeiTaiwan
- School of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Pei‐Chang Lee
- School of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Division of Gastroenterology and HepatologyTaipei Veterans General HospitalTaipeiTaiwan
| | - Yen‐Hwa Chang
- Department of UrologyTaipei Veterans General HospitalTaipeiTaiwan
| | - Muh‐Hwa Yang
- Department of OncologyTaipei Veterans General HospitalTaipeiTaiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung UniversityTaipeiTaiwan
- School of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Chao‐Hua Chiu
- Department of Chest MedicineTaipei Veterans General HospitalTaipeiTaiwan
| | - Ming‐Huang Chen
- Department of OncologyTaipei Veterans General HospitalTaipeiTaiwan
- School of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Keng‐Hsin Lan
- School of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Division of Gastroenterology and HepatologyTaipei Veterans General HospitalTaipeiTaiwan
| | - I‐Cheng Lee
- School of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Division of Gastroenterology and HepatologyTaipei Veterans General HospitalTaipeiTaiwan
| | - Ming‐Chih Hou
- School of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Yee Chao
- Department of OncologyTaipei Veterans General HospitalTaipeiTaiwan
| | - Yi‐Hsiang Huang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung UniversityTaipeiTaiwan
- School of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Division of Gastroenterology and HepatologyTaipei Veterans General HospitalTaipeiTaiwan
- Healthcare and Services CenterTaipei Veterans General HospitalTaipeiTaiwan
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14
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Long D, Ding Y, Wang P, Wei L, Ma K. Multi-Omics Analysis Reveals Immune Infiltration and Clinical Significance of Phosphorylation Modification Enzymes in Lung Adenocarcinoma. Int J Mol Sci 2025; 26:1066. [PMID: 39940833 PMCID: PMC11817228 DOI: 10.3390/ijms26031066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 01/21/2025] [Accepted: 01/21/2025] [Indexed: 02/16/2025] Open
Abstract
Protein phosphorylation is a dynamic and reversible modification involved in almost all cellular processes. Numerous investigations have shown that protein phosphorylation modification enzymes (PPMEs) that regulate protein phosphorylation play an important role in the occurrence and treatment of tumors. However, there is still a lack of effective insights into the value of PPMEs in the classification and treatment of patients with lung adenocarcinoma (LUAD). Here, four topological algorithms identified 15 hub PPMEs from a protein-protein interaction (PPI) network. This PPI network was constructed using 124 PPMEs significantly correlated with 35 cancer hallmark-related pathways. Our study illustrates that these hub PPMEs can affect the survival of patients with LUAD in the form of somatic mutation or expression perturbation. Consistency clustering based on hub PPMEs recognized two phosphorylation modification subtypes (namely cluster1 and cluster2) from LUAD. Compared with patients in cluster1, the survival prognosis of patients in cluster2 is worse. This disparity is probably attributed to the higher tumor mutation burden, the higher male proportion, and the more significant expression disturbance in patients in cluster2. Moreover, phosphorylation modification subtypes also have different characteristics in terms of immune activity, immune infiltration level, immunotherapy response, and drug sensitivity. We constructed a PSig scoring system by using a principal component analysis algorithm to estimate the level of phosphorylation modification in individual LUAD patients. Patients in the high and low PSig score groups demonstrated different characteristics in terms of survival rate, tumor mutation burden, somatic gene mutation rate, immune cell abundance, and sensitivity to immunotherapy and drug treatment. This work reveals that phosphorylation plays a non-negligible role in the tumor microenvironment and immunotherapy of LUAD. Evaluating the phosphorylation status of individual LUAD patients by the PSig score can contribute to enhancing our cognition of the tumor microenvironment and guiding the formulation of more effective personalized treatment strategies.
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Affiliation(s)
- Deyu Long
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University Medical College, Shihezi 832000, China
- Center of Bioinformatics, College of Life Sciences, Northwest A&F University, Yangling 712100, China
| | - Yanheng Ding
- Center of Bioinformatics, College of Life Sciences, Northwest A&F University, Yangling 712100, China
| | - Peng Wang
- Center of Bioinformatics, College of Life Sciences, Northwest A&F University, Yangling 712100, China
| | - Lili Wei
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University Medical College, Shihezi 832000, China
| | - Ketao Ma
- The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University Medical College, Shihezi 832000, China
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15
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Gondal MN, Cieslik M, Chinnaiyan AM. Integrated cancer cell-specific single-cell RNA-seq datasets of immune checkpoint blockade-treated patients. Sci Data 2025; 12:139. [PMID: 39843468 PMCID: PMC11754430 DOI: 10.1038/s41597-025-04381-6] [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: 01/23/2024] [Accepted: 01/02/2025] [Indexed: 01/24/2025] Open
Abstract
Immune checkpoint blockade (ICB) therapies have emerged as a promising avenue for the treatment of various cancers. Despite their success, the efficacy of these treatments is variable across patients and cancer types. Numerous single-cell RNA-sequencing (scRNA-seq) studies have been conducted to unravel cell-specific responses to ICB treatment. However, these studies are limited in their sample sizes and require advanced coding skills for exploration. Here, we have compiled eight scRNA-seq datasets from nine cancer types, encompassing 223 patients, 90,270 cancer cells, and 265,671 other cell types. This compilation forms a unique resource tailored to investigate how cancer cells respond to ICB treatment across cancer types. We meticulously curated, quality-checked, pre-processed, and analyzed the data, ensuring easy access for researchers. Moreover, we designed a user-friendly interface for seamless exploration. By sharing the code and data for creating these interfaces, we aim to assist fellow researchers. These resources offer valuable support to those interested in leveraging and exploring single-cell datasets across diverse cancer types, facilitating a comprehensive understanding of ICB responses.
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Affiliation(s)
- Mahnoor N Gondal
- Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Marcin Cieslik
- Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
- University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
| | - Arul M Chinnaiyan
- Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
- University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
- Department of Urology, University of Michigan, Ann Arbor, MI, USA.
- Howard Hughes Medical Institute, Ann Arbor, MI, USA.
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16
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Takemoto M, Delghandi S, Abo M, Yurimoto K, Odagi M, Singh VP, Wang J, Nakagawa R, Sato SI, Takemoto Y, Farrag AMAS, Kawaguchi Y, Nagasawa K, Honjo T, Chamoto K, Uesugi M. Covalent Plant Natural Product that Potentiates Antitumor Immunity. J Am Chem Soc 2025; 147:2902-2912. [PMID: 39794153 DOI: 10.1021/jacs.4c17837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2025]
Abstract
Despite the unprecedented therapeutic potential of immune checkpoint antibody therapies, their efficacy is limited partly by the dysfunction of T cells within the cancer microenvironment. Combination therapies with small molecules have also been explored, but their clinical implementation has been met with significant challenges. To search for antitumor immunity activators, the present study developed a cell-based system that emulates cancer-attenuated T cells. The cell-based screening of 232 natural products containing electrophilic reactive functional groups led to the identification of arvenin I, also known as cucurbitacin B 2-O-β-d-glucoside (CuBg), as a plant natural product that activates T cells within the cancer-competitive environment. Chemoproteomic and mechanistic analyses indicated that arvenin I covalently reacts with and hyperactivates MKK3, thereby reviving the mitochondrial fitness of exhausted T cells through the activation of the p38MAPK pathway. In mice, administration of arvenin I enhanced the efficacy of cancer immunotherapy when used alone or in combination with an immune checkpoint inhibitor. These findings highlight the potential of arvenin I as a covalent kinase activator that potentiates antitumor immunity.
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Affiliation(s)
- Misao Takemoto
- Division of Biochemistry, Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Sara Delghandi
- Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Masahiro Abo
- Division of Biochemistry, Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Keiko Yurimoto
- Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Minami Odagi
- Department of Biotechnology and Life Science, Graduate School of Technology, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
| | - Vaibhav Pal Singh
- Division of Biochemistry, Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Jun Wang
- Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Reiko Nakagawa
- Laboratory for Cell-Free Protein Synthesis, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan
| | - Shin-Ichi Sato
- Division of Biochemistry, Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Yasushi Takemoto
- Division of Biochemistry, Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Asmaa M A S Farrag
- Division of Biochemistry, Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Yoshimasa Kawaguchi
- Division of Biochemistry, Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011, Japan
| | - Kazuo Nagasawa
- Department of Biotechnology and Life Science, Graduate School of Technology, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
| | - Tasuku Honjo
- Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Kenji Chamoto
- Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
- Department of Immuno-Oncology PDT, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Motonari Uesugi
- Division of Biochemistry, Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011, Japan
- Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8372, Japan
- School of Pharmacy, Fudan University, Shanghai 201203, China
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17
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Zhang F, Chow RD, He E, Dong C, Xin S, Mirza D, Feng Y, Tian X, Verma N, Majety M, Zhang Y, Wang G, Chen S. Multiplexed inhibition of immunosuppressive genes with Cas13d for combinatorial cancer immunotherapy. Nat Biotechnol 2025:10.1038/s41587-024-02535-2. [PMID: 39820813 DOI: 10.1038/s41587-024-02535-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 12/13/2024] [Indexed: 01/19/2025]
Abstract
The complex nature of the immunosuppressive tumor microenvironment (TME) requires multi-agent combinations for optimal immunotherapy. Here we describe multiplex universal combinatorial immunotherapy via gene silencing (MUCIG), which uses CRISPR-Cas13d to silence multiple endogenous immunosuppressive genes in the TME, promoting TME remodeling and enhancing antitumor immunity. MUCIG vectors targeting four genes delivered by adeno-associated virus (AAV) (Cd274/Pdl1, Lgals9/Galectin9, Lgals3/Galectin3 and Cd47; AAV-Cas13d-PGGC) demonstrate significant antitumor efficacy across multiple syngeneic tumor models, remodeling the TME by increasing CD8+ T-cell infiltration while reducing neutrophils. Whole transcriptome profiling validates the on-target knockdown of the four target genes and shows limited potential off-target or downstream gene alterations. AAV-Cas13d-PGGC outperforms corresponding shRNA treatments and individual gene knockdown. We further optimize MUCIG by employing high-fidelity Cas13d (hfCas13d), which similarly showed potent gene silencing and in vivo antitumor efficacy, without weight loss or liver toxicity. MUCIG represents a universal method to silence multiple immune genes in vivo in a programmable manner, offering broad efficacy across multiple tumor types.
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Affiliation(s)
- Feifei Zhang
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Center for Cancer Systems Biology, Yale University, West Haven, CT, USA
| | - Ryan D Chow
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Center for Cancer Systems Biology, Yale University, West Haven, CT, USA
- M.D.-Ph.D. Program, Yale University, West Haven, CT, USA
- Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA
| | - Emily He
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Center for Cancer Systems Biology, Yale University, West Haven, CT, USA
- Yale College, New Haven, CT, USA
| | - Chuanpeng Dong
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Center for Cancer Systems Biology, Yale University, West Haven, CT, USA
| | - Shan Xin
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Center for Cancer Systems Biology, Yale University, West Haven, CT, USA
| | - Daniyal Mirza
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Center for Cancer Systems Biology, Yale University, West Haven, CT, USA
- Yale College, New Haven, CT, USA
| | - Yanzhi Feng
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Center for Cancer Systems Biology, Yale University, West Haven, CT, USA
- Immunobiology Program, Yale University, New Haven, CT, USA
| | - Xiaolong Tian
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Center for Cancer Systems Biology, Yale University, West Haven, CT, USA
| | - Nipun Verma
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Center for Cancer Systems Biology, Yale University, West Haven, CT, USA
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA
| | - Medha Majety
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Center for Cancer Systems Biology, Yale University, West Haven, CT, USA
- Yale College, New Haven, CT, USA
| | - Yueqi Zhang
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Center for Cancer Systems Biology, Yale University, West Haven, CT, USA
| | - Guangchuan Wang
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
- System Biology Institute, Yale University, West Haven, CT, USA.
- Center for Cancer Systems Biology, Yale University, West Haven, CT, USA.
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
| | - Sidi Chen
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
- System Biology Institute, Yale University, West Haven, CT, USA.
- Center for Cancer Systems Biology, Yale University, West Haven, CT, USA.
- M.D.-Ph.D. Program, Yale University, West Haven, CT, USA.
- Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA.
- Yale College, New Haven, CT, USA.
- Immunobiology Program, Yale University, New Haven, CT, USA.
- Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
- Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
- Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA.
- Yale Center for Biomedical Data Science, Yale University School of Medicine, New Haven, CT, USA.
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18
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Wynter C, Natarajan A, John C, Jain K, Paulmurugan R. Molecular Imaging of Tumor-Infiltrating Lymphocytes in Living Animals Using a Novel mCD3 Fibronectin Scaffold. Bioconjug Chem 2025; 36:104-115. [PMID: 39681342 DOI: 10.1021/acs.bioconjchem.4c00501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2024]
Abstract
The interaction between cancer cells and immune cells in the tumor microenvironment (TME) plays a crucial role in determining tumor growth, metastasis, and response to treatment. Tumor-infiltrating lymphocytes (TILs) in TME could be a predictive marker for treatment response in various therapeutic interventions, including chemotherapy and immunotherapy. Thus, imaging the tumor immune microenvironment is important for selecting the optimal treatment strategies in cancer therapy. The CD3 protein represents a promising target for diagnostic imaging of TILs in vivo to assess the immune state of the TME. Although many anti-CD3 antibodies have been explored for this application, the nonspecific immune activation by these antibodies limits their applications. To overcome this issue, we engineered a novel fibronectin III domain (FN3) protein binder (mCD3-FN3;11.8 kDa) against mouse CD3 antigen protein using a yeast display library to image TILs homing in vivo into the TME. We performed in vitro and in vivo assays to test the mCD3-FN3 binder purity as well as in vivo targetability in mouse models of syngeneic tumors. We used near-infrared 800 dye conjugated with mCD3-FN3 (IR800-mCD3-FN3) for in vivo tracking of TILs via optical imaging. We used three different syngeneic tumors in mice (mCD3+ EL4 tumor in C57BL/6 mice, mCD3- CT26 colon tumor, and mCD3- 4T1 breast tumor in BALB/c mice) for imaging TILs in vivo. C57BL/6 mice bearing EL4 tumors were separated into two groups (blocking [Blk] and nonblocking [Nblk]; n = 3 per group) and used for in vivo imaging. Blocking groups received 200 μg of unlabeled mCD3-FN3 2 h prior to the administration of IR800-mCD3-FN3 binder. Each mouse was administered with 25 μg of the IR800-mCD3-FN3 binder and tracked using an IVIS optical imaging system over time. C57BL/6/EL4 mice were imaged at 4 and 24 h post injection of the IR800-mCD3-FN3 binder, and mouse organs were collected at 24 h after final imaging and used for ex vivo histological imaging. In CT26 and 4T1 tumor models, TILs in TME were imaged 4, 24, and 48 h after binder injection. The NIR imaging of EL4 tumors showed that IR800-mCD3-FN3 can detect both TILs within the tumor and the tumor cells with a high signal-to-background ratio 24 h after initial binder injection with a total radiant efficiency (mean TRE ± SD) of 6.5 × 1010 ± 1.5 × 1010 [photons/s]/[μW/cm2]. The animals received preinjection of unlabeled mCD3-FN3(Blk) prior to IR800-mCD3-FN3 binder administration and showed a significant level of fluorescence signal reduction (mean TRE ± SD: 1.6 × 1010 ± 4.1 × 109) in the tumor when compared to the EL4-Nblk tumors (p = 0.006). The mouse group with CT26 and 4T1 tumors where the probe can only bind to TILs within the tumor showed a specific imaging signal (mean TRE ± SD) of 1.1 × 1011 ± 5.2 × 1010 and 9.5 × 1010 ± 4.6 × 1010, respectively, at 48 h p.i. For these groups, the ex vivo tumor-to-muscle ratios were 20- and 27-fold for CT26 and 4T1 tumors, respectively. These results clearly demonstrate the in vivo binding ability of the mCD3-FN3 binder to mCD3 marker expressed by T cells in the TME. The ex vivo histological analysis of tumors, and the organs of animals with EL4 tumors, and TILs imaging of CT26, and 4T1 tumors (at 48 p.i.) confirmed that the IR800-mCD3-FN3 probe was able to specifically bind to CD3 markers expressed by the T cells. In summary, both in vitro and in vivo data indicated that the engineered mCD3-FN3 binder by this study is a promising ligand for diagnostic imaging of tumors in vivo for the assessment of mCD3 expressing TILs in the TME. This can be used as a prognostic marker in evaluating tumor response to therapeutic intervention as well as a diagnostic marker in imaging tumor response to immune checkpoint blockade cancer therapies.
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Affiliation(s)
- Char Wynter
- Canary Center for Cancer Early Detection, Department of Radiology, Stanford University, Palo Alto, California 94304, United States
| | - Arutselvan Natarajan
- Canary Center for Cancer Early Detection, Department of Radiology, Stanford University, Palo Alto, California 94304, United States
| | - Clyde John
- Canary Center for Cancer Early Detection, Department of Radiology, Stanford University, Palo Alto, California 94304, United States
| | - Kaahini Jain
- Canary Center for Cancer Early Detection, Department of Radiology, Stanford University, Palo Alto, California 94304, United States
| | - Ramasamy Paulmurugan
- Canary Center for Cancer Early Detection, Department of Radiology, Stanford University, Palo Alto, California 94304, United States
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19
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Du R, Zhang J, Lukas RV, Tripathi S, Ahrendsen JT, Curran MA, Dmello C, Zhang P, Stupp R, Rao G, Heimberger AB. Is modulation of immune checkpoints on glioblastoma-infiltrating myeloid cells a viable therapeutic strategy? Neuro Oncol 2025; 27:33-49. [PMID: 39427326 PMCID: PMC11726257 DOI: 10.1093/neuonc/noae193] [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] [Indexed: 10/22/2024] Open
Abstract
The field of immunology has traditionally focused on immune checkpoint modulation of adaptive immune cells. However, many malignancies such as glioblastoma are mostly devoid of T cells and rather are enriched with immunosuppressive myeloid cells of the innate immune system. While some immune checkpoint targets are shared between adaptive and innate immunity, myeloid-specific checkpoints could also serve as potential therapeutics. To better understand the impact of immune checkpoint blockade on myeloid cells, we systematically summarize the current literature focusing on the direct immunological effects of PD-L1/PD-1, CD24/Siglec-10, collagen/LAIR-1, CX3CL1/CX3CR1, and CXCL10/CXCR3. By synthesizing the molecular mechanisms and the translational implications, we aim to prioritize agents in this category of therapeutics for glioblastoma.
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Affiliation(s)
- Ruochen Du
- Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Jianzhong Zhang
- Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Rimas V Lukas
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Shashwat Tripathi
- Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Jared T Ahrendsen
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA (J.T.A.)
- Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Michael A Curran
- Department of Immunology, MD Anderson Cancer Center, the University of Texas, Houston, Texas, USA
| | - Crismita Dmello
- Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Peng Zhang
- Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Roger Stupp
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Ganesh Rao
- Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA
| | - Amy B Heimberger
- Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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20
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Zhou H, Bao G, Zhao J, Zhu X. Nuclear Molecular Imaging for Evaluating T Cell Exhaustion. Mol Pharm 2025; 22:103-112. [PMID: 39586059 DOI: 10.1021/acs.molpharmaceut.4c00970] [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: 11/27/2024]
Abstract
T cells are indispensable for the therapeutic efficacy of cancer immunotherapies, including immune checkpoint blockade. However, prolonged antigen exposure also drives T cells into exhaustion, which is characterized by upregulated inhibitory molecules, impaired effector functions, reduced cytotoxicity, altered metabolism, etc. Noninvasive monitoring of T cell exhaustion allows a timely identification of cancer patients that are most likely to benefit from immunotherapies. In this Review, we briefly explain the biological cascades underlying the modulation of inhibitory molecules, present a concise update on the nuclear molecular imaging tracers of T cell exhaustion, and then discuss the potential opportunities for future development.
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Affiliation(s)
- Huimin Zhou
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Guangfa Bao
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
- Department of Nuclear Medicine, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, China
| | - Jun Zhao
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
- Department of Anatomy, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Xiaohua Zhu
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
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21
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Liu Z, Chu H, Zhao W, Yang C, Liu T, Shen N, Tang Z. Polymeric Multivalent Fc Binding Peptides-Fabricated Clinical Compounding Bispecific Antibody Potentiates Dual Immunotherapy Targeting PD1 and CTLA-4. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2408899. [PMID: 39606809 PMCID: PMC11744713 DOI: 10.1002/advs.202408899] [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: 07/31/2024] [Revised: 11/17/2024] [Indexed: 11/29/2024]
Abstract
Dual Opdivo plus Yervoy immunotherapy, targeting the immune checkpoints PD1 and CTLA-4, is successful in clinical use. However, it is associated with a high incidence of adverse events, and its therapeutic efficacy needs improving. In this study, polymeric multivalent Fc-binding peptides (PLG-Fc-III-4C) are employed to fabricate a bispecific antibody (PD1/CTLA-4 BsAb) to potentiate dual immunotherapy targeting PD1 and CTLA-4. The PD1/CTLA-4 BsAb is prepared by mixing PLG-Fc-III-4C with aPD1 and aCTLA-4 in an aqueous solution for 3 h using the clinically optimal 3:1 proportion of aPD1 to aCTLA-4. PD1/CTLA-4 BsAb significantly inhibits tumors in MC38 colon cancer-bearing mice more effectively than the combination of aPD1 and aCTLA-4, with tumor suppression rates of 96.8% and 77.3%, respectively. It also induces a higher percentage of CD8+ T cells and increases the secretion of effector cytokines while reducing Treg levels in tumors compared to phosphate-buffered saline, indicating significant tumor immunity regulation. Mechanistically, a 6.3-fold increase in PD1/CTLA-4 BsAb accumulation in tumors due to the tumor targeting ability of aPD1, and the PD1/CTLA-4 BsAb significantly reduces the adverse colitis event in healthy mice, compared to aPD1 and aCTLA-4. Thus, these findings provide a novel approach to enhance antitumor therapy using aPD1 and aCTLA-4.
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Affiliation(s)
- Zongyu Liu
- Department of Colorectal and Anal SurgeryThe Second Hospital of Jilin UniversityChangchunJilin130000China
| | - Hongyu Chu
- Department of Gastrointestinal Colorectal and Anal SurgeryChina‐Japan Union Hospital of Jilin UniversityChangchunJilin130033China
| | - Weidong Zhao
- Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchunJilin130022China
| | - Chenguang Yang
- Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchunJilin130022China
| | - Tongjun Liu
- Department of Colorectal and Anal SurgeryThe Second Hospital of Jilin UniversityChangchunJilin130000China
| | - Na Shen
- Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchunJilin130022China
| | - Zhaohui Tang
- Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchunJilin130022China
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22
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Ali MS, Ahn J, Espat NJ, Calvino AS, Koness J, Somasundar P, Kwon S. Disparities in utilization of novel cancer therapies in advanced stage III and IV melanoma and variance in outcomes. Immunotherapy 2025; 17:37-46. [PMID: 39825755 PMCID: PMC11834448 DOI: 10.1080/1750743x.2025.2452836] [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: 06/06/2024] [Accepted: 01/09/2025] [Indexed: 01/20/2025] Open
Abstract
INTRODUCTION Significant gains in advanced melanoma have been made through immunotherapy trials. Factors influencing equitable access and survival impact of these novel therapies are not well-defined. METHOD Retrospective analysis using National Cancer Database of patients with advanced stage III and IV melanoma from 2004 to 2021. Multivariable logistic regression was used to study the use of immunotherapy and Cox proportional hazard regression to evaluate overall survival (OS). RESULTS 47,427 patients with increasing utilization of immunotherapy from 13.78% in 2004 to 65.88% by 2021. Inequitable adoption were impacted by age, sex, socioeconomic status/affordability, insurance types and residential educational/income level. Receiving immunotherapy was associated with a 44% improvement in OS (HR 0.56, 95% CI 0.54-0.57) and receiving a clinical trial-based therapy was associated with a 37% improvement (HR 0.63, 95% CI 0.53-0.75). Among patients who received immunotherapy or clinical trial-base therapy, there was 40% worse survival in non-Hispanic Black patients (HR 1.40, 95% CI 1.16-1.69) compared to non-Hispanic Whites. CONCLUSION There are disparities in utilization of immunotherapy that is influenced by socioeconomic status. Race and ethnicity had a significant influence in differential impact on survival outcomes of immunotherapies highlighting the importance of increasing underrepresented population participation in trials that lead to novel therapies.
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Affiliation(s)
- Mohammad S. Ali
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center, Providence, RI, USA
- Department of Surgery, Boston University Medical Center, Boston, MA, USA
| | - Jae Ahn
- Department of Surgery, Boston University Medical Center, Boston, MA, USA
| | - N. Joseph Espat
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center, Providence, RI, USA
- Department of Surgery, Boston University Medical Center, Boston, MA, USA
- Department of Surgery, Roger Williams Surgery and Cancer Outcomes Research and Equity (RWSCORE) Center, Providence, RI, USA
| | - Abdul S. Calvino
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center, Providence, RI, USA
- Department of Surgery, Boston University Medical Center, Boston, MA, USA
- Department of Surgery, Roger Williams Surgery and Cancer Outcomes Research and Equity (RWSCORE) Center, Providence, RI, USA
| | - James Koness
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center, Providence, RI, USA
- Department of Surgery, Boston University Medical Center, Boston, MA, USA
| | - Ponnandai Somasundar
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center, Providence, RI, USA
- Department of Surgery, Boston University Medical Center, Boston, MA, USA
- Department of Surgery, Roger Williams Surgery and Cancer Outcomes Research and Equity (RWSCORE) Center, Providence, RI, USA
| | - Steve Kwon
- Department of Surgery, Division of Surgical Oncology, Roger Williams Medical Center, Providence, RI, USA
- Department of Surgery, Boston University Medical Center, Boston, MA, USA
- Department of Surgery, Roger Williams Surgery and Cancer Outcomes Research and Equity (RWSCORE) Center, Providence, RI, USA
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23
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Ashizawa T, Iizuka A, Kanematsu A, Ando T, Maeda C, Miyata H, Yamashita K, Ikeya T, Kikuchi Y, Maruyama K, Nagashima T, Urakami K, Yamaguchi K, Akiyama Y. In Vivo Antitumor Activity of the PD-1/PD-L1 Inhibitor SCL-1 in Various Mouse Tumor Models. In Vivo 2025; 39:80-95. [PMID: 39740910 PMCID: PMC11705142 DOI: 10.21873/invivo.13805] [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: 09/17/2024] [Revised: 09/26/2024] [Accepted: 09/27/2024] [Indexed: 01/02/2025]
Abstract
BACKGROUND/AIM Immune checkpoint blockade has achieved great success as a targeted immunotherapy for solid cancers. However, small molecules that inhibit programmed death 1/programmed death ligand 1 (PD-1/PD-L1) binding are still being developed and have several advantages, such as high bioavailability. Previously, we reported a novel PD-1/PD-L1-inhibiting small compound, SCL-1, which showed potent antitumor effects on PD-L1+ tumors. These effects were dependent on CD8+ T-cell infiltration and PD-L1 expression on tumors. The present study investigated the in vivo antitumor activity of SCL-1 in various mouse syngeneic tumor models. MATERIALS AND METHODS Twelve syngeneic mice models of tumors, such as colon, breast, bladder, kidney, pancreatic, non-small cell lung cancers, melanoma, and lymphomas, were used for in vivo experiments. Tumor mutation burden (TMB) was analyzed by whole exome sequencing (WES) using reference DNA from mouse blood. The proportion of CD8+ T-cells infiltrating tumors before and after treatment was assessed using flow cytometry and immunohistochemistry (IHC). RESULTS SCL-1 had a markedly greater antitumor effect (11 sensitive tumors and 1 resistant tumor among the 12 tumor types) than the anti-mouse PD-1 antibody (8 sensitive tumors and 4 resistant tumors). In addition, the tumor growth inhibition rate (%) was more closely associated with TMB in the SCL-1 group than in the anti-PD-1 antibody group. Furthermore, in vivo experiments using PD-L1 gene knockout and lymphocyte-depletion technologies demonstrated that the antitumor activity of SCL-1 was dependent on CD8+ T-cell infiltration and PD-L1 expression in tumors. CONCLUSION SCL-1 has great potential as an oral immunotherapy that targets immune checkpoint molecules in cancer treatment.
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Affiliation(s)
- Tadashi Ashizawa
- Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Akira Iizuka
- Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Akari Kanematsu
- Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Takayuki Ando
- Department of Drug and Food Science, Shizuoka Institute of Environment and Hygiene, Shizuoka, Japan
| | - Chie Maeda
- Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Haruo Miyata
- Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Kazue Yamashita
- Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Tomoatsu Ikeya
- Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Yasufumi Kikuchi
- Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Kouji Maruyama
- Experimental Animal Facility, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Takeshi Nagashima
- SRL, Tokyo, Japan
- Cancer Diagnostic Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Kenichi Urakami
- Cancer Diagnostic Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Ken Yamaguchi
- Office of the President Emeritus, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Yasuto Akiyama
- Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan;
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24
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Bhaliya KR, Anwer M, Munn A, Wei MQ. New horizons in cancer immunotherapy: The evolving role of R848 and R837 (Review). Mol Clin Oncol 2025; 22:4. [PMID: 39563999 PMCID: PMC11574705 DOI: 10.3892/mco.2024.2799] [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: 06/04/2024] [Accepted: 08/07/2024] [Indexed: 11/21/2024] Open
Abstract
Therapeutic approaches that increase the efficacy and safety of cancer treatments and improve disease outcomes have been developed worldwide. Immunotherapy uses the body's immune system to inhibit cancerous growth in tissues and organs. Various approaches have been developed to effectively control and inhibit cancerous growth, including checkpoint inhibitors, T-cell transfer therapy, monoclonal antibodies, vaccines and immunomodulators. Toll-like receptors (TLRs) target malignant cells by equipping the immune response. In addition, TLR agonists serve a key role in promoting the innate immune system and initiating antigen-specific T-cell responses. Notably, TLRs and TLR agonists have been utilized as monotherapies or in combination for the treatment of cancer. The present study aimed to review the use of R848 and R837 as TLR agonists, and outline their use as key immunomodulators in cancer therapy.
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Affiliation(s)
- Krupa R Bhaliya
- Menzies Health Institute, School of Medical Science, Griffith University, Southport, Queensland 4215, Australia
| | - Muneera Anwer
- Menzies Health Institute, School of Medical Science, Griffith University, Southport, Queensland 4215, Australia
| | - Alan Munn
- Menzies Health Institute, School of Medical Science, Griffith University, Southport, Queensland 4215, Australia
| | - Ming Q Wei
- Menzies Health Institute, School of Medical Science, Griffith University, Southport, Queensland 4215, Australia
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Lefler DS, Manobianco SA, Bashir B. Immunotherapy resistance in solid tumors: mechanisms and potential solutions. Cancer Biol Ther 2024; 25:2315655. [PMID: 38389121 PMCID: PMC10896138 DOI: 10.1080/15384047.2024.2315655] [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: 07/24/2023] [Accepted: 02/04/2024] [Indexed: 02/24/2024] Open
Abstract
While the emergence of immunotherapies has fundamentally altered the management of solid tumors, cancers exploit many complex biological mechanisms that result in resistance to these agents. These encompass a broad range of cellular activities - from modification of traditional paradigms of immunity via antigen presentation and immunoregulation to metabolic modifications and manipulation of the tumor microenvironment. Intervening on these intricate processes may provide clinical benefit in patients with solid tumors by overcoming resistance to immunotherapies, which is why it has become an area of tremendous research interest with practice-changing implications. This review details the major ways cancers avoid both natural immunity and immunotherapies through primary (innate) and secondary (acquired) mechanisms of resistance, and it considers available and emerging therapeutic approaches to overcoming immunotherapy resistance.
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Affiliation(s)
- Daniel S. Lefler
- Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Steven A. Manobianco
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Babar Bashir
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
- Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA
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26
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Liu H, Gou X, Tan Y, Fan Q, Chen J. Immunotherapy and delivery systems for melanoma. Hum Vaccin Immunother 2024; 20:2394252. [PMID: 39286868 PMCID: PMC11409522 DOI: 10.1080/21645515.2024.2394252] [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: 05/10/2024] [Revised: 08/01/2024] [Accepted: 08/15/2024] [Indexed: 09/19/2024] Open
Abstract
Melanoma is a highly malignant tumor of melanocyte origin that is prone to early metastasis and has a very poor prognosis. Early melanoma treatment modalities are mainly surgical, and treatment strategies for advanced or metastatic melanoma contain chemotherapy, radiotherapy, targeted therapy and immunotherapy. The efficacy of chemotherapy and radiotherapy has been unsatisfactory due to low sensitivity and strong toxic side effects. And targeted therapy is prone to drug resistance, so its clinical application is limited. Melanoma has always been the leader of immunotherapy for solid tumors, and how to maximize the role of immunotherapy and how to implement immunotherapy more accurately are still urgent to be explored. This review summarizes the common immunotherapies and applications for melanoma, illustrates the current research status of melanoma immunotherapy delivery systems, and discusses the advantages and disadvantages of each delivery system and its prospects for clinical application.
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Affiliation(s)
- Hui Liu
- Jiangxi Province Key Laboratory of Immunology and Inflammation, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xi Gou
- Jiangxi Province Key Laboratory of Immunology and Inflammation, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yuanfang Tan
- Jiangxi Province Key Laboratory of Immunology and Inflammation, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Qiuying Fan
- Jiangxi Province Key Laboratory of Immunology and Inflammation, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Juanjuan Chen
- Jiangxi Province Key Laboratory of Immunology and Inflammation, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
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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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Sedhai YR, Acharya R, Bhat P, Saeed S, Sohail H, Kunwar S, Kadariya S, Ahmed MA, Waheed I, Steff R, Khan TMA, Kazimuddin N, Singh K. Primary malignant melanoma of the lung; a case report and literature review. Respir Med Case Rep 2024; 53:102161. [PMID: 39867939 PMCID: PMC11763600 DOI: 10.1016/j.rmcr.2024.102161] [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: 11/16/2024] [Accepted: 12/25/2024] [Indexed: 01/28/2025] Open
Abstract
Primary pulmonary malignant melanoma is an extremely rare non-epithelial malignancy. Literature is merely limited to a few anecdotal case reports. Herein we present a case of a 74-year-old female who was diagnosed with primary malignant melanoma of the lung. To fully appraise the available evidence, we have sought to perform narrative review of the existing literature.
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Affiliation(s)
- Yub Raj Sedhai
- Division of Pulmonary Disease and Critical Care Medicine, University of Kentucky College of Medicine, Bowling Green, KY, USA
| | - Roshan Acharya
- Division of Pulmonary Disease and Critical Care Medicine, Carillion Clinic, Roanoke, VA, USA
| | - Priyanka Bhat
- Division of Pulmonary Disease and Critical Care Medicine, University of Kentucky College of Medicine, Bowling Green, KY, USA
| | - Subha Saeed
- Division of Pulmonary Disease and Critical Care Medicine, University of Kentucky College of Medicine, Bowling Green, KY, USA
| | - Hamza Sohail
- Division of Internal Medicine, University of Kentucky College of Medicine, Bowling Green, KY, USA
| | | | | | - Muhammad Altaf Ahmed
- Division of Pulmonary Disease and Critical Care Medicine, University of Kentucky College of Medicine, Bowling Green, KY, USA
| | - Irfan Waheed
- Division of Pulmonary Disease and Critical Care Medicine, University of Kentucky College of Medicine, Bowling Green, KY, USA
| | - Rodney Steff
- Division of Pulmonary Disease and Critical Care Medicine, University of Kentucky College of Medicine, Bowling Green, KY, USA
| | - Tahir Muhammad Abdullah Khan
- Division of Pulmonary Disease and Critical Care Medicine, University of Kentucky College of Medicine, Bowling Green, KY, USA
| | - Nisar Kazimuddin
- Division of Pulmonary Disease and Critical Care Medicine, University of Kentucky College of Medicine, Bowling Green, KY, USA
| | - Karan Singh
- Division of Pulmonary Disease and Critical Care Medicine, University of Kentucky College of Medicine, Bowling Green, KY, USA
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Gencsoy Eker S, Inetas Yengin G, Tatar C, Oktem G. A Comprehensive Review of the Mechanisms and Clinical Development of Monoclonal Antibodies in Cancer Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024. [PMID: 39666264 DOI: 10.1007/5584_2024_838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2024]
Abstract
Cancer is still the disease that ranks first in human mortality in the twenty-first century. In the last 20 years, the concept of molecular targeted therapy has come to the fore with the use of small molecule agents or signal transduction inhibitors that show anticancer effects for certain types of cancer. Monoclonal antibodies, which have a therapeutic effect, especially by providing signal transduction inhibition, are used clinically as first-line treatment in various types of cancer. Molecular targeted therapies are critical for eliminating the adverse effects and drug resistance problems that occur in traditional cancer treatments. This review summarizes current information on various targeted therapeutic agents, including the structure and classification of monoclonal antibodies, their production methods and mechanisms of action, the monoclonal antibodies used in clinical trials, the complement system mechanism and cancer relationship, and the relationship between complement-dependent cytotoxicity and monoclonal antibodies.
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Affiliation(s)
- Selen Gencsoy Eker
- Department of Stem Cell, Graduate School of Health Sciences, Ege University, Izmir, Turkey
| | - Gizem Inetas Yengin
- Department of Genetics and Bioengineering, Yeditepe University, Istanbul, Turkey
| | - Cansu Tatar
- Department of Molecular Biology and Genetics, Yildiz Technical University, Istanbul, Turkey
| | - Gulperi Oktem
- Department of Stem Cell, Graduate School of Health Sciences, Ege University, Izmir, Turkey.
- Department of Histology and Embryology, Faculty of Medicine, Ege University, Izmir, Turkey.
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30
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Dougherty SC, Flowers WL, Gaughan EM. Precision Oncology in Melanoma: Changing Practices. J Nucl Med 2024; 65:1838-1845. [PMID: 39542696 PMCID: PMC11619585 DOI: 10.2967/jnumed.124.267781] [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: 03/25/2024] [Accepted: 10/22/2024] [Indexed: 11/17/2024] Open
Abstract
Over the last 2 decades, significant progress has been made in our understanding of the genomics, tumor immune microenvironment, and immunogenicity of malignant melanoma. Historically, the prognosis for metastatic melanoma was poor because of limited treatment options. However, after multiple landmark clinical trials displaying the efficacy of combined BRAF/MEK inhibition for BRAF-mutant melanoma and the application of immune checkpoint inhibitors targeting the programmed death-1, cytotoxic T-lymphocyte antigen-4, and lymphocyte activation gene-3 molecules, overall survival rates have dramatically improved. The role of immune checkpoint inhibition has since expanded to the neoadjuvant and adjuvant settings with multiple regimens in routine use. Personalized therapies, including tumor-infiltrating lymphocytes that are extracted from a patient's melanoma and eventually reinfused into the patient, and messenger RNA vaccines used to target neoantigens unique to a patient's tumor, show promise. Improvements in accompanying imaging modalities, particularly within the field of nuclear medicine, have allowed for more accurate staging of disease and assessment of treatment response. Continued growth in the role of nuclear medicine in the evaluation of melanoma, including the incorporation of artificial intelligence into image interpretation and use of radiolabeled tracers allowing for intricate imaging of the tumor immune microenvironment, is expected in the coming years.
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Affiliation(s)
- Sean C Dougherty
- Division of Hematology/Oncology, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia; and
| | - William L Flowers
- Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, Virginia
| | - Elizabeth M Gaughan
- Division of Hematology/Oncology, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia; and
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31
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Song P, Pan G, Zhang Y, Ni Y, Wang Q, Shi J, Peng Y, Jing R, Luo D. Prospects and Challenges of Immunotherapy for Thyroid Cancer. Endocr Pract 2024:S1530-891X(24)00840-1. [PMID: 39631664 DOI: 10.1016/j.eprac.2024.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 10/21/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND Thyroid cancer generally boasts a favorable prognosis; however, advanced and refractory cases exhibit aggressive characteristics and resistance to conventional therapies, necessitating the investigation of innovative treatment modalities. Immunotherapy, which harnesses the body's immune system to target cancer cells, has shown considerable promise for specific thyroid cancer subtypes. OBJECTIVE This review article aims to encapsulate the latest advancements in immunotherapy for thyroid cancer, examining its mechanisms, therapeutic efficacy, ongoing challenges, and the potential benefits of combination therapy approaches. METHODS An extensive literature review and critical analysis of clinical trial data were conducted to inform this synthesis. RESULTS The review reveals that immunotherapy strategies, encompassing immune checkpoint inhibitors, CAR-T cell therapy, tumor vaccines, and immunomodulators, are demonstrating efficacy in the treatment of thyroid cancer. Notably, checkpoint inhibitors have been particularly effective in anaplastic and poorly differentiated thyroid cancers, albeit with challenges such as treatment resistance and adverse effects. The application of CAR-T cell therapy, successful in hematologic cancers, provides a novel perspective for thyroid cancer treatment, although its efficacy in solid tumors requires further study. Additionally, research into tumor vaccines and immunomodulators is advancing, with preliminary evidence suggesting their therapeutic potential for thyroid cancer patients. CONCLUSION The recognition of the immune microenvironment's role in treatment responsiveness is pivotal for enhancing the care of thyroid cancer patients. This review underscores the significance of combination therapy as a means to optimize treatment outcomes and charts a course for future research endeavors to broaden the spectrum of effective treatment options available to thyroid cancer patients.
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Affiliation(s)
- Ping Song
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - Gang Pan
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - Yu Zhang
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - Yeqin Ni
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - Qianyu Wang
- The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jingjng Shi
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - You Peng
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China
| | - Ruirui Jing
- Department of Translational Medicine and Clinical Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Dingcun Luo
- Department of Surgical Oncology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China; The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China; College of Mathematical Medicine, Zhejiang Normal University, Jinhua, Zhejiang, China.
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32
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Ali A, Alamri A, Hajar A. NK/DC crosstalk-modulating antitumor activity via Sema3E/PlexinD1 axis for enhanced cancer immunotherapy. Immunol Res 2024; 72:1217-1228. [DOI: https:/doi.org/10.1007/s12026-024-09536-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 08/29/2024] [Indexed: 01/06/2025]
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33
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McKechnie T, Talwar G, Grewal S, Wang A, Eskicioglu C, Parvez E. The impact of statins on melanoma survival: a systematic review and meta-analysis. Melanoma Res 2024; 34:475-486. [PMID: 39264579 DOI: 10.1097/cmr.0000000000001001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
Statin use may decrease recurrence and improve survival in patients with melanoma. In this systematic review and meta-analysis, we examine the current body of literature concerning the use of statins as an adjunctive therapy in melanoma, Medline, EMBASE, CENTRAL, and PubMed were systematically searched from inception through to April 2023. Studies were included if they compared patients with melanoma receiving and not receiving statin therapy concurrently with their oncologic treatment in terms of long-term oncologic outcomes. The primary outcome was 5-year overall survival (OS). Meta-analyses was performed with DerSimonian and Laird random effects. Risk of bias was assessed with the ROBINS-I and GRADE was used to assess certainty of evidence. From 952 citations, eight non-randomized studies were identified. Included studies were conducted between 2007 and 2022. Random effects meta-analysis of adjusted hazard ratios from three studies suggested an improvement in 5-year OS with statin use with wide 95% confidence intervals (CIs) crossing the line of no effect (hazard ratio 0.87, 95% CI: 0.73-1.04, P = 0.12, I2 = 95%, very-low certainty). Outcome reporting was heterogeneous across all other oncologic outcomes such that pooling of data was not possible. Risk of bias was serious for seven studies and moderate for one study. This systematic review of studies evaluating the impact of statin use on survival in patients with melanoma found a 13% reduction in risk of death at 5 years from diagnosis - a point estimate suggesting benefit. However, the wide 95% CIs and resultant type II error risk create significant uncertainty.
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Affiliation(s)
- Tyler McKechnie
- Division of General Surgery, Department of Surgery, McMaster University
| | - Gaurav Talwar
- Division of General Surgery, Department of Surgery, McMaster University
| | - Shan Grewal
- Department of Health Sciences, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Austine Wang
- Department of Health Sciences, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Cagla Eskicioglu
- Division of General Surgery, Department of Surgery, McMaster University
- Department of Health Sciences, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Elena Parvez
- Division of General Surgery, Department of Surgery, McMaster University
- Department of Health Sciences, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
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Enríquez-Fuentes JE, Lorenzo-Castro J, Pascual-Santiago MA, Colino-Gallardo AM, Arriola-Villalobos P. Bilateral Panuveitis After Endometrial Cancer Treatment with Dostarlimab: A Case Report. Ocul Immunol Inflamm 2024; 32:2594-2596. [PMID: 39284117 DOI: 10.1080/09273948.2024.2404515] [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: 07/09/2024] [Revised: 09/06/2024] [Accepted: 09/10/2024] [Indexed: 11/28/2024]
Abstract
PURPOSE To report a case of bilateral panuveitis following Dostarlimab therapy for endometrial cancer. METHODS Case report. RESULTS A 73-year-old woman with a history of endometrial cancer, previously treated with Dostarlimab (an immune checkpoint inhibitor), presented to the ophthalmology emergency department with decreased visual acuity in her left eye. Her medical history included immune-mediated thyroid involvement, which led to the discontinuation of Dostarlimab. Subsequently, she developed pneumonitis and pancreatitis. On initial examination in the emergency room, she had poor vision (hand motion in the right eye and 20/200 on the Snellen chart in the left eye), an inflammatory reaction in the anterior chamber, with 1+ cells, small keratic precipitates and broad posterior synechiae in both eyes. Examination of the posterior pole revealed 3+ vitritis, which made it difficult to evaluate the retina. Treatment with oral and topical corticosteroids was initiated, resulting in an improvement in symptoms and the resolution of intraocular inflammation in several weeks. CONCLUSION Immune checkpoint inhibitors are used in the treatment of various types of cancer, with their efficacy demonstrated in different clinical trials. However, they are also associated with a range of adverse reactions. To date, no ocular adverse reactions related to the use of Dostarlimab have been published. A case of bilateral panuveitis potentially induced by Dostarlimab is described.
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35
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Janssen JC, van Dijk B, Hoeijmakers LL, Grünhagen DJ, Bramer WM, Verhoef C, de Gruijl TD, Blank CU, van der Veldt AAM. Local administration of immunotherapy for patients with skin cancer: A systematic review. Cancer Treat Rev 2024; 131:102848. [PMID: 39486396 DOI: 10.1016/j.ctrv.2024.102848] [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: 09/18/2024] [Revised: 10/16/2024] [Accepted: 10/18/2024] [Indexed: 11/04/2024]
Abstract
Since the introduction of immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 receptors, survival has improved significantly for patients with irresectable and metastatic skin cancer, including cutaneous squamous cell cancer and melanoma. However, systemic administration of these drugs is associated with immune related adverse events (irAEs), which can be severe, irreversible and even fatal. To reduce the risk of irAEs associated with systemic exposure to immunotherapeutic drugs, local administration of low doses could be considered. This systematic review provides an overview of early phase clinical trials with drugs that are currently under investigation for intratumoral administration in patients with melanoma and non-melanoma skin cancer.
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Affiliation(s)
- J C Janssen
- Department of Medical Oncology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands; Department of Surgical Oncology and Gastro Intestinal Surgery, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - B van Dijk
- Department of Medical Oncology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - L L Hoeijmakers
- Department of Medical Oncology, Antoni van Leeuwenhoek - Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - D J Grünhagen
- Department of Surgical Oncology and Gastro Intestinal Surgery, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - W M Bramer
- Medical Library, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - C Verhoef
- Department of Surgical Oncology and Gastro Intestinal Surgery, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - T D de Gruijl
- Department of Immunology, Amsterdam UMC, University Medical Center, Amsterdam, the Netherlands
| | - C U Blank
- Department of Medical Oncology, Antoni van Leeuwenhoek - Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands
| | - A A M van der Veldt
- Department of Medical Oncology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands; Department of Radiology & Nuclear Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
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36
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Cao Y, Li X, Pan Y, Wang H, Yang S, Hong L, Ye L. CRISPR-based genetic screens advance cancer immunology. SCIENCE CHINA. LIFE SCIENCES 2024; 67:2554-2562. [PMID: 39048715 DOI: 10.1007/s11427-023-2571-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 03/18/2024] [Indexed: 07/27/2024]
Abstract
CRISPR technologies have revolutionized research areas ranging from fundamental science to translational medicine. CRISPR-based genetic screens offer a powerful platform for unbiased screening in various fields, such as cancer immunology. Immune checkpoint blockade (ICB) therapy has been shown to strongly affect cancer treatment. However, the currently available ICBs are limited and do not work in all cancer patients. Pooled CRISPR screens enable the identification of previously unknown immune regulators that can regulate T-cell activation, cytotoxicity, persistence, infiltration into tumors, cytokine secretion, memory formation, T-cell metabolism, and CD4+ T-cell differentiation. These novel targets can be developed as new immunotherapies or used with the current ICBs as new combination therapies that may yield synergistic efficacy. Here, we review the progress made in the development of CRISPR technologies, particularly technological advances in CRISPR screens and their application in novel target identification for immunotherapy.
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Affiliation(s)
- Yuanfang Cao
- Institute of Modern Biology, Nanjing University, Nanjing, 210008, China
| | - Xueting Li
- Institute of Modern Biology, Nanjing University, Nanjing, 210008, China
| | - Yumu Pan
- Institute of Modern Biology, Nanjing University, Nanjing, 210008, China
| | - Huahe Wang
- Institute of Modern Biology, Nanjing University, Nanjing, 210008, China
| | - Siyu Yang
- Institute of Modern Biology, Nanjing University, Nanjing, 210008, China
| | - Lingjuan Hong
- Institute of Modern Biology, Nanjing University, Nanjing, 210008, China
| | - Lupeng Ye
- Institute of Modern Biology, Nanjing University, Nanjing, 210008, China.
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37
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Zhang Z, Lu Y, Liu W, Huang Y. Nanomaterial-assisted delivery of CpG oligodeoxynucleotides for boosting cancer immunotherapy. J Control Release 2024; 376:184-199. [PMID: 39368710 DOI: 10.1016/j.jconrel.2024.09.044] [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: 05/09/2024] [Revised: 08/03/2024] [Accepted: 09/26/2024] [Indexed: 10/07/2024]
Abstract
Cancer immunotherapy aims to improve immunity to not only eliminate the primary tumor but also inhibit metastasis and recurrence. It is considered an extremely promising therapeutic approach that breaks free from the traditional paradigm of oncological treatment. As the medical community learns more about the immune system's mechanisms that "turn off the brake" and "step on the throttle", there is increasingly successful research on immunomodulators. However, there are still more restrictions than countermeasures with immunotherapy related to immunomodulators, such as low responsiveness and immune-related adverse events that cause multiple adverse reactions. Therefore, medical experts and materials scientists attempted to the efficacy of immunomodulatory treatments through various methods, especially nanomaterial-assisted strategies. CpG oligodeoxynucleotides (CpG) not only act as an adjuvant to promote immune responses, but also induce autophagy. In this review, the enhancement of immunotherapy using nanomaterial-based CpG formulations is systematically elaborated, with a focus on the delivery, protection, synergistic promotion of CpG efficacy by nanomaterials, and selection of the timing of treatment. In addition, we also discuss and prospect the existing problems and future directions of research on nanomaterials in auxiliary CpG therapy.
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Affiliation(s)
- Zhiyu Zhang
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University/Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Yu Lu
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University/Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
| | - Wenjing Liu
- Department of Pharmacology, Beijing Chest Hospital, Capital Medical University/Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
| | - Yuanyu Huang
- School of Life Science, Advanced Research Institute of Multidisciplinary Science, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing 100081, China
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Ali A, Alamri A, Hajar A. NK/DC crosstalk-modulating antitumor activity via Sema3E/PlexinD1 axis for enhanced cancer immunotherapy. Immunol Res 2024; 72:1217-1228. [PMID: 39235526 DOI: 10.1007/s12026-024-09536-y] [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: 06/14/2024] [Accepted: 08/29/2024] [Indexed: 09/06/2024]
Abstract
The complex relationship between natural killer (NK) cells and dendritic cells (DCs) within the tumor microenvironment significantly impacts the success of cancer immunotherapy. Recent advancements in cancer treatment have sought to bolster innate and adaptive immune responses through diverse modalities, aiming to tilt the immune equilibrium toward tumor elimination. Optimal antitumor immunity entails a multifaceted interplay involving NK cells, T cells and DCs, orchestrating immune effector functions. Although DC-based vaccines and NK cells' cytotoxic capabilities hold substantial therapeutic potential, their interaction is frequently hindered by immunosuppressive elements such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells. Chemokines and cytokines, such as CXCL12, CCL2, interferons, and interleukins, play crucial roles in modulating NK/DC interactions and enhancing immune responses. This review elucidates the mechanisms underlying NK/DC interaction, emphasizing their pivotal roles in augmenting antitumor immune responses and the impediments posed by tumor-induced immunosuppression. Furthermore, it explores the therapeutic prospects of restoring NK/DC crosstalk, highlighting the significance of molecules like Sema3E/PlexinD1 in this context, offering potential avenues for enhancing the effectiveness of current immunotherapeutic strategies and advancing cancer treatment paradigms. Harnessing the dynamic interplay between NK and DC cells, including the modulation of Sema3E/PlexinD1 signaling, holds promise for developing more potent therapies that harness the immune system's full potential in combating cancer.
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Affiliation(s)
- Awais Ali
- Department of Biochemistry, Abdul Wali Khan University Mardan (AWKUM), Mardan, 23200, Pakistan.
| | - Abdulaziz Alamri
- Department of Biochemistry, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Azraida Hajar
- Department of Biology, Faculty of Sciences Semlalia, Cadi Ayyad University, Marrakech, Morocco
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Leitner J, Aigner‐Radakovics K, Steinberger P. LAG-3-An incompletely understood target in cancer therapy. FASEB J 2024; 38:e70190. [PMID: 39560030 PMCID: PMC11698013 DOI: 10.1096/fj.202401639r] [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: 07/16/2024] [Revised: 10/23/2024] [Accepted: 11/05/2024] [Indexed: 11/20/2024]
Abstract
LAG-3 is a member of the immunoglobulin superfamily expressed on activated T cells, but also on other immune cells. It has significant homology to CD4. Both molecules have four extracellular Ig-like domains with similar structural motifs but the sequence identity between LAG-3 and CD4 is low. Furthermore, unlike CD4 LAG-3 restrains T cell responses and antibodies targeting this receptor are emerging drugs in cancer immunotherapy. A combination of LAG-3 and PD-1 antibodies has already been approved for the treatment of metastatic melanoma. Despite this success, its biology is still not well understood. Here we summarize the current knowledge on expression, ligands, and function of LAG-3. We point to the differences between LAG-3 and other inhibitory immune checkpoints and describe obstacles to study the role of this receptor in T cell activation processes. Finally, we discuss future directions for scientific efforts to come to a more complete understanding of the biology of this eminent immune checkpoint.
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Affiliation(s)
- Judith Leitner
- Division for Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and ImmunologyMedical University of ViennaViennaAustria
| | - Katharina Aigner‐Radakovics
- Division for Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and ImmunologyMedical University of ViennaViennaAustria
| | - Peter Steinberger
- Division for Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and ImmunologyMedical University of ViennaViennaAustria
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Ben Saad E, Oroya A, Anto NP, Bachais M, Rudd CE. PD-1 endocytosis unleashes the cytolytic potential of checkpoint blockade in tumor immunity. Cell Rep 2024; 43:114907. [PMID: 39471174 DOI: 10.1016/j.celrep.2024.114907] [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: 10/03/2023] [Revised: 09/12/2024] [Accepted: 10/08/2024] [Indexed: 11/01/2024] Open
Abstract
PD-1 immune checkpoint blockade (ICB) is a key cancer treatment. While blocking PD-1 binding to ligand is known, the role of internalization in enhancing ICB efficacy is less explored. Our study reveals that PD-1 internalization helps unlock ICB's full potential in cancer immunotherapy. Anti-PD-1 induces 50%-60% surface PD-1 internalization from human and mouse cells, leaving low to intermediate levels of resistant receptors. Complexes then appear in early and late endosomes. Both CD4 and CD8 T cells, especially CD8+ effectors, are affected. Nivolumab outperforms pembrolizumab in human T cells, while PD-1 internalization requires crosslinking by bivalent antibody. While mono- and bivalent anti-PD-1 inhibit tumor growth with CD8 tumor-infiltrating cells expressing increased granzyme B, bivalent antibody is more effective where the combination of steric blockade and endocytosis induces greater CD8+ T cell tumor infiltration and the expression of the cytolytic pore protein, perforin. Our findings highlight an ICB mechanism that combines steric blockade and PD-1 endocytosis for optimal checkpoint immunotherapy.
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Affiliation(s)
- Elham Ben Saad
- Department of Medicine, Universite de Montréal, Montréal, QC H3C 3J7, Canada; Centre de Recherche Hopital Maisonneuve-Rosemont, Montréal, Quebec, QC H1T 2M4, Canada; Department of Biochemistry and Molecular Medicine, Universite de Montréal, Montréal, QC H3T 1J4, Canada
| | - Andres Oroya
- Department of Medicine, Universite de Montréal, Montréal, QC H3C 3J7, Canada; Centre de Recherche Hopital Maisonneuve-Rosemont, Montréal, Quebec, QC H1T 2M4, Canada; Department of Microbiology, Infection and Immunology, Universite de Montréal, Montréal, QC, Canada
| | - Nikhil Ponnoor Anto
- Department of Medicine, Universite de Montréal, Montréal, QC H3C 3J7, Canada; Centre de Recherche Hopital Maisonneuve-Rosemont, Montréal, Quebec, QC H1T 2M4, Canada; Department of Microbiology, Infection and Immunology, Universite de Montréal, Montréal, QC, Canada
| | - Meriem Bachais
- Department of Medicine, Universite de Montréal, Montréal, QC H3C 3J7, Canada; Centre de Recherche Hopital Maisonneuve-Rosemont, Montréal, Quebec, QC H1T 2M4, Canada; Department of Microbiology, Infection and Immunology, Universite de Montréal, Montréal, QC, Canada
| | - Christopher E Rudd
- Department of Medicine, Universite de Montréal, Montréal, QC H3C 3J7, Canada; Centre de Recherche Hopital Maisonneuve-Rosemont, Montréal, Quebec, QC H1T 2M4, Canada; Department of Biochemistry and Molecular Medicine, Universite de Montréal, Montréal, QC H3T 1J4, Canada; Department of Microbiology, Infection and Immunology, Universite de Montréal, Montréal, QC, Canada.
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Nishikawa T, Kakunaga S, Tamura K, Ando M, Ozaki T, Kawai A, Ueda T, Kawasaki M, Tomatsuri S, Okamura N, Kamikura M, Hamada A, Yoshida A, Hirakawa A, Shibata T, Nakamura K, Yonemori K. Efficacy and safety of nivolumab monotherapy in patients with unresectable clear cell sarcoma and alveolar soft part sarcoma (OSCAR Trial/NCCH1510). Cancer 2024; 130:3836-3844. [PMID: 39077795 DOI: 10.1002/cncr.35483] [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: 03/21/2024] [Revised: 06/07/2024] [Accepted: 06/21/2024] [Indexed: 07/31/2024]
Abstract
BACKGROUND Clear cell sarcoma (CCS) and alveolar soft part sarcoma (ASPS) are rare, and standard systemic therapy is not established except for sunitinib in ASPS. It is known that CCS and ASPS have a common biological feature of melanoma and Xp11.2/TFE3 translocation renal cell carcinoma, and immune-checkpoint inhibitors (ICIs) are effective in these tumors. The authors conducted a phase 2 trial to evaluate the efficacy and safety of nivolumab for CCS and ASPS. METHODS The number of patients expected to be enrolled was 15-25 and was determined based on the Bayesian design. The primary end point was the confirmed objective response rate (ORR) according to the central review and the secondary end points included ORR, progression-free survival (PFS), overall survival (OS), and safety. RESULTS A total of 26 patients (CCS, 12; ASPS, 14) were enrolled. Efficacy and safety were analyzed on 25 and 26 patients, respectively. The minimum number of responses required for a positive conclusion regarding the efficacy was four. However, only one patient (4.0%) with ASPS had a partial response. Complete response, stable disease, progression disease, and not evaluable were 0%, 60%, 32%, and 4.0%, respectively. Adverse events of grade 3 or 4 occurred in 57.7% (15 of 26). The median PFS was 4.9 months (95% confidence interval [CI], 3.7-8.6 months) and the median OS was 15.8 months (95% CI, 8.2-not reached). CONCLUSIONS The primary end point of the ORR was not met for CCS and ASPS on the central review. Further studies are needed to evaluate ICIs in patients with ASPS.
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Affiliation(s)
- Tadaaki Nishikawa
- Department of Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Shigeki Kakunaga
- Department of Orthopedic Surgery, National Hospital Organization Osaka National Hospital, Chuo-ku, Osaka, Japan
- Department of Orthopedic Surgery, Osaka International Cancer Institute, Chuo-ku, Osaka, Japan
| | - Kenji Tamura
- Department of Medical Oncology, Shimane University, Izumo, Shimane, Japan
| | - Masashi Ando
- Department of Medical Oncology, Aichi Cancer Center, Chikusa-ku, Nagoya, Aichi, Japan
| | - Toshifumi Ozaki
- Department of Orthopedic Surgery, Okayama University, Kita-ku, Okayama, Japan
| | - Akira Kawai
- Department of Musculoskeletal Oncology and Rehabilitation Medicine, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Takafumi Ueda
- Department of Orthopedic Surgery, Kodama Hospital, Takarazuka, Hyogo, Japan
| | - Mamiko Kawasaki
- Clinical Research Support Office, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Sawako Tomatsuri
- Clinical Research Support Office, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Nobuko Okamura
- Clinical Research Support Office, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Masahisa Kamikura
- Clinical Research Support Office, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Akinobu Hamada
- Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo, Japan
| | - Akihiko Yoshida
- Department of Diagnostic Pathology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Akihiro Hirakawa
- Department of Clinical Biostatistics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Taro Shibata
- Biostatistics Division, Center for Research Administration and Support, National Cancer Center, Chuo-ku, Tokyo, Japan
| | - Kenichi Nakamura
- Clinical Research Support Office, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Kan Yonemori
- Department of Medical Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
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Long GV, Larkin J, Schadendorf D, Grob JJ, Lao CD, Márquez-Rodas I, Wagstaff J, Lebbé C, Pigozzo J, Robert C, Ascierto PA, Atkinson V, Postow MA, Atkins MB, Sznol M, Callahan MK, Topalian SL, Sosman JA, Kotapati S, Thakkar PK, Ritchings C, Pe Benito M, Re S, Soleymani S, Hodi FS. Pooled Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone in Patients With Advanced Melanoma. J Clin Oncol 2024:JCO2400400. [PMID: 39504507 DOI: 10.1200/jco.24.00400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 07/30/2024] [Accepted: 08/23/2024] [Indexed: 11/08/2024] Open
Abstract
PURPOSE Nivolumab (NIVO) + ipilimumab (IPI) combination and NIVO monotherapy have demonstrated durable clinical benefit in patients with unresectable/metastatic melanoma. This analysis describes long-term overall survival (OS) with the combination or monotherapy pooled across all major company-sponsored trials, as well as clinical factors associated with survival, in patients with immune checkpoint inhibitor (ICI) treatment-naïve unresectable/metastatic melanoma. METHODS Data were pooled from six CheckMate studies in ICI treatment-naïve patients receiving NIVO + IPI (NIVO 1 mg/kg + IPI 3 mg/kg or NIVO 3 mg/kg + IPI 1 mg/kg) or NIVO monotherapy (3 mg/kg). OS was assessed for each treatment, as well as in select subgroups. Cox proportional multivariate analysis (MVA) and classification and regression tree (CART) analyses were performed within treatment arms. RESULTS Median follow-up for OS was 45.0 months for patients treated with NIVO + IPI (n = 839) and 35.8 months for patients treated with NIVO (n = 536). OS was longer with NIVO + IPI versus NIVO monotherapy (hazard ratio, 0.78 [95% CI, 0.67 to 0.91]), with 6-year OS rates of 52% versus 41%, respectively. Consistent benefit was observed in BRAF-mutant and BRAF-wild-type patients and those with normal and elevated lactate dehydrogenase (LDH). Numerical difference in OS was also observed across PD-L1 expression levels, although more pronounced with no/low PD-L1 expression. Clinical factors associated with decreased survival in both the MVA and CART analyses were LDH > upper limit of normal with either treatment, age ≥65 years with NIVO + IPI, and the presence of liver metastases with NIVO monotherapy. CONCLUSION In this large, pooled nonrandomized retrospective analysis, we observed that NIVO + IPI provides longer OS than NIVO in patients with ICI treatment-naïve advanced melanoma and identifies clinical factors that appear to be associated with survival for each treatment, which may assist with treatment decision making.
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Affiliation(s)
- Georgina V Long
- Melanoma Institute Australia and Royal North Shore and Mater Hospitals, The University of Sydney, Sydney, NSW, Australia
| | - James Larkin
- The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom
| | - Dirk Schadendorf
- University Hospital, German Cancer Consortium (DKTK), National Center for Tumor Diseases (NCT)-West, Campus Essen, & Research Alliance Ruhr, Research Center One Health, University Duisburg-Essen, Essen, Germany
| | | | | | | | - John Wagstaff
- Swansea University Medical School, Swansea, United Kingdom
| | - Céleste Lebbé
- Université Paris Cité, AP-HP Dermato-oncology, Cancer Institute AP-HP, Nord Paris Cité, INSERM U976, Saint Louis Hospital, Paris, France
| | | | - Caroline Robert
- Gustave Roussy, Institut National de la Santé et de la Recherche Médicale U981, Paris, France
| | - Paolo A Ascierto
- Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy
| | - Victoria Atkinson
- Princess Alexandra Hospital, Woolloongabba, and Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD, Australia
| | - Michael A Postow
- Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY
| | | | - Mario Sznol
- Yale University School of Medicine and Yale Cancer Center, New Haven, CT
| | - Margaret K Callahan
- Princess Alexandra Hospital, Woolloongabba, and Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD, Australia
| | - Suzanne L Topalian
- Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
| | | | | | | | | | | | - Sandra Re
- Bristol Myers Squibb, Princeton, NJ
- Current address Daiichi Sankyo, Inc, Basking Ridge, NJ
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Wang Q, Su T, Cheng F, Zhou S, Liu X, Wang M, Xu Y, Tang R, Liao S, Dailey J, Xiao G, Yang C, Wen H, Zheng W, Wen B, Tyc KM, Liu J, Sun D, Wang S, Zhu G. Proteolysis-targeting vaccines (PROTAVs) for robust combination immunotherapy of melanoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.01.616069. [PMID: 39574605 PMCID: PMC11580958 DOI: 10.1101/2024.10.01.616069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/30/2024]
Abstract
Protein/peptide subunit vaccines are promising to promote the tumor therapeutic efficacy of immune checkpoint blockade (ICB). However, current protein/peptide vaccines elicit limited antitumor T cell responses, leading to suboptimal therapeutic efficacy. Here, we present proteolysis-targeting vaccines (PROTAVs) that facilitate antigen proteolytic processing and cross-presentation to potentiate T cell responses for robust ICB combination immunotherapy of melanoma. PROTAVs are modular conjugates of protein/peptide antigens, E3 ligase-binding ligands, and linkers. In antigen-presenting cells (APCs), PROTAVs bind to E3 ligases to rapidly ubiquitinate PROTAV antigens, facilitating antigen proteolytic processing by proteasome, and thereby promoting antigen cross-presentation to T cells and potentiating CD8+ T cell responses. We developed a melanoma PROTAV using a tandem peptide of trivalent melanoma-associated antigens. Co-delivered by lipid nanoparticles (LNPs) with bivalent immunostimulant adjuvants, this PROTAV promotes the quantity and quality of melanoma-specific CD8+ T cells in mice. Further, combining PROTAV and ICB ameliorates the immunosuppressive melanoma microenvironment. As a result, PROTAV and ICB combination enhances melanoma complete regression rates and eradicated 100% large Braf V600E melanoma without recurrence in syngeneic mice. PROTAVs hold the potential for robust tumor combination immunotherapy.
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Affiliation(s)
- Qiyan Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Ting Su
- Department of Pharmaceutics and Center for Pharmaceutical Engineering, College of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620, China
| | - Furong Cheng
- Department of Pharmaceutics and Center for Pharmaceutical Engineering, College of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Shurong Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Xiang Liu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Mi Wang
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - You Xu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Ri Tang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Shimiao Liao
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jordan Dailey
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Guolan Xiao
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Chunpeng Yang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Hanning Wen
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
| | - Weijia Zheng
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Bo Wen
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Katarzyna M Tyc
- Department of Biostatistics, School of Public Health; Bioinformatics Shared Resource, Massey Comprehensive Cancer Center; Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Jinze Liu
- Department of Biostatistics, School of Public Health; Bioinformatics Shared Resource, Massey Comprehensive Cancer Center; Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Duxin Sun
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Shaomeng Wang
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
| | - Guizhi Zhu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
- Bioinnovations in Brain Cancer, Biointerfaces Institute; Center for RNA Biomedicine. University of Michigan, Ann Arbor, MI 48109, USA
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Teo AYT, Yau CE, Low CE, Pereira JVB, Ng JYX, Soong TK, Lo JYT, Yang VS. Effectiveness of immune checkpoint inhibitors and other treatment modalities in patients with advanced mucosal melanomas: a systematic review and individual patient data meta-analysis. EClinicalMedicine 2024; 77:102870. [PMID: 39416390 PMCID: PMC11474374 DOI: 10.1016/j.eclinm.2024.102870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 09/17/2024] [Accepted: 09/17/2024] [Indexed: 10/19/2024] Open
Abstract
Background Mucosal melanomas (MM) are an aggressive subtype of melanoma. Given the rarity of this disease, the conduct of clinical trials is challenging and has been limited. Current treatment options have been extrapolated from the more common cutaneous melanoma even though MM is distinct in pathogenesis, etiology and prognosis. This is the first meta-analysis to comprehensively assess the efficacy of immune checkpoint inhibitors (anti-PD1 and anti-CTLA4) and other treatment modalities (targeted therapy such as KIT inhibitors and VEGF inhibitors, as well as radiotherapy) on survival outcomes in MM to develop clinical guidelines for evidence-based management. Methods The protocol was prospectively registered on PROSPERO (PROSPERO ID: CRD42023411195). PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and Google Scholar were searched from inception until 25 July 2024, for all cohort and observational studies. Eligible studies included those with five or more participants with locally advanced or metastatic MM treated with anti-PD1, anti-CTLA4, VEGF inhibitors and/or KIT inhibitors. Titles and abstracts of potential articles were screened and full texts of all potentially eligible studies were retrieved and reviewed by two independent reviewers. Individual patient data (IPD) from published Kaplan-Meier curves were reconstructed using a graphical reconstruction method and pooled as a one-stage meta-analysis. A sensitivity analysis using a two-stage meta-analysis approach was conducted. Extracted outcomes included overall survival (OS) and progression-free survival (PFS). For each treatment arm, median survival time and 12-month survival proportion were estimated. Data from double-arm trials was pooled to estimate hazard ratios (HRs), ratios of restricted mean time lost (RMTL) and restricted mean survival time (RMST). Findings From a total of 7402 studies, 35 eligible studies comprising a total of 2833 participants were included. Combined anti-PD1 and anti-CTLA4 therapy had the highest 12-month OS and 12-month PFS at 71.8% (95% CI: 67.6%, 76.2%, n = 476) and 35.1% (95% CI: 30.5%, 40.4%, n = 401) respectively, followed by anti-PD1 therapy alone (OS: 64.0% (95% CI: 61.4%, 66.7%, n = 1399); PFS: was 28.3% (95% CI: 25.8%, 31.2%, n = 1142), anti-PD1 and VEGF inhibitor combination therapy (OS: 57.1% (95% CI: 51.0%, 63.9%)), KIT inhibitors (OS: 48.2% (95% CI: 37.6%, 61.8%); PFS: 8.3% (95% CI: 3.7%, 18.7%)) and anti-CTLA4 therapy alone (OS: 33.3% (95% CI: 28.4%, 39.1%); PFS: 9.8% (95% CI: 5.9%, 16.5%)). In the double-arm studies, combination therapy with anti-PD1 and anti-CTLA4 had similar OS and PFS with anti-PD1 alone (OS: HR 0.856 (95% CI: 0.704, 1.04); RMTL ratio 0.932 (95% CI: 0.832, 1.044, P = 0.225); RMST ratio 1.102 (95% CI: 0.948, 1.281, P = 0.204); PFS: HR 0.919 (95% CI: 0.788, 1.07); RMTL ratio 0.936 (95% CI: 0.866, 1.013, P = 0.100); RMST ratio 1.21 (95% CI: 0.979, 1.496, P = 0.078)), however, anti-PD1 therapy alone had significantly better PFS than anti-CTLA4 alone (HR 0.548 (95% CI: 0.376, 0.799); RMTL ratio 0.715 (95% CI: 0.606, 0.844, P < 0.001); RMST ratio 1.659 (95% CI: 1.316, 2.092, P < 0.001)). Anti-PD1 therapy with radiotherapy versus anti-PD1 alone showed no significant difference (OS: HR 0.854 (95% CI: 0.567, 1.29); RMTL ratio 0.855 (95% CI: 0.675, 1.083, P = 0.193); RMST ratio 1.194 (95% CI: 0.928, 1.536, P = 0.168; PFS: HR 0.994 (95% CI: 0.710, 1.39); RMTL ratio 1.006 (95% CI: 0.87, 1.162, P = 0.939); RMST ratio 0.984 (95% CI: 0.658, 1.472, P = 0.939)). Interpretation For the systemic treatment of MM, anti-PD1 is the best monotherapy. While combining anti-PD1 with other treatment options such as anti-CTLA4, VEGF inhibitors or radiotherapy might achieve better outcomes, these improvements did not reach statistical significance when evaluated by HR, RMTL and RMST ratios. Funding This work was supported by the National Medical Research Council Transition Award (TA20nov-0020), SingHealth Duke-NUS Oncology Academic Clinical Programme (08/FY2020/EX/67-A143 and 08/FY2021/EX/17-A47), the Khoo Pilot Collaborative Award (Duke-NUS-KP(Coll)/2022/0020A), the National Medical Research Council Clinician Scientist-Individual Research Grant-New Investigator Grant (CNIGnov-0025), the Terry Fox Grant (I1056) and the Khoo Bridge Funding Award (Duke-NUS-KBrFA/2024/0083I).
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Affiliation(s)
- Andrea York Tiang Teo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
- Singapore General Hospital, Singapore, 169608, Singapore
| | - Chun En Yau
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Chen Ee Low
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | | | | | | | - Jack Yu Tung Lo
- Department of Neurosurgery, National Neuroscience Institute, Singapore, 308433, Singapore
| | - Valerie Shiwen Yang
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, 169610, Singapore
- Translational Precision Oncology Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, 138673, Singapore
- Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore, 169857, Singapore
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Song Q, Jiang M, Pan X, Zhou G, Zhang X. A study on the efficacy and Safety Evaluation of a novel PD-1/CTLA-4 bispecific antibody. Immunobiology 2024; 229:152844. [PMID: 39226691 DOI: 10.1016/j.imbio.2024.152844] [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: 02/08/2024] [Revised: 07/22/2024] [Accepted: 08/23/2024] [Indexed: 09/05/2024]
Abstract
Tumors constitute a significant health concern for humans, and PD-1 and CTLA-4 monoclonal antibodies have been proven effective in cancer treatment. Some researchers have identified that the combination of PD-1 and CTLA-4 dual blockade demonstrates superior therapeutic efficacy. However, the development of PD-1/CTLA-4 bispecific antibodies faces challenges in terms of both safety and efficacy. The present study discloses a novel PD-1/CTLA-4 bispecific antibody, designated as SH010. Experimental validation through surface plasmon resonance (SPR) confirmed that SH010 exhibits favorable binding activity with both PD-1 and CTLA-4. Flow cytometry analysis demonstrated stable binding of SH010 antibody to CHOK1 cells overexpressing human or cynomolgus monkey PD-1 protein and to 293F cells overexpressing human or cynomolgus monkey CTLA-4 protein. Moreover, it exhibited excellent blocking capabilities in protein binding between human PD-1 and PD-L1, as well as human CTLA-4 and CD80/CD86. Simultaneously, in vitro experiments indicate that SH010 exerts a significant activating effect on hPBMCs. In murine transplant models of human prostate cancer (22RV1) and small cell lung cancer (NCI-H69), administration of varying concentrations of the bispecific antibody significantly inhibits tumor growth. MSD analysis revealed that stimulation of hPBMCs from three different donors with SH010 did not induce the production of cytokine release syndrome. Furthermore, Single or repeated intravenous administrations of SH010 in cynomolgus monkeys show favorable systemic exposure without noticeable drug accumulation or apparent toxicity. In conclusion, SH010 represents a novel cancer therapeutic drug poised to enter clinical trials and obtain market approval.
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Affiliation(s)
- Qi Song
- Department of Pharmacology, SanHome, Nanjing, PR China; College of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China
| | - Meiling Jiang
- Department of Pharmacology, SanHome, Nanjing, PR China
| | - Xinrong Pan
- Department of Pharmacology, SanHome, Nanjing, PR China
| | - Guanyue Zhou
- Department of Pharmacology, SanHome, Nanjing, PR China
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Hussein NI, Molina AH, Sunga GM, Amit M, Lei YL, Zhao X, Hartgerink JD, Sikora AG, Young S. Localized intratumoral delivery of immunomodulators for oral cancer and oral potentially malignant disorders. Oral Oncol 2024; 158:106986. [PMID: 39137489 DOI: 10.1016/j.oraloncology.2024.106986] [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: 04/26/2024] [Revised: 07/26/2024] [Accepted: 08/06/2024] [Indexed: 08/15/2024]
Abstract
Immunotherapy has developed into an important modality of modern cancer treatment. Unfortunately, checkpoint inhibitor immunotherapies are currently delivered systemically and require frequent administration, which can result in toxicity and severe, sometimes fatal, adverse events. Localized delivery of immunomodulators for oral cancer and oral potentially malignant disorders offers the promise of maximum therapeutic potential and reduced systemic adverse effects. This review will discuss the limitations of current standard-of-care systemic therapies and highlight research advances in localized, intratumoral delivery platforms for immunotherapy for oral cancer and oral potentially malignant disorders.
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Affiliation(s)
- Nourhan I Hussein
- Katz Department of Oral and Maxillofacial Surgery, The University of Texas Health Science Center at Houston, School of Dentistry, 7500 Cambridge St, SOD-6510, Houston, TX 77054, USA
| | - Andrea H Molina
- Katz Department of Oral and Maxillofacial Surgery, The University of Texas Health Science Center at Houston, School of Dentistry, 7500 Cambridge St, SOD-6510, Houston, TX 77054, USA
| | - Gemalene M Sunga
- Katz Department of Oral and Maxillofacial Surgery, The University of Texas Health Science Center at Houston, School of Dentistry, 7500 Cambridge St, SOD-6510, Houston, TX 77054, USA; Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Pickens-1550, Houston, TX 77030, USA
| | - Moran Amit
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Pickens-1550, Houston, TX 77030, USA
| | - Yu Leo Lei
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Pickens-1550, Houston, TX 77030, USA
| | - Xiao Zhao
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Pickens-1550, Houston, TX 77030, USA
| | - Jeffrey D Hartgerink
- Department of Chemistry and Department of Bioengineering, Rice University, 6500 Main St, BRC-319, Houston, TX 77030, USA
| | - Andrew G Sikora
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Pickens-1550, Houston, TX 77030, USA
| | - Simon Young
- Katz Department of Oral and Maxillofacial Surgery, The University of Texas Health Science Center at Houston, School of Dentistry, 7500 Cambridge St, SOD-6510, Houston, TX 77054, USA.
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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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Moës B, Gao Y, Demina E, Kremer R, Rudd CE. Anti-PTHrP blockade limits CD8+ T-cell exhaustion in anti-cancer immunotherapy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.23.619890. [PMID: 39554058 PMCID: PMC11566012 DOI: 10.1101/2024.10.23.619890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Cancer is a major global health concern, with immune suppression hindering treatment. Immunotherapy, specifically immune checkpoint blockage on T cells, has revolutionized cancer treatment. T-cell exhaustion is an abnormal activation state that develops when continuous exposure to antigens, like cancer. In this context, recent evidence suggests that parathyroid hormone-related protein (PTHrP) plays a previously underappreciated role in fostering an immunosuppressive tumor microenvironment. Further, blocking PTHrP activity reduces primary tumor growth, prevents metastasis, and prolongs survival in mice with various cancers. Here, we confirm that administration of anti-PTHrP monoclonal antibodies can reduce the growth of B16-PDL1 melanoma tumors and that although the therapy did not alter the presence of CD4+ and CD8+ TILs, we noted that all stages of T-cell exhaustion were reduced. Further, the expression of cytolytic proteins PERFORIN and GZMB also increased. By contrast, anti-PTHrP therapy increased the relative presence of pre-pro B cells with a decline in mature B cells in the bone marrow. Overall, our data indicates that anti-PTHrP therapy acts by reducing T-cell exhaustion and by affecting B-cell development. These provide further mechanistic evidence to support the application of anti-PTHrP blockade as an alternate therapeutic approach to boost anti-tumor immunity.
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Cheema PK, Iafolla MAJ, Abdel-Qadir H, Bellini AB, Chatur N, Chandok N, Comondore VR, Cunningham M, Halperin I, Hu AB, Jaskolka D, Darvish-Kazem S, Khandaker MH, Kitchlu A, Sachdeva JS, Shapera S, Woolnough NRJ, Nematollahi M. Managing Select Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitors. Curr Oncol 2024; 31:6356-6383. [PMID: 39451777 PMCID: PMC11506662 DOI: 10.3390/curroncol31100473] [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: 09/17/2024] [Revised: 10/12/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024] Open
Abstract
The increased use of immune checkpoint inhibitors (ICIs) across cancer programs has created the need for standardized monitoring and management of immune-related adverse events (irAEs). Delayed recognition without appropriate treatment can have serious and life-threatening consequences. The management of irAEs presents a unique set of challenges that must be addressed at a multidisciplinary level. Although various national and international guidelines and working groups provide high-level recommendations for the management of irAEs, practical guidance is lacking. Furthermore, timely collaboration between specialists requires institutional protocols that enable the early recognition, assessment, and treatment of irAEs. Such protocols should be developed by institution specialists and include algorithms for all healthcare providers involved in the care of patients treated with ICIs. At William Osler Health System in Brampton, Ontario, practical step-by-step multidisciplinary treatment approaches with recommendations for the management of irAEs were developed in collaboration with experts across Canada. Here, we provide an in-depth description of the approaches, outlining baseline investigations prior to the initiation of ICIs, as well as the monitoring and management of irAEs based on symptoms, severity, and involved organ systems. We encourage other centres to adapt and modify our approaches according to their specific needs and requirements.
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Affiliation(s)
- Parneet K. Cheema
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Marco A. J. Iafolla
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Husam Abdel-Qadir
- Women’s College Hospital Research Institute, Toronto, ON M5S 1B2, Canada;
- Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, ON M5G 2N2, Canada
| | - Andrew B. Bellini
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Nazira Chatur
- Division of Gastroenterology, Faculty of Medicine, Vancouver General Hospital (Sanders), University of British Columbia, Vancouver, BC V5Z 1M9, Canada;
| | - Natasha Chandok
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Vikram R. Comondore
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Morven Cunningham
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON M5G 2C4, Canada;
| | - Ilana Halperin
- Division of Endocrinology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada;
| | - Anne B. Hu
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Diana Jaskolka
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Saeed Darvish-Kazem
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Masud H. Khandaker
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Abhijat Kitchlu
- Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, ON M5G 2C4, Canada;
| | - Jasdip S. Sachdeva
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Shane Shapera
- Department of Medicine, University of Toronto, Toronto, ON M5G 2N2, Canada;
| | - Nicholas R. J. Woolnough
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Massey Nematollahi
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
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Singh A, Miranda Bedate A, von Richthofen HJ, Vijver SV, van der Vlist M, Kuhn R, Yermanos A, Kuball JJ, Kesmir C, Pascoal Ramos MI, Meyaard L. A novel bioinformatics pipeline for the identification of immune inhibitory receptors as potential therapeutic targets. eLife 2024; 13:RP92870. [PMID: 39377459 PMCID: PMC11460946 DOI: 10.7554/elife.92870] [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] [Indexed: 10/09/2024] Open
Abstract
Despite major successes with inhibitory receptor blockade in cancer, the identification of novel inhibitory receptors as putative drug targets is needed due to lack of durable responses, therapy resistance, and side effects. Most inhibitory receptors signal via immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and previous studies estimated that our genome contains over 1600 ITIM-bearing transmembrane proteins. However, testing and development of these candidates requires increased understanding of their expression patterns and likelihood to function as inhibitory receptor. Therefore, we designed a novel bioinformatics pipeline integrating machine learning-guided structural predictions and sequence-based likelihood models to identify putative inhibitory receptors. Using transcriptomics data of immune cells, we determined the expression of these novel inhibitory receptors, and classified them into previously proposed functional categories. Known and putative inhibitory receptors were expressed across different immune cell subsets with cell type-specific expression patterns. Furthermore, putative immune inhibitory receptors were differentially expressed in subsets of tumour infiltrating T cells. In conclusion, we present an inhibitory receptor pipeline that identifies 51 known and 390 novel human inhibitory receptors. This pipeline will support future drug target selection across diseases where therapeutic targeting of immune inhibitory receptors is warranted.
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Affiliation(s)
- Akashdip Singh
- Center for Translational Immunology, University Medical Centre Utrecht, Utrecht UniversityUtrechtNetherlands
- Oncode InstituteUtrechtNetherlands
| | - Alberto Miranda Bedate
- Center for Translational Immunology, University Medical Centre Utrecht, Utrecht UniversityUtrechtNetherlands
- Department of Hematology, University Medical Center Utrecht, Utrecht UniversityUrechtNetherlands
| | - Helen J von Richthofen
- Center for Translational Immunology, University Medical Centre Utrecht, Utrecht UniversityUtrechtNetherlands
- Oncode InstituteUtrechtNetherlands
| | - Saskia V Vijver
- Center for Translational Immunology, University Medical Centre Utrecht, Utrecht UniversityUtrechtNetherlands
- Oncode InstituteUtrechtNetherlands
| | - Michiel van der Vlist
- Center for Translational Immunology, University Medical Centre Utrecht, Utrecht UniversityUtrechtNetherlands
- Oncode InstituteUtrechtNetherlands
| | - Raphael Kuhn
- Department of Biosystems Science and Engineering, ETH ZurichZurichSwitzerland
| | - Alexander Yermanos
- Center for Translational Immunology, University Medical Centre Utrecht, Utrecht UniversityUtrechtNetherlands
- Department of Biosystems Science and Engineering, ETH ZurichZurichSwitzerland
| | - Jürgen J Kuball
- Center for Translational Immunology, University Medical Centre Utrecht, Utrecht UniversityUtrechtNetherlands
- Department of Hematology, University Medical Center Utrecht, Utrecht UniversityUrechtNetherlands
| | - Can Kesmir
- Theoretical Biology and Bioinformatics, Department of Biology, Utrecht UniversityUtrechtNetherlands
| | - M Ines Pascoal Ramos
- Center for Translational Immunology, University Medical Centre Utrecht, Utrecht UniversityUtrechtNetherlands
- Oncode InstituteUtrechtNetherlands
| | - Linde Meyaard
- Center for Translational Immunology, University Medical Centre Utrecht, Utrecht UniversityUtrechtNetherlands
- Oncode InstituteUtrechtNetherlands
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