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Du XY, Xia RJ, Shen LW, Ma JG, Yao WQ, Xu W, Lin ZP, Ma LB, Niu GQ, Fan RF, Xu SM, Yan L. Quadruple therapy with immunotherapy and chemotherapy as first-line conversion treatment for unresectable advanced gastric adenocarcinoma: A case report. World J Gastrointest Oncol 2025; 17:102258. [DOI: 10.4251/wjgo.v17.i4.102258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 01/20/2025] [Accepted: 02/24/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND The treatment of gastric cancer remains highly challenging, particularly in cases of unresectable locally advanced or metastatic disease. Although chemotherapy and immunotherapy have shown some efficacy in such patients, significant limitations persist in extending survival and enhancing safety. To address these challenges, we designed an innovative first-line quadruple conversion therapy regimen that integrates a programmed cell death protein 1 (PD-1) inhibitor with chemotherapy, and we successfully implemented this therapy regimen in the treatment of a patient with unresectable locally advanced gastric adenocarcinoma.
CASE SUMMARY We report the case of a 55-year-old male who was diagnosed with unresectable locally advanced gastric adenocarcinoma and presented with intermittent epigastric pain and multiple lymph node metastases in the abdominal cavity, with the metastasis being notably large in size. The tumor tissue was negative for human epidermal growth factor receptor 2 by immunohistochemistry. Considering the patient's status, the multidisciplinary team decided to administer sintilimab in combination with albumin-bound paclitaxel (nab-paclitaxel), S-1, and oxaliplatin as a quadruple drug conversion therapy. After 4 cycles of conversion therapy, the patient's epigastric pain was significantly alleviated, his stool color normalized, the volume of the primary tumor and lymph node metastases was markedly reduced, and the tumor marker levels decreased to within the normal range. The patient subsequently underwent laparoscopic total gastrectomy with abdominal lymph node dissection, and postoperative pathological biopsy revealed a pathological complete response and R0 resection, after which the patient recovered to an excellent physical status.
CONCLUSION To the best of our knowledge, this is the first reported case of unresectable locally advanced gastric adenocarcinoma successfully treated with quadruple therapy with a PD-1 inhibitor and chemotherapy as a first-line conversion regimen. This first-line conversion therapy with the quadruple regimen may be effective and safe for unresectable locally advanced gastric adenocarcinoma.
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Affiliation(s)
- Xiao-Yu Du
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
- Department of Medicine, Northwest Minzu University, Lanzhou 730050, Gansu Province, China
| | - Ren-Jie Xia
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
- Department of Medicine, Northwest Minzu University, Lanzhou 730050, Gansu Province, China
| | - Li-Wen Shen
- Department of Medical Support Center, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Jian-Guo Ma
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
- First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou 730030, Gansu Province, China
| | - Wei-Qing Yao
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
- Department of Medicine, Northwest Minzu University, Lanzhou 730050, Gansu Province, China
| | - Wei Xu
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Zhi-Peng Lin
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Liang-Bin Ma
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Guo-Qiang Niu
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Rui-Fang Fan
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Shu-Mei Xu
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Long Yan
- Department of Hepatobiliary Surgery and General Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
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Yao Y, Yang X, Li J, Guo E, Wang H, Sun C, Hong Z, Zhang X, Jia J, Wang R, Ma J, Dai Y, Deng M, Yu C, Sun L, Xie L. Preclinical Characterization of Efficacy and Pharmacodynamic Properties of Finotonlimab, a Humanized Anti-PD-1 Monoclonal Antibody. Pharmaceuticals (Basel) 2025; 18:395. [PMID: 40143171 PMCID: PMC11946465 DOI: 10.3390/ph18030395] [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: 02/10/2025] [Revised: 03/04/2025] [Accepted: 03/10/2025] [Indexed: 03/28/2025] Open
Abstract
Background/Objectives: Finotonlimab (SCTI10A) is a humanized anti-PD-1 antibody tested in Phase III trials for several solid tumor types. Methods: This study characterized the in vitro and in vivo efficacy, Fc-mediated effector function, and non-clinical PK/PD properties of finotonlimab. Results: The results demonstrated that finotonlimab is effective in stimulating human T cell function in vitro and exhibits marked antitumor efficacy in vivo using both PD-1-humanized and PBMC-reconstructed mouse models. Additionally, finotonlimab exhibited minimal impact on the activation of effector cells via Fc receptor-dependent pathways, potentially facilitating PD-1+ T cell killing. In cynomolgus monkeys, finotonlimab exhibited a nonlinear pharmacokinetic (PK) profile in a dose-dependent manner, and a receptor occupancy rate of approximately 90% was observed at 168 h following a single administration of 1 mg/kg. Finotonlimab's PK profile (especially Cmax) was better than that of marketed antibodies. Following a 13-week successive administration of finotonlimab, a pharmacodynamic analysis revealed that a sustained mean receptor occupancy of PD-1 molecules on circulating T cells remained at or above 93% for up to 8 weeks, even at a dose of 3 mg/kg, and that there were higher antibody accumulations in different dose groups. Conclusions: Taken together, the preclinical findings are promising and provide the groundwork for evaluating the efficacy and pharmacodynamic characteristics of finotonlimab in clinical trials.
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Affiliation(s)
- Yunqi Yao
- Beijing Engineering Research Center of Protein and Antibody, Sinocelltech Ltd., Beijing 100176, China; (Y.Y.); (X.Y.); (J.L.); (E.G.); (H.W.); (C.S.); (X.Z.); (J.J.); (R.W.); (J.M.); (Y.D.); (M.D.); (C.Y.); (L.S.)
| | - Xiaoning Yang
- Beijing Engineering Research Center of Protein and Antibody, Sinocelltech Ltd., Beijing 100176, China; (Y.Y.); (X.Y.); (J.L.); (E.G.); (H.W.); (C.S.); (X.Z.); (J.J.); (R.W.); (J.M.); (Y.D.); (M.D.); (C.Y.); (L.S.)
| | - Jing Li
- Beijing Engineering Research Center of Protein and Antibody, Sinocelltech Ltd., Beijing 100176, China; (Y.Y.); (X.Y.); (J.L.); (E.G.); (H.W.); (C.S.); (X.Z.); (J.J.); (R.W.); (J.M.); (Y.D.); (M.D.); (C.Y.); (L.S.)
| | - Erhong Guo
- Beijing Engineering Research Center of Protein and Antibody, Sinocelltech Ltd., Beijing 100176, China; (Y.Y.); (X.Y.); (J.L.); (E.G.); (H.W.); (C.S.); (X.Z.); (J.J.); (R.W.); (J.M.); (Y.D.); (M.D.); (C.Y.); (L.S.)
| | - Huiyu Wang
- Beijing Engineering Research Center of Protein and Antibody, Sinocelltech Ltd., Beijing 100176, China; (Y.Y.); (X.Y.); (J.L.); (E.G.); (H.W.); (C.S.); (X.Z.); (J.J.); (R.W.); (J.M.); (Y.D.); (M.D.); (C.Y.); (L.S.)
| | - Chunyun Sun
- Beijing Engineering Research Center of Protein and Antibody, Sinocelltech Ltd., Beijing 100176, China; (Y.Y.); (X.Y.); (J.L.); (E.G.); (H.W.); (C.S.); (X.Z.); (J.J.); (R.W.); (J.M.); (Y.D.); (M.D.); (C.Y.); (L.S.)
| | - Zhangyong Hong
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Cancer Biology Center, Frontiers Science Center for New Organic Matter, College of Life Sciences, Nankai University, Tianjin 300071, China;
| | - Xiao Zhang
- Beijing Engineering Research Center of Protein and Antibody, Sinocelltech Ltd., Beijing 100176, China; (Y.Y.); (X.Y.); (J.L.); (E.G.); (H.W.); (C.S.); (X.Z.); (J.J.); (R.W.); (J.M.); (Y.D.); (M.D.); (C.Y.); (L.S.)
| | - Jilei Jia
- Beijing Engineering Research Center of Protein and Antibody, Sinocelltech Ltd., Beijing 100176, China; (Y.Y.); (X.Y.); (J.L.); (E.G.); (H.W.); (C.S.); (X.Z.); (J.J.); (R.W.); (J.M.); (Y.D.); (M.D.); (C.Y.); (L.S.)
| | - Rui Wang
- Beijing Engineering Research Center of Protein and Antibody, Sinocelltech Ltd., Beijing 100176, China; (Y.Y.); (X.Y.); (J.L.); (E.G.); (H.W.); (C.S.); (X.Z.); (J.J.); (R.W.); (J.M.); (Y.D.); (M.D.); (C.Y.); (L.S.)
| | - Juan Ma
- Beijing Engineering Research Center of Protein and Antibody, Sinocelltech Ltd., Beijing 100176, China; (Y.Y.); (X.Y.); (J.L.); (E.G.); (H.W.); (C.S.); (X.Z.); (J.J.); (R.W.); (J.M.); (Y.D.); (M.D.); (C.Y.); (L.S.)
| | - Yaqi Dai
- Beijing Engineering Research Center of Protein and Antibody, Sinocelltech Ltd., Beijing 100176, China; (Y.Y.); (X.Y.); (J.L.); (E.G.); (H.W.); (C.S.); (X.Z.); (J.J.); (R.W.); (J.M.); (Y.D.); (M.D.); (C.Y.); (L.S.)
| | - Mingjing Deng
- Beijing Engineering Research Center of Protein and Antibody, Sinocelltech Ltd., Beijing 100176, China; (Y.Y.); (X.Y.); (J.L.); (E.G.); (H.W.); (C.S.); (X.Z.); (J.J.); (R.W.); (J.M.); (Y.D.); (M.D.); (C.Y.); (L.S.)
| | - Chulin Yu
- Beijing Engineering Research Center of Protein and Antibody, Sinocelltech Ltd., Beijing 100176, China; (Y.Y.); (X.Y.); (J.L.); (E.G.); (H.W.); (C.S.); (X.Z.); (J.J.); (R.W.); (J.M.); (Y.D.); (M.D.); (C.Y.); (L.S.)
| | - Lingling Sun
- Beijing Engineering Research Center of Protein and Antibody, Sinocelltech Ltd., Beijing 100176, China; (Y.Y.); (X.Y.); (J.L.); (E.G.); (H.W.); (C.S.); (X.Z.); (J.J.); (R.W.); (J.M.); (Y.D.); (M.D.); (C.Y.); (L.S.)
| | - Liangzhi Xie
- Beijing Engineering Research Center of Protein and Antibody, Sinocelltech Ltd., Beijing 100176, China; (Y.Y.); (X.Y.); (J.L.); (E.G.); (H.W.); (C.S.); (X.Z.); (J.J.); (R.W.); (J.M.); (Y.D.); (M.D.); (C.Y.); (L.S.)
- Beijing Key Laboratory of Monoclonal Antibody Research and Development, Sino Biological Inc., Beijing 100176, China
- Cell Culture Engineering Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
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Park CK, Khalil M, Pham NA, Wong S, Ly D, Sacher A, Tsao MS. Humanized Mouse Models for Immuno-Oncology Research: A Review and Implications in Lung Cancer Research. JTO Clin Res Rep 2025; 6:100781. [PMID: 39990135 PMCID: PMC11847118 DOI: 10.1016/j.jtocrr.2024.100781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 11/13/2024] [Accepted: 11/22/2024] [Indexed: 02/25/2025] Open
Abstract
Cancer immunotherapy has brought significant clinical benefits to patients with cancer, including those with lung cancer. Patient-derived tumor xenograft mouse models have become the preferred animal model for translational cancer research and preclinical studies. Given the unmet need for improved predictive models in immuno-oncology, humanized mouse models which are co-engrafted with both human tumors and immune system components have been used to investigate novel immunotherapeutics. These models have similarly been used to predict immune-related adverse events and to develop predictive biomarkers. This review summarizes key concepts related to humanized mouse models. We highlight the various approaches to generate them, factors that are critical to successfully establishing such models, their respective limitations, and considerations in model selection for preclinical lung cancer immuno-oncology research and therapeutic studies.
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Affiliation(s)
- Cheol-Kyu Park
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Internal Medicine, Chonnam National University Medical School and Hwasun Hosptial, Hwasun, Republic of Korea
- Research Institute of Medical Science, Chonnam National University, Gwangju, Republic of Korea
| | - Maryam Khalil
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University Health Network, Toronto, Ontario, Canada
| | - Nhu-An Pham
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Stephanie Wong
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Dalam Ly
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Adrian Sacher
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
- Division of Medical Oncology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Ming-Sound Tsao
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University Health Network, Toronto, Ontario, Canada
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Pyreddy S, Kim S, Miyamoto W, Talib Z, GnanaDev DA, Rahnemai-Azar AA. Current Advances in Immunotherapy Management of Esophageal Cancer. Cancers (Basel) 2025; 17:851. [PMID: 40075698 PMCID: PMC11898678 DOI: 10.3390/cancers17050851] [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: 12/16/2024] [Revised: 02/03/2025] [Accepted: 02/10/2025] [Indexed: 03/14/2025] Open
Abstract
Esophageal cancer is one of the most common and deadliest cancers worldwide. Rates of esophageal cancer worldwide have been steadily rising over the past decade due to higher incidence of gastroesophageal reflux disease (GERD). Current therapies include surgical resection, chemotherapy, and limited targeted therapies. One obstacle to care is tumor cells' ability to evade immune surveillance, which can render certain therapeutics ineffective. Immunotherapy provides a new paradigm to cancer treatment, which has proven to be effective in evasive tumors. In recent years, PD-1/PD-L1 and CLTA-4 inhibitors have been used as frontline treatment and have shown to be extremely effective in the treatment of hard-to-treat tumors. Here, we aim to analyze the current literature regarding current therapeutics along with emerging techniques and future receptor targets for immunotherapy.
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Affiliation(s)
- Sagar Pyreddy
- School of Medicine, California University of Science and Medicine, Colton, CA 92324, USA; (S.P.); (S.K.); (W.M.); (Z.T.)
| | - Sarah Kim
- School of Medicine, California University of Science and Medicine, Colton, CA 92324, USA; (S.P.); (S.K.); (W.M.); (Z.T.)
| | - William Miyamoto
- School of Medicine, California University of Science and Medicine, Colton, CA 92324, USA; (S.P.); (S.K.); (W.M.); (Z.T.)
| | - Zohray Talib
- School of Medicine, California University of Science and Medicine, Colton, CA 92324, USA; (S.P.); (S.K.); (W.M.); (Z.T.)
| | - Dev A. GnanaDev
- Department of Surgery, Arrowhead Regional Medical Center, Colton, CA 92324, USA;
| | - Amir A. Rahnemai-Azar
- Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA 92324, USA
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Liu Z, Liu A, Li M, Xiang J, Yu G, Sun P. Efficacy and safety of sintilimab combined with trastuzumab and chemotherapy in HER2-positive advanced gastric or gastroesophageal junction cancer. Front Immunol 2025; 16:1545304. [PMID: 40028325 PMCID: PMC11867958 DOI: 10.3389/fimmu.2025.1545304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Accepted: 01/27/2025] [Indexed: 03/05/2025] Open
Abstract
Background To evaluate the efficacy and safety of sintilimab in combination with trastuzumab and chemotherapy for HER2-positive advanced gastric/gastroesophageal junction cancer (GC/GEJC). Methods HER2-positive advanced GC/GEJC patients admitted to our department between January 2018 and October 2024 were included in this study. Patients who received sintilimab in combination with trastuzumab and chemotherapy were assigned to cohort A, while patients who received trastuzumab and chemotherapy alone were assigned to cohort B. The primary endpoints were progression-free survival (PFS) and overall survival (OS), while the secondary endpoints included disease control rate (DCR), objective response rate (ORR), and safety. Results A total of 103 patients were analyzed, with 46 in cohort A and 57 in cohort B. The ORR was 65.2% in cohort A compared to 40.4% in cohort B, while the DCR was 87.0% in cohort A and 70.2% in cohort B. The median follow-up duration was 14.0 months. Median PFS (mPFS) was 9.4 months (95% CI: 5.6-13.2) for cohort A and 7.4 months (95% CI: 6.1-8.7) for cohort B (p = 0.089). Median OS (mOS) was 16.4 months (95% CI: 11.5-21.3) in cohort A versus 14.2 months (95% CI: 11.2-17.2) in cohort B (p = 0.069). Adverse events were predominantly mild, and no treatment-related deaths occurred. Conclusion Sintilimab combined with trastuzumab and chemotherapy showed promising efficacy and acceptable safety in HER2-positive advanced GC/GEJC. However, no statistically significant improvement in survival outcomes was observed compared to trastuzumab and chemotherapy alone.
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Affiliation(s)
- Zeyu Liu
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Aina Liu
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Ming Li
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jinyu Xiang
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Guohua Yu
- Department of Pathology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Ping Sun
- Department of Oncology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
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Liu T, He J, Wang Y, Yang Y, Zhang L, Shi M, Liu J, Sun D, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Huang Y, Fang W, Yang Y, Zhao Y, Zhang L. Health-related quality of life and symptoms in patients with previously untreated, locally advanced or metastatic non-squamous non-small cell lung cancer treated with sintilimab or placebo plus pemetrexed and platinum (ORIENT-11): A randomized, double-blind, phase 3 trial. Lung Cancer 2025; 200:108108. [PMID: 39884222 DOI: 10.1016/j.lungcan.2025.108108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Accepted: 01/21/2025] [Indexed: 02/01/2025]
Abstract
BACKGROUND In the phase 3 ORIENT-11 study, sintilimab plus pemetrexed-platinum provided statistically significant longer overall survival and progression-free survival versus placebo plus pemetrexed-platinum as first-line treatment in patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC). Here, we report the patient-reported outcomes (PRO) analysis findings in ORIENT-11. METHODS PROs were measured using the European Organization for Research and Treatment of Cancer Quality of Life of Cancer Patients Questionnaire Core 30 items (EORTC QLQ-C30) and the Lung Cancer Symptom Scale (LCSS) questionnaire. PRO endpoints included evaluation of least square (LS) mean changes from baseline to week 12 (platinum-containing treatment) and week 21 (maintenance treatment), time to true deterioration (TTD), and overall improvement or stability rate for QLQ-C30 and LCSS scales. PRO scores in two groups were compared using the Mann-Whitney test. Least squares (LS) mean changes from baseline to week 12, week 21, and other time points were assessed with mixed-effect model repeated measures analysis. TTD was calculated using the Kaplan-Meier method and compared with the Cox proportional hazards model between groups. RESULTS 252 (94.7 %) patients in the sintilimab-combination group and 123 (93.9 %) patients in the placebo-combination group had a baseline and at least one postbaseline PRO assessment. Change from baseline to week 12 or 21 favored the sintilimab-combination group on QLQ-C30 global health status/quality of life (GHS/QoL), most function and symptoms scales, and most LCSS scales. Notably, the QLQ-C30 pain score change gradually deteriorated in the placebo-combination group with increased treatment. At the same time, it improved in the sintilimab-combination group significantly from 6 weeks later, with the improvement sustained in subsequent courses of treatment. Sintilimab plus chemotherapy significantly delayed the TTD in most QLQ-C30 and LCSS scales compared with placebo plus chemotherapy, and the overall improvement or stability rates were higher in the former. CONCLUSIONS The addition of sintilimab to chemotherapy maintained or improved health-related quality of life and symptoms compared with chemotherapy. Along with the previous efficacy and safety results, these data support the addition of sintilimab to standard chemotherapy as first-line therapy in locally advanced or metastatic non-squamous NSCLC. CLINICAL TRIAL REGISTRATION NCT03607539.
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Affiliation(s)
- Tingting Liu
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Junyi He
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Yalan Wang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Yuwen Yang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Lin Zhang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Mengting Shi
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Jiaqing Liu
- Department of Intensive Care Unit, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Dongcheng Sun
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Zhehai Wang
- Medical Oncology Department, Shandong Cancer Hospital, Jinan, Shandong, PR China
| | - Jian Fang
- Department of Thoracic Oncology II, Peking University Cancer Hospital, Beijing, PR China
| | - Qitao Yu
- Department of Respiratory Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning City, Guangxi, PR China
| | - Baohui Han
- Department of Respiration, Shanghai Chest Hospital, Shanghai, PR China
| | - Shundong Cang
- Department of Oncology, The Henan Province Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Gongyan Chen
- Department of Respiration, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, PR China
| | - Xiaodong Mei
- Department of Respiration, Anhui Provincial Hospital, Hefei, Anhui, PR China
| | - Zhixiong Yang
- Department of Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, PR China
| | - Yan Huang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Wenfeng Fang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China
| | - Yunpeng Yang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China.
| | - Yuanyuan Zhao
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China.
| | - Li Zhang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China.
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Xu H, Yao X, He Z, Luo H, Li G, Guo J, Diao L, Fan Y, Li Y, Fan J, Hu X, Lu P, Shi H, Chen K, Tan P, Fan S, Shi M, Su W, Ye D. Fruquintinib Plus Sintilimab in Patients with Treatment-Naive and Previously Treated Advanced Renal Cell Carcinoma: Results from a Phase Ib/II Clinical Trial. Target Oncol 2025; 20:113-125. [PMID: 39806128 DOI: 10.1007/s11523-024-01120-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/03/2024] [Indexed: 01/16/2025]
Abstract
BACKGROUND Antiangiogenic inhibitors plus immune checkpoint inhibitors have synergistic antitumor activity and have improved treatment outcomes in patients with renal cell carcinoma (RCC). OBJECTIVE We report the RCC cohort from a phase Ib/II study in Chinese patients evaluating the efficacy and safety of fruquintinib plus sintilimab in treating advanced clear cell RCC (ccRCC). PATIENTS AND METHODS Eligible patients had pathologically confirmed advanced ccRCC. Patients received fruquintinib 5 mg once daily, 2 weeks on/1 week off, plus sintilimab 200 mg every 3 weeks in 3-week cycles. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS By March 31, 2023, 42 patients (median age 58.9 years; 81.0% male) had been treated in the RCC cohort. Among treatment-naive patients (n = 22), confirmed ORR was 68.2% (95% confidence interval [CI] 45.1-86.1). The median progression-free survival (PFS) was not reached, and 18-month PFS rate was 59.4%. Among previously treated patients (n = 20), the confirmed ORR was 60.0% (95% CI 36.1-80.9), and the median PFS was 15.9 (95% CI 5.4-19.3) months. All patients had adverse events related to study treatment, 52.4% of which were grade ≥ 3 in severity. Treatment-related adverse events with an incidence of ≥ 40% included proteinuria, hypothyroidism, hypercholesterolemia, hypertriglyceridemia, and hypoalbuminemia. CONCLUSIONS Fruquintinib plus sintilimab demonstrated promising efficacy in advanced ccRCC and was well tolerated. A phase III study (FRUSICA-02) using this combination regimen in patients with previously treated advanced ccRCC is ongoing. TRIAL REGISTRATION NUMBER The study was registered with ClinicalTrials.gov (NCT03903705).
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Affiliation(s)
- Hua Xu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xin Yao
- Key Laboratory of Cancer Prevention and Therapy, Department of Genitourinary Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
| | - Zhisong He
- Department of Urology, Peking University First Hospital, Institute of Urology, National Urological Cancer Center of China, Peking University, Beijing, China
| | - Hong Luo
- Department of Urology, Chongqing University Cancer Hospital, Chongqing, China
| | - Guiling Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianming Guo
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lei Diao
- Key Laboratory of Cancer Prevention and Therapy, Department of Genitourinary Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
| | - Yu Fan
- Department of Urology, Peking University First Hospital, Institute of Urology, National Urological Cancer Center of China, Peking University, Beijing, China
| | - Yuan Li
- Department of Urology, Chongqing University Cancer Hospital, Chongqing, China
| | - Jiquan Fan
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyi Hu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Puhan Lu
- HUTCHMED Limited, Shanghai, China
| | | | | | | | | | | | | | - Dingwei Ye
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Wang J, Li S, Jiang H, Chang YJ, Zhao X, Jia J, Zhu X, Gong L, Liu X, Yu W, Huang X. Sintilimab plus decitabine for higher-risk treatment-naïve myelodysplastic syndromes: efficacy, safety, and biomarker analysis of a phase II, single-arm trial. J Immunother Cancer 2024; 12:e010355. [PMID: 39577869 PMCID: PMC11590843 DOI: 10.1136/jitc-2024-010355] [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: 08/14/2024] [Accepted: 10/29/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND Immunotherapy combined with azacitidine was feasible in higher-risk myelodysplastic syndromes (MDSs) with limited sample size of treatment-naïve patients, while the optimization of treatment strategies, including the optimal immune checkpoint inhibitor and hypomethylating agent and possible benefiting population, remained undefined. This study first evaluates the efficacy and safety of sintilimab, a PD-1 blockade, plus decitabine in treatment-naïve higher-risk MDS patients and investigates biomarkers for predicting treatment response. METHODS In this phase II, single-arm trial (ChiCTR2100044393), treatment-naïve higher-risk MDS patients with an International Prognostic Scoring System-Revised score >3.5 received sintilimab (200 mg, days 1 and 22) and decitabine (20 mg/m2, day 1-5) over 6-week cycles. The primary endpoint was the overall response rate (ORR), including complete remission (CR), partial remission (PR) or marrow CR. RESULTS A total of 54 eligible patients were enrolled and treated, with 25 (46.3%) having very high-risk MDS. Among 53 evaluable patients, the ORR was 77.4% (n=41), including 26.4% CR (n=14). The overall clinical improvement rate (CR, PR, marrow CR or hematological improvement) reached 81.1%. With a median follow-up of 20.0 months, the median event-free survival was 23 months with 12 progressing to acute myeloid leukemia. Median overall survival was not reached. Treatment was generally well tolerated, with hematologic toxicities being the most common adverse events. Biomarker analysis highlighted a negative correlation between T cell exhaustion markers, particularly TIM-3 and PD-1, with ORR. CONCLUSIONS The combination of sintilimab and decitabine shows promise efficacy for higher-risk MDS, with a favorable safety profile. The potential predictive value of T cell exhaustion biomarkers might help screen the possible benefiting population. TRIAL REGISTRATION NUMBER ChiCTR210044393.
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Affiliation(s)
- Jing Wang
- Peking University Institute of Hematology. National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Siqi Li
- Peking University Institute of Hematology. National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Hao Jiang
- Peking University Institute of Hematology. National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Ying-Jun Chang
- Peking University Institute of Hematology. National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Xiaosu Zhao
- Peking University Institute of Hematology. National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Jinsong Jia
- Peking University Institute of Hematology. National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Xiaolu Zhu
- Peking University Institute of Hematology. National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Lizhong Gong
- Peking University Institute of Hematology. National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Xiaohong Liu
- Peking University Institute of Hematology. National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Wenjing Yu
- Peking University Institute of Hematology. National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
| | - Xiaojun Huang
- Peking University Institute of Hematology. National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Beijing, China
- Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Sciences, Beijing, China
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Lin Y, Zhang L, Zhang X, Wei X, Liu X, Xie Y, Han G. Preliminary report on the short-term efficacy and safety of SAPO-S1 therapy for locally advanced gastric cancer with a deep learning perspective. Biotechnol Genet Eng Rev 2024; 40:2704-2719. [PMID: 37078530 DOI: 10.1080/02648725.2023.2202513] [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: 02/16/2023] [Accepted: 04/10/2023] [Indexed: 04/21/2023]
Abstract
The neoadjuvant therapeutic effects of various chemotherapeutic drugs on gastric cancer have reached the corresponding plateau. Whether the combination of sindilizumab and albumin-bound paclitaxel+oxaliplatin+S-1 chemotherapy (SAPO-S1 therapy) regimen can bring better efficacy and observe the incidence of adverse reactions in the neoadjuvant treatment of Gastric Cancer (GC) may be the direction of our research. This study aimed to evaluate the efficacy of S1 chemotherapy regimen combined with multiple chemotherapy drugs sindilizumab (PD-1 inhibitor), albumin-bound paclitaxel and oxaliplatin) for neoadjuvant therapy in locally advanced Gastric Cancer (LA-GC). The patients were given 4 cycles of sindilizumab combined with albumin paclitaxel+oxaliplatin+S-1 chemotherapy (SAPO-S1) before surgery. The R0 resection rate, surgical complications, pathologic complete response, complete pathologic response (pCR) the main pathological response rates (residual tumor cells≤10%, major pathological response) were observed. MPR and postoperative pathological tumor regression grade (TRG), using the response evaluation criteria in solid tumors (RECIST1.1) to evaluate the efficacy of new adjuvant therapy and record the short-term adverse events (adverse event, AE) of patients after medication to evaluate safety. The overall response rate (ORR) was achieved to 53.3% and disease control rate (DCR) was achieved in 28 patients (93.3%), and the descending phase was achieved in 17 patients (56.7%). The tumor resolution grades of TRG 0, TRG 1, TRG 2 and TRG 3 were 16.7%, 13.3%, 43.3% and 16.7%, respectively. The pCR rate was 16.7%, the MPR rate was 30.0%, and the R0 resection rate was 90.0%. In addition, SAPO-S1 therapy has fewer side effects. Overall, SAPO-S1 therapy has a good therapeutic effect and safety in LA-GC.
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Affiliation(s)
- Yecheng Lin
- First Department of Gastrointestinal Surgery, Cangzhou Central Hospital, Cangzhou, China
| | - Lei Zhang
- Department of Clinical Laboratory, Cangzhou Central hospital, Cangzhou, China
| | - Xiaoling Zhang
- Department of Pathology, Cangzhou Central Hospital, Cangzhou, China
| | - Xiaonan Wei
- First Department of Gastrointestinal Surgery, Cangzhou Central Hospital, Cangzhou, China
| | - Xu Liu
- First Department of Gastrointestinal Surgery, Cangzhou Central Hospital, Cangzhou, China
| | - Yanchao Xie
- First Department of Gastrointestinal Surgery, Cangzhou Central Hospital, Cangzhou, China
| | - Guoda Han
- First Department of Gastrointestinal Surgery, Cangzhou Central Hospital, Cangzhou, China
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Knockenhauer KE, Copeland RA. The importance of binding kinetics and drug-target residence time in pharmacology. Br J Pharmacol 2024; 181:4103-4116. [PMID: 37160660 DOI: 10.1111/bph.16104] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/19/2023] [Accepted: 04/27/2023] [Indexed: 05/11/2023] Open
Abstract
A dominant assumption in pharmacology throughout the 20th century has been that in vivo target occupancy-and attendant pharmacodynamics-depends on the systemic concentration of drug relative to the equilibrium dissociation constant for the drug-target complex. In turn, the duration of pharmacodynamics is temporally linked to the systemic pharmacokinetics of the drug. Yet, there are many examples of drugs for which pharmacodynamic effect endures long after the systemic concentration of a drug has waned to (equilibrium) insignificant levels. To reconcile such data, the drug-target residence time model was formulated, positing that it is the lifetime (or residence time) of the binary drug-target complex, and not its equilibrium affinity per se, that determines the extent and duration of drug pharmacodynamics. Here, we review this model, its evolution over time, and its applications to natural ligand-macromolecule biology and synthetic drug-target pharmacology.
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11
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Pan J, Yin W, Chen Y, Wang H, Wu W, Wang S, Li D, Ma Q. Sustained Response to Anti-PD-1 Therapy in Combination with Nab-Paclitaxel in Metastatic Testicular Germ Cell Tumor Harboring the KRAS-G12V Mutation: A Case Report. Urol Int 2024:1-9. [PMID: 39362200 DOI: 10.1159/000541588] [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: 06/10/2024] [Accepted: 09/04/2024] [Indexed: 10/05/2024]
Abstract
INTRODUCTION Cisplatin-based standardized therapy has been established for metastatic testicular germ cell tumors (TGCTs). However, the patient prognosis is considerably less favorable if the disease recurs following failure of first-line therapies. There is a need for novel treatment options for patients with recurrent or metastatic TGCTs, notably for those that are not sensitive to first-line chemotherapy. With the development of next-generation sequencing technologies, an increasing number of gene mutations has been identified in TGCTs. Previously published research studies have established a link between KRAS mutations and chemotherapy resistance, and have demonstrated that KRAS mutations are associated with inflammatory tumor microenvironment and tumor immunogenicity, leading to an improved response to inhibition of programmed death (PD-1) protein expression. Previous studies have reported that the tumor immune microenvironment of TGCT influences therapeutic efficacy. CASE PRESENTATION A 65-year-old metastatic patient with TGCT and a KRAS-12 valine-for-glycine gene mutation was described. This patient initially underwent inguinal orchiectomy and received two prior chemotherapeutic regimens. Following the rapid progression of the disease, the patient was treated with anti-PD-1 therapy and nab-paclitaxel chemotherapy, and his condition was successfully controlled by this combination treatment. CONCLUSION To the best of our knowledge, this is the first successful case of KRAS-mutation patient with TGCT who achieved partially and sustained disease remission by combining immune checkpoint inhibitors with chemotherapy. This case provides an excellent example for personalized treatment of metastatic TGCTs.
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Affiliation(s)
- Jinfeng Pan
- Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, China
- Comprehensive Genitourinary Cancer Center, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Weiqi Yin
- Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Yingzhi Chen
- Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Hui Wang
- Department of Medical Oncology, Zhejiang University Mingzhou Hospital, Ningbo, China
| | - Wei Wu
- Department of Medical Oncology, Zhejiang University Mingzhou Hospital, Ningbo, China
| | - Suying Wang
- Department of Tissue Pathology, Ningbo Clinical Pathological Diagnosis Center, Ningbo, China
| | - Da Li
- Department of Medical Oncology, Sir Run Run Shaw Hospital Affiliated to Zhejiang University Medical School, Hangzhou, China
| | - Qi Ma
- Comprehensive Genitourinary Cancer Center, The First Affiliated Hospital of Ningbo University, Ningbo, China
- Ningbo Clinical Research Center for Urological Disease, Ningbo, China
- Translational Research Laboratory for Urology, The Key Laboratory of Ningbo City, The First Affiliated Hospital of Ningbo University, Ningbo, China
- Yi-Huan Genitourinary Cancer Group, Ningbo, China
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Feng Q, Yu W, Feng JH, Huang Q, Xiao GX. Jejunal sarcomatoid carcinoma: A case report and review of literature. World J Gastrointest Oncol 2024; 16:3723-3731. [PMID: 39171179 PMCID: PMC11334045 DOI: 10.4251/wjgo.v16.i8.3723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/03/2024] [Accepted: 06/17/2024] [Indexed: 08/07/2024] Open
Abstract
BACKGROUND Sarcomatoid carcinoma (SCA) of the jejunum is a rare and aggressive neoplasm affecting the smooth muscle cells of the jejunum. This study presents a recent case of jejunal SCA, detailing its diagnosis and treatment, thereby providing a reference for clinical practice. CASE SUMMARY A 65-year-old male presented to Yichang Central People's Hospital with a chief complaint of hemorrhoids. A computed tomography (CT) scan incidentally revealed multiple abnormal signals in the liver. Subsequent positron emission tomography/CT at Wuhan Union Hospital indicated malignant tumor progression, with a primary duodenal tumor and multiple metastases in the upper left abdomen. Intraoperatively, a large tumor was identified on the omentum. Histopathological and immunohistochemical analyses of the resected specimen confirmed the diagnosis of jejunal SCA. The patient received a combination therapy of sintilimab, nanoparticle albumin-bound paclitaxel, and anlotinib. Follow-up imaging demonstrated significant reduction of hepatic and peritoneal lesions. The patient has remained stable for over one year postoperatively. CONCLUSION This case suggests that chemotherapy, immunotherapy, plus targeted therapy may represent an optimal treatment for intestinal SCA, meriting further investigation.
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Affiliation(s)
- Qian Feng
- The First College of Clinical Medical Science, China Three Gorges University, Yichang 443000, Hubei Province, China
- Department of Oncology, Yichang Central People's Hospital, Yichang 443000, Hubei Province, China
| | - Wei Yu
- The First College of Clinical Medical Science, China Three Gorges University, Yichang 443000, Hubei Province, China
- Department of Oncology, Yichang Central People's Hospital, Yichang 443000, Hubei Province, China
| | - Jing-Hui Feng
- The First College of Clinical Medical Science, China Three Gorges University, Yichang 443000, Hubei Province, China
- Department of Oncology, Yichang Central People's Hospital, Yichang 443000, Hubei Province, China
| | - Qiao Huang
- The First College of Clinical Medical Science, China Three Gorges University, Yichang 443000, Hubei Province, China
- Department of Oncology, Yichang Central People's Hospital, Yichang 443000, Hubei Province, China
| | - Gui-Xiang Xiao
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
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Cui C, Li J, Yang Y, Si L, Chi Z, Mao L, Wang X, Tang B, Yan X, Li S, Zhou L, Wei X, Shen Y, Guo Q, Zheng S, Guo J, Lian B. IBI310 (anti-CTLA-4 antibody) monotherapy or in combination with sintilimab in advanced melanoma or urothelial carcinoma. Innovation (N Y) 2024; 5:100638. [PMID: 38881798 PMCID: PMC11179243 DOI: 10.1016/j.xinn.2024.100638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 05/09/2024] [Indexed: 06/18/2024] Open
Abstract
IBI310 is a recombinant fully human IgG1 antibody against cytotoxic T lymphocyte antigen 4. This study was conducted to evaluate IBI310 monotherapy or combination therapy with sintilimab in the patients with advanced melanoma or urothelial carcinoma (UC). Patients in phase 1a received IBI310 at 0.3/1/2/3 mg/kg intravenously (IV) every 3 weeks (Q3W) following the accelerated titration and 3 + 3 escalation design. Patients in phase 1b received IBI310 (1/2/3 mg/kg IV, Q3W) plus sintilimab (200 mg IV, Q3W) for four cycles, followed by sintilimab maintenance therapy. The phase 1b expansion of IBI310 plus sintilimab was performed in patients with advanced melanoma or UC. Overall, 53 patients were enrolled, including 10 patients with melanoma in phase 1a, 34 with melanoma, and 9 with UC in phase 1b. Overall, 94.3% of patients (50/53) experienced at least one treatment-related adverse event (TRAE) with most being grade 1-2; 26.4% of patients (14/53) experienced grade 3 or higher TRAEs. In phase 1a, the disease control rate (DCR) was 50.0% (95% confidence interval [CI], 18.7%-81.3%). In phase 1b, the objective response rate (ORR) and DCR were 17.6% (95% CI, 6.8%-34.5%) and 44.1% (95% CI, 27.2%-62.1%), respectively, for melanoma, and were 22.2% (95% CI, 2.8%-60.0%) and 66.7% (95% CI, 29.9%-92.5%), respectively, for UC. IBI310 monotherapy or combination therapy with sintilimab was well tolerated with favorable antitumor activity across patients with advanced melanoma and UC.
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Affiliation(s)
- Chuanliang Cui
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing 100142, China
| | - Juan Li
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing 100142, China
| | - Yue Yang
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing 100142, China
| | - Lu Si
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing 100142, China
| | - Zhihong Chi
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing 100142, China
| | - Lili Mao
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing 100142, China
| | - Xuan Wang
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing 100142, China
| | - Bixia Tang
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing 100142, China
| | - Xieqiao Yan
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing 100142, China
| | - Siming Li
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing 100142, China
| | - Li Zhou
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing 100142, China
| | - Xiaoting Wei
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing 100142, China
| | - Yuping Shen
- Innovent Biologics, Inc., Suzhou 215123, China
| | - Qun Guo
- Innovent Biologics, Inc., Suzhou 215123, China
| | | | - Jun Guo
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing 100142, China
| | - Bin Lian
- Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing 100142, China
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Zheng Y, Zhu J, Xiong J, Jiang O, Wang H, Xie Y, Zhou Y, Xu N. Phase 1b/2 study of penpulimab (AK105), an antiprogrammed cell death-1 immunoglobulin G1 antibody, in advanced or metastatic solid tumors (AK105-204). Cancer 2024; 130:2180-2190. [PMID: 38412283 DOI: 10.1002/cncr.35259] [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: 05/05/2023] [Revised: 12/11/2023] [Accepted: 01/30/2024] [Indexed: 02/29/2024]
Abstract
BACKGROUND Penpulimab, a new-generation antiprogrammed cell death-1 immunoglobulin G1 monoclonal antibody, was engineered to optimize receptor occupancy and eliminate fragment crystallizable γ-mediated effector function. In this multicenter, phase 1b/2, multicohort study, the objective was to investigate the efficacy, safety, and immunogenicity of penpulimab in advanced solid tumors. METHODS Patients who had unresectable, advanced solid tumors were enrolled from six centers and received 200 mg penpulimab on day 1 every 2 weeks for up to 24 months. The primary end point was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors, version criteria 1.1. RESULTS Between September 2, 2019, and January 1, 2020, 65 patients were enrolled and received penpulimab. At the time of data cutoff (May 11, 2022), the median follow-up was 12.6 months (range, 1.1-28.6 months). The ORR was 12.3 (95% confidence interval [CI], 5.5%-22.8%), with three (4.6%) complete responses and five (7.7%) partial responses. Twelve patients (18.5%) achieved stable disease, resulting in a disease control rate of 30.8% (95% CI, 19.9%-43.4%). The median duration of response was not reached (95% CI, 6.70 months to not estimable). In all cohorts, the median progression-free survival was 1.74 months (95% CI, 1.41-2.69 months), and the median overall survival was 16.59 months (95% CI, 7.82-22.18 months). Grade 3 or greater treatment-related adverse events and immune-related adverse events occurred in 9.2% and 27.7% of patients, respectively. Positive antidrug antibody responses to penpulimab were observed in one patient (1.8%). CONCLUSIONS Penpulimab showed promising antitumor activity with an acceptable safety profile, offering a potential new treatment approach for solid tumors. These findings supported the evaluation of penpulimab's durable activity and safety, as monotherapy or in combination therapy, in specific malignancies.
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Affiliation(s)
- Yulong Zheng
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jianqing Zhu
- Department of Gynecologic Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Ou Jiang
- Department of Tumor Surgery, Neijiang Second People's Hospital, Neijiang, Sichuan, China
| | - Hong Wang
- Department of Oncology, The Third Hospital of Nanchang, Nanchang, Jiangxi, China
| | - Yanru Xie
- Department of Oncology, Lishui City Central Hospital, Lishui, Zhejiang, China
| | - Yuefen Zhou
- Department of Oncology, Lishui City Central Hospital, Lishui, Zhejiang, China
| | - Nong Xu
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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Li W, Wan L. Cost-utility of sintilimab plus chemotherapy vs chemotherapy as first-line treatment of advanced gastric or gastroesophageal junction cancer in China. Expert Rev Pharmacoecon Outcomes Res 2024; 24:671-678. [PMID: 38594905 DOI: 10.1080/14737167.2024.2341859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 04/03/2024] [Indexed: 04/11/2024]
Abstract
OBJECTIVES ORIENT-16, a phase III clinical trial conducted at 62 hospitals in China, reported that add-on sintilimab (Sin) to chemotherapy (Chemo) had favorable efficacy (p < 0.05) for patients with advanced HER2-negative gastric or gastroesophageal junction cancer (GC/GEJC). This study aimed to evaluate the cost-utility of the Sin+Chemo based on results of ORIENT-16 from the perspective of Chinese healthcare payers. METHODS A three-state partitioned survival model was developed to simulate the 10-year life expectancy and total healthcare costs for patients with advanced HER2-negative GC/GEJC. Primary measure outcomes were: cost, quality-adjusted life-years (QALYs), and incremental cost-utility ratios (ICURs). Sensitivity/scenario analyses were conducted to assess the model robustness. RESULTS In all patients, Sin+Chemo vs Chemo increased costs by $6,472, additionally providing 0.61 QALYs, resulting in an ICUR of $10,610/QALY. While, in PD-L1 combined positive score ≥ 5 cohort, the ICUR was $9,738/QALYs. The ICUR was most sensitive to the utility of progression-free survival. The probabilistic sensitivity analysis showed that add-on Sin had a 100% probability of being cost-effective at a willingness-to-pay threshold of $18,625/QALY gained. CONCLUSIONS Sin+Chemo is a cost-effective first-line treatment option for advanced HER2-negative GC/GEJC in China. CLINICAL TRIAL REGISTRATION ORIENT-16, www.clinicaltrials.gov, identifier is NCT03745170.
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Affiliation(s)
- Wei Li
- Department of Pharmacy, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Wan
- Department of Pharmacy, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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16
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Paul S, Konig MF, Pardoll DM, Bettegowda C, Papadopoulos N, Wright KM, Gabelli SB, Ho M, van Elsas A, Zhou S. Cancer therapy with antibodies. Nat Rev Cancer 2024; 24:399-426. [PMID: 38740967 PMCID: PMC11180426 DOI: 10.1038/s41568-024-00690-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/29/2024] [Indexed: 05/16/2024]
Abstract
The greatest challenge in cancer therapy is to eradicate cancer cells with minimal damage to normal cells. Targeted therapy has been developed to meet that challenge, showing a substantially increased therapeutic index compared with conventional cancer therapies. Antibodies are important members of the family of targeted therapeutic agents because of their extraordinarily high specificity to the target antigens. Therapeutic antibodies use a range of mechanisms that directly or indirectly kill the cancer cells. Early antibodies were developed to directly antagonize targets on cancer cells. This was followed by advancements in linker technologies that allowed the production of antibody-drug conjugates (ADCs) that guide cytotoxic payloads to the cancer cells. Improvement in our understanding of the biology of T cells led to the production of immune checkpoint-inhibiting antibodies that indirectly kill the cancer cells through activation of the T cells. Even more recently, bispecific antibodies were synthetically designed to redirect the T cells of a patient to kill the cancer cells. In this Review, we summarize the different approaches used by therapeutic antibodies to target cancer cells. We discuss their mechanisms of action, the structural basis for target specificity, clinical applications and the ongoing research to improve efficacy and reduce toxicity.
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Affiliation(s)
- Suman Paul
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
| | - Maximilian F Konig
- Division of Rheumatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Drew M Pardoll
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Chetan Bettegowda
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Katharine M Wright
- Discovery Chemistry, Merck Research Laboratory, Merck and Co, West Point, PA, USA
| | - Sandra B Gabelli
- Discovery Chemistry, Merck Research Laboratory, Merck and Co, West Point, PA, USA.
| | - Mitchell Ho
- Antibody Engineering Program, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
| | | | - Shibin Zhou
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
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Fan M, Ma Y, Deng G, Si H, Jia R, Wang Z, Dai G. A real-world analysis of second-line treatment option, gemcitabine plus anlotinib and anti-PD1, in advanced pancreatic cancer. Pancreatology 2024; 24:579-583. [PMID: 38553260 DOI: 10.1016/j.pan.2024.03.017] [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: 02/19/2023] [Revised: 03/04/2024] [Accepted: 03/23/2024] [Indexed: 06/12/2024]
Abstract
BACKGROUND In the second-line treatment of advanced pancreatic cancer (APC), there is only one approved regimen based on the phase III NAPOLI-1 trial. However, for patients progressing after Nab-paclitaxel and Gemcitabine (Nab-P/Gem) or Nab-P combinations, second-line treatment were very limited. METHODS This is a retrospective single-center analysis of patients. Our aim was to determine the effectiveness and tolerability of a novel regimen, gemcitabine plus Anlotinib and anti-PD1, in APC patients and to compare it with oxaliplatin, irinotecan, leucovorin, and fluorouracil (FOLFIRINOX) in the second-line setting who have failed on the first-line Nab-P combinations. RESULTS In total, twenty-three patients received Gemcitabine plus Anlotinib and anti-PD1 in the second-line, 28 patients were treated with FOLFORINOX. There was no significant difference in overall survival (OS) or progression free survival (PFS) for either of the two sequences (p > 0.05). Patients who received Gemcitabine plus Anlotinib and anti-PD1 had a median PFS of 4.0 months (95% CI: 1.1-6.9) versus 3.5 months (95% CI 1.8-5.2) in FOLFORINOX group (p = 0.953). The median OS of Gemcitabine plus Anlotinib and anti-PD1 was 9.0 months (95% CI: 4.0-13.7) and 8.0 months (95% CI: 5.5-10.5) in FOLFORINOX group (p = 0.373). Grade ≥3 treatment-emergent adverse events (AEs) occurred for 13% of patients with Gemcitabine plus Anlotinib and anti-PD1 and 40% for FOLFORINOX. CONCLUSION Our data confirms the effectiveness of Gemcitabine plus Anlotinib and anti-PD1 as a well-tolerated regimen in the second-line treatment of APC and extends available data on its use as a second-line treatment option when compared with FOLFIRINOX.
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Affiliation(s)
- Mengjiao Fan
- Medical School of Chinese People's Liberation Army, Beijing, China; Medical Oncology Department, The Fifth Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China; Medical Oncology Department, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China.
| | - Yue Ma
- Medical School of Chinese People's Liberation Army, Beijing, China; Medical Oncology Department, The Fifth Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China; Medical Oncology Department, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China.
| | - Guochao Deng
- Medical Oncology Department, The Fifth Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China.
| | - Haiyan Si
- Medical Oncology Department, The Fifth Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China.
| | - Ru Jia
- Medical Oncology Department, The Fifth Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China.
| | - Zhikuan Wang
- Medical Oncology Department, The Fifth Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China.
| | - Guanghai Dai
- Medical Oncology Department, The Fifth Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China; Medical Oncology Department, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China.
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Wang DQ, Xu WH, Cheng XW, Hua L, Ge XS, Liu L, Gao X. Interpretable machine learning for predicting the response duration to Sintilimab plus chemotherapy in patients with advanced gastric or gastroesophageal junction cancer. Front Immunol 2024; 15:1407632. [PMID: 38840913 PMCID: PMC11150638 DOI: 10.3389/fimmu.2024.1407632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 05/08/2024] [Indexed: 06/07/2024] Open
Abstract
Background Sintilimab plus chemotherapy has proven effective as a combination immunotherapy for patients with advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJC). A multi-center study conducted in China revealed a median progression-free survival (PFS) of 7.1 months. However, the prediction of response duration to this immunotherapy has not been thoroughly investigated. Additionally, the potential of baseline laboratory features in predicting PFS remains largely unexplored. Therefore, we developed an interpretable machine learning (ML) framework, iPFS-SC, aimed at predicting PFS using baseline (pre-treatment) laboratory features and providing interpretations of the predictions. Materials and methods A cohort of 146 patients with advanced GC/GEJC, along with their baseline laboratory features, was included in the iPFS-SC framework. Through a forward feature selection process, predictive baseline features were identified, and four ML algorithms were developed to categorize PFS duration based on a threshold of 7.1 months. Furthermore, we employed explainable artificial intelligence (XAI) methodologies to elucidate the relationship between features and model predictions. Results The findings demonstrated that LightGBM achieved an accuracy of 0.70 in predicting PFS for advanced GC/GEJC patients. Furthermore, an F1-score of 0.77 was attained for identifying patients with PFS durations shorter than 7.1 months. Through the feature selection process, we identified 11 predictive features. Additionally, our framework facilitated the discovery of relationships between laboratory features and PFS. Conclusion A ML-based framework was developed to predict Sintilimab plus chemotherapy response duration with high accuracy. The suggested predictive features are easily accessible through routine laboratory tests. Furthermore, XAI techniques offer comprehensive explanations, both at the global and individual level, regarding PFS predictions. This framework enables patients to better understand their treatment plans, while clinicians can customize therapeutic approaches based on the explanations provided by the model.
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Affiliation(s)
- Dan-qi Wang
- Big Data Center, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Wen-huan Xu
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Xiao-wei Cheng
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Lei Hua
- Big Data Center, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Xiao-song Ge
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Li Liu
- Big Data Center, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Xiang Gao
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
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He W, Song C, Ren J, Ji X, Wang X, Liu L. Case report: Robust response to sintilimab in advanced distal cholangiocarcinoma with PD-L1 expression and DNA damage repair. Front Pharmacol 2024; 15:1336699. [PMID: 38659574 PMCID: PMC11039799 DOI: 10.3389/fphar.2024.1336699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 03/26/2024] [Indexed: 04/26/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a highly heterogeneous tumor that occurs in the bile duct epithelium; adenosquamous carcinoma is a rare pathological subtype of CCA. The clinical treatment of patients with metastatic distal CCA poses significant challenges. We report a 53-year-old female diagnosed with a stage III adenosquamous carcinomas of distal CCA. Metastasis occurred 4 months postoperatively and she was diagnosed with stage IV disease. The patient was treated with Gemcitabine + Oxaliplatin (GEMOX) and Capecitabine + Oxaliplatin (CAPEOX), followed by sintilimab monotherapy. After two cycles of treatment, the patient achieved partial response (PR) and the lesion continued to shrink. After 37 months of follow-up, the patient's liver metastasis had almost completely disappeared, and complete response (CR) was achieved. Moreover, she had more than 46 months of disease progression-free survival (PFS). Immunohistochemical testing showed high expression of PD-L1, and next-generation sequencing revealed the presence of mutations in DNA damage repair (DDR) pathway genes. To the best of our knowledge, this is the first reported case of the successful treatment of metastatic distal adenosquamous CCA with sintilimab alone. Remarkably, patients of CCA with high PD-L1 expression and DDR pathway gene mutations may benefit from sintilimab treatment.
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Affiliation(s)
- Wenguang He
- Traditional Chinese Medicine Department, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Congcong Song
- Shenzhen Engineering Center for Translational Medicine of Precision Cancer Immunodiagnosis and Therapy, YuceBio Technology Co., Ltd., Shenzhen, China
| | - Jiwei Ren
- Traditional Chinese Medicine Department, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Xiao Ji
- Traditional Chinese Medicine Department, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Xiuyan Wang
- Shenzhen Engineering Center for Translational Medicine of Precision Cancer Immunodiagnosis and Therapy, YuceBio Technology Co., Ltd., Shenzhen, China
| | - Lixia Liu
- Traditional Chinese Medicine Department, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
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20
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Li N, Li Z, Fu Q, Zhang B, Zhang J, Wan XB, Lu CM, Wang JB, Deng WY, Ma YJ, Bie LY, Wang MY, Li J, Xia QX, Wei C, Luo SX. Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study. Int J Surg 2024; 110:2071-2084. [PMID: 38320099 PMCID: PMC11020066 DOI: 10.1097/js9.0000000000001119] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 01/09/2024] [Indexed: 02/08/2024]
Abstract
BACKGROUND The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. METHODS Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m 2 docetaxel, 80 mg/m 2 oxaliplatin, 200 mg/m 2 calcium levofolinate, 2600 mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. RESULTS Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. CONCLUSIONS The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.
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Affiliation(s)
- Ning Li
- Departments of Medical Oncology
| | | | | | | | | | | | | | | | | | | | | | | | | | - Qing-Xin Xia
- Pathology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
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Huang J, Wang F, Du X, Li Y, Zhuang Y, Gan Z, Long S, Wu W, Yang X. Complete response in patient with locally advanced lung large cell neuroendocrine carcinoma under sintilimab plus platinum-based chemotherapy: A case report. Heliyon 2024; 10:e27105. [PMID: 38439872 PMCID: PMC10909757 DOI: 10.1016/j.heliyon.2024.e27105] [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: 02/17/2023] [Revised: 02/20/2024] [Accepted: 02/23/2024] [Indexed: 03/06/2024] Open
Abstract
Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is an uncommon subtype of lung cancer with bleak prognosis. Its optimal treatment remains undetermined due to its malignancy. A 66-year-old man diagnosed with unresectable locally advanced LCNEC exhibited partial radiographic response to chemo-immunotherapy. He underwent salvage surgery after 4 rounds of docetaxel/nedaplatin (DP) regimen plus sintilimab, a highly selective monoclonal antibody which targets human anti-programmed death-ligand 1 (PD-L1). In addition, the pathologic examination of the excision demonstrated that there were no viable residuary tumor cells. This case indicates that neoadjuvant chemo-immunotherapy might benefit patients with locally advanced LCNEC, which deserves further investigation.
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Affiliation(s)
- Jinpeng Huang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Oncology Department, Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Feiye Wang
- Department of Oncology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaohua Du
- Pathology Department, Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yongfeng Li
- Thoracic Surgery Department, Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuanyuan Zhuang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Oncology Department, Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ziyan Gan
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Oncology Department, Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shunqin Long
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Oncology Department, Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wanyin Wu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Oncology Department, Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaobing Yang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Oncology Department, Guangdong Provincial Hospital of Chinese Medicine, the Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
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Gao L, Tang L, Li X, Peng J, Hu Z, Liu B. Efficacy and safety of sintilimab combined with apatinib as third-line or above therapy for patients with advanced or metastatic gastric cancer. Anticancer Drugs 2024; 35:277-283. [PMID: 37948350 PMCID: PMC10833188 DOI: 10.1097/cad.0000000000001554] [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: 10/16/2023] [Accepted: 10/17/2023] [Indexed: 11/12/2023]
Abstract
This study aimed to evaluate the efficacy and safety of the combination of sintilimab and apatinib for the treatment of patients with advanced or metastatic gastric cancer (GC) and gastroesophageal junction (GEJ) cancer. This retrospective study analyzed data from 34 patients who had advanced or metastatic GC/GEJ cancer and received the combination therapy of sintilimab and apatinib as a third-line or above treatment. The primary endpoint was progression-free survival (PFS), and secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Among the 34 patients, none achieved a complete response (CR), 3 patients (8.8%) achieved a partial response, 23 patients (67.6%) had stable disease, and 8 patients (23.5%) experienced progressive disease. The ORR and DCR were 8.8% and 76.5%, respectively. The median PFS was 6.0 months (95% CI: 3.6-8.4), and the median OS was 11.6 months (95% CI: 8.1-15.1). Subgroup analysis revealed significant differences in OS between patients with high and low Eastern Cooperative Oncology Group Performance Status scores and between patients with and without a history of gastrectomy. Common adverse events (AEs) during treatment included fatigue (52.9%), anemia (47.1%), leukopenia (26.5%), hypothyroidism (23.5%), nausea and vomiting (20.6%), neutropenia (20.6%), and thrombocytopenia (17.6%), most of which were grade 1 and 2 AEs. No deaths occurred due to AEs. These findings indicate that the combination of sintilimab and apatinib has a favorable therapeutic effect in patients with advanced GC. Moreover, the AEs associated with this therapy are generally manageable.
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Affiliation(s)
- Loulu Gao
- School of Clinical Medicine, Weifang Medical University, Weifang
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
| | - Lin Tang
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
- Department of Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Xiaoqian Li
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
| | - Jieqiong Peng
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
| | - Zixuan Hu
- School of Clinical Medicine, Weifang Medical University, Weifang
| | - Bo Liu
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
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Maggie Liu SY, Huang J, Deng JY, Xu CR, Yan HH, Yang MY, Li YS, Ke EE, Zheng MY, Wang Z, Lin JX, Gan B, Zhang XC, Chen HJ, Wang BC, Tu HY, Yang JJ, Zhong WZ, Li Y, Zhou Q, Wu YL. PD-L1 expression guidance on sintilimab versus pembrolizumab with or without platinum-doublet chemotherapy in untreated patients with advanced non-small cell lung cancer (CTONG1901): A phase 2, randomized, controlled trial. Sci Bull (Beijing) 2024; 69:535-543. [PMID: 38185589 DOI: 10.1016/j.scib.2023.12.046] [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: 09/12/2023] [Revised: 11/22/2023] [Accepted: 12/25/2023] [Indexed: 01/09/2024]
Abstract
No direct comparison has been performed between different programmed cell death-1 (PD-1) inhibitors for first-line treatment in patients with advanced non-small cell lung cancer (NSCLC). The feasibility of using PD-L1-expression-guided immunotherapy remains unknown. In this open-label, phase 2 study (NCT04252365), patients with advanced NSCLC without EGFR or ALK alterations were randomized (1:1) to receive sintilimab or pembrolizumab monotherapy (PD-L1 expression ≥ 50%), or sintilimab or pembrolizumab plus platinum-based chemotherapy (PD-L1 expression < 50%). The sample size was calculated by optimal two-stage design. The primary endpoint was the objective response rate (ORR). The study included 71 patients (sintilimab arms, n = 35; pembrolizumab arms, n = 36) and met its primary endpoint, with a confirmed ORR of 51.4% (18/35) in the sintilimab arms. The confirmed ORR (95% confidence interval) was 46.2% (19.2%, 74.9%) and 42.9% (17.7%, 71.1%) for patients treated with sintilimab and pembrolizumab monotherapy; and 54.5% (32.2%, 75.6%) and 45.4% (24.4%, 67.8%) for those treated with sintilimab- and pembrolizumab-based combination therapies. The median progression-free survival was 6.9 versus 8.1 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 7.6 versus 11.0 months in monotherapy and 7.4 versus 7.1 months in combination therapies. The median overall survival was 14.9 versus 21.3 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 14.9 versus 22.6 months in monotherapy and 14.7 versus 17.3 months in combination therapies. Treatment-related adverse events were consistent with safety outcomes of monotherapy and combination therapy in previous phase III studies. However, the incidence of rash was higher with sintilimab than pembrolizumab monotherapy. This is the first prospective phase 2 study to directly compare two anti-PD-1 antibodies as first-line treatment in advanced NSCLC. Sintilimab was efficacious and well-tolerated irrespective of PD-L1 expression level in patients with advanced NSCLC and had similar efficacy and safety to pembrolizumab.
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Affiliation(s)
- Si-Yang Maggie Liu
- Department of Hematology, The First Affiliated Hospital, Jinan University, Guangzhou 510632, China
| | - Jie Huang
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Jia-Yi Deng
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Chong-Rui Xu
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Hong-Hong Yan
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; Chinese Thoracic Oncology Group (CTONG), Guangzhou 510055, China
| | - Ming-Yi Yang
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Yang-Si Li
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - E-E Ke
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Ming-Ying Zheng
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Zhen Wang
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Jia-Xin Lin
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Bin Gan
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Xu-Chao Zhang
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Hua-Jun Chen
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Bin-Chao Wang
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Hai-Yan Tu
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Jin-Ji Yang
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Wen-Zhao Zhong
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - Yangqiu Li
- Department of Hematology, The First Affiliated Hospital, Jinan University, Guangzhou 510632, China; Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou 510632, China.
| | - Qing Zhou
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; Chinese Thoracic Oncology Group (CTONG), Guangzhou 510055, China.
| | - Yi-Long Wu
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; Chinese Thoracic Oncology Group (CTONG), Guangzhou 510055, China.
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Zhao Y, Chen X, Yao J, Long J, Mao Y, Wu D, Zang A, Zhao J, Liu Z, Meng R, Chen Y, Luo Y, Guo Q, Li L, Cui J. A phase Ib study evaluating the safety and efficacy of IBI310 plus sintilimab in patients with advanced non-small-cell lung cancer who have progressed after anti-PD-1/L1 therapy. Cancer Med 2024; 13:e6855. [PMID: 38214075 PMCID: PMC10905228 DOI: 10.1002/cam4.6855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 12/07/2023] [Accepted: 12/11/2023] [Indexed: 01/13/2024] Open
Abstract
BACKGROUND The development of immune checkpoint inhibitors has made a significant breakthrough in the treatment of non-small-cell lung cancer (NSCLC). However, there remains a huge unmet clinical need for patients with acquired resistance after initial treatment response. METHODS This study evaluated the combination of IBI310 (an anti-cytotoxic T lymphocyte-associated antigen-4 [CTLA-4] antibody) and sintilimab (an anti-programmed death 1 [PD-1]) antibody) in NSCLC patients who have previously been treated with anti-PD-1/ligand (L)1 and acquired resistance. The patients were randomly assigned to receive either a lower dose of IBI310 (1 mg/kg Q3W, cohort A) or a higher dose of IBI310 (3 mg/kg Q3W, cohort B) in combination with sintilimab (200 mg Q3W). The primary endpoints of the study were objective response rate (ORR) assessed by RECISTv1.1 and safety, while secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS As of November 2, 2023, the study had enrolled 30 patients, with 15 patients in each cohort. The ORR was 13.3% (2/15, 95% confidence interval [CI], 1.7-40.5) in cohort B. DCR were 46.7% (95% CI, 21.3-73.4) and 66.7% (95% CI, 38.4-88.2) in cohorts A and B, respectively. In cohorts A and B of this trial, the median follow-up times were 4.2 and 5.6 months, respectively. Median PFS was 1.45 (95% CI, 1.35-2.73) versus 2.73 (95% CI, 1.41-4.90) months for cohort A versus B; the median OS was 7.03 (95% CI, 3.09-not calculable [NC]) months in cohort A and 8.90 (95% CI, 5.13-NC) months in cohort B. Of the 30 patients, 86.7% in both cohorts experienced treatment-related adverse events (TRAEs) with Grade ≥3 TRAEs occurring in 40% and 53.3% of patients in cohorts A and B, respectively. CONCLUSION IBI310 3 mg/kg Q3W plus sintilimab was effective in a small number of previously treated anti-PD-1/L1-resistant NSCLC patients.
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Affiliation(s)
- Yuguang Zhao
- The First Hospital of Jilin University, Changchun, China
| | - Xiao Chen
- The First Hospital of Jilin University, Changchun, China
| | - Jun Yao
- The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
| | - Jianlin Long
- Chongqing University Affiliated Cancer Hospital, Chongqing, China
| | - Yong Mao
- Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Di Wu
- The First Hospital of Jilin University, Changchun, China
| | - Aimin Zang
- Affiliated Hospital of Hebei University, Baoding, China
| | - Jun Zhao
- Beijing Cancer Hospital, Beijing, China
| | - Ziling Liu
- The First Hospital of Jilin University, Changchun, China
| | - Rui Meng
- Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Ye Chen
- Innovent Biologics, Inc., Suzhou, China
| | - Yang Luo
- Innovent Biologics, Inc., Suzhou, China
| | - Qun Guo
- Innovent Biologics, Inc., Suzhou, China
| | - Li Li
- Innovent Biologics, Inc., Suzhou, China
| | - Jiuwei Cui
- The First Hospital of Jilin University, Changchun, China
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Li T, Chen C, Liu L, Qin J, Qiu L, Wang A, Dong W, Zhang G, Li Y, Zhao L, Zhang F, Hu Y. A multicenter, real-world study on effectiveness and safety of first-line modified PD-1 inhibitors with chemotherapy in advanced non-small cell lung cancer (aNSCLC) with drive gene-negative. Cancer Med 2024; 13:e7024. [PMID: 38400661 PMCID: PMC10891446 DOI: 10.1002/cam4.7024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 02/01/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
OBJECTIVES The use of immune checkpoint inhibitors, particularly PD-1 inhibitors, has revolutionized the treatment of advanced tumors and shown significant improvements in patient survival rates. However, which PD-1 inhibitor is more effective and safer for a specific indication remains unclear. To address this problem, our study aimed to evaluate the effectiveness and safety of different PD-1 inhibitors in combination with chemotherapy as first-line therapy for individuals with advanced non-small-cell lung cancer (NSCLC) without driver genes in the real world. MATERIALS AND METHODS We conducted a retrospective study of individuals diagnosed with aNSCLC who received immune checkpoint inhibitors (ICIs) with modified PD-1 inhibitors, including Sintilimab, Toripalimab, Tislelizumab, Camrelizumab, or Pembrolizumab as first-line treatment between March 5th, 2016 and October 20th, 2022. We assessed demographic and clinical information and analyzed clinical response, survival outcomes, and safety profiles. The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. RESULTS As of the date cut-off on October 20th, 2022, the median follow-up time was 20.62 months. A total of 204 patients were enrolled in the study, including 56 (27.5%) patients receiving modified PD-1 inhibitors (Sintilimab, Toripalimab, Tislelizumab, or Camrelizumab) in combination with chemotherapy and 148 (72.5%) patients receiving Pembrolizumab in combination with chemotherapy. In the overall cohort, the median overall survival (OS) was 26.9 months (95%CI, 22.3-31.6), the median progression-free survival (PFS) was 8.4 months (95%CI, 6.9-9.8), and the objective response rate (ORR) and disease control rate (DCR) were 47.6% (95%CI, 29.9-43.6) and 84.3% (95%CI, 78.4-88.9). The mOS of modified PD-1 inhibitors group and Pembrolizumab group were 30.7 (95%CI, 17.3-44.4) months and 26.8 (95%CI, 22.2-31.4) months. The mPFS of two groups were 8.3(95%CI, 6.9-9.6) months and 8.8 (95%CI, 6.9-10.7) months, respectively. There was no statistical difference between the two groups in terms of OS or PFS. The ORR for the two groups was 48.2% (95%CI, 34.8-61.8) and 47.3% (95%CI, 39.1-5.6), respectively. However, due to the limited sample size, the difference was not statistically significant. On the other hand, the DCR tended to be higher in the Pembrolizumab group (86.5%; 95%CI, 79.7-91.4) compared to the modified PD-1 inhibitors group (78.6%; 95%CI, 65.2-87.9), and this difference was statistically significant (p = 0.006). In terms of safety, both groups exhibited favorable clinical safety profiles. The only two types of potentially immune-related adverse events reported were pneumonitis and reactive cutaneous capillary endothelial proliferation (RCCEP). CONCLUSIONS The modified PD-1 inhibitors showed comparable survival outcomes and manageable safety profiles in NSCLC compared to Pembrolizumab. Moreover, these inhibitors exhibited improved accessibility and economic outcomes compared to Pembrolizumab. While there were similarities in drug-related and immunotherapy-related adverse reactions between the modified PD-1 inhibitors and Pembrolizumab, there were some slight differences. Further prospective and retrospective studies would be necessary to validate these findings beyond the scope of the CTONG1901 study.
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Affiliation(s)
- Tao Li
- Medical School of Chinese PLABeijingChina
- Department of Oncology, the First Medical CenterChinese PLA General Hospital; Chinese PLA Key Laboratory of Oncology, Key Laboratory for Tumor Targeting Therapy and Antibody Drugs Ministry of EducationChina
| | - Chao Chen
- Internal Medicine Emergency DepartmentThe Second Hospital of BeijingBeijingChina
| | - Lu Liu
- Medical School of Chinese PLABeijingChina
- Department of Nutrition, The First Medical CenterChinese PLA General Hospital
| | - Jiapei Qin
- Medical School of Chinese PLABeijingChina
- Department of Oncology, the First Medical CenterChinese PLA General Hospital; Chinese PLA Key Laboratory of Oncology, Key Laboratory for Tumor Targeting Therapy and Antibody Drugs Ministry of EducationChina
| | - Lupeng Qiu
- Medical School of Chinese PLABeijingChina
- Department of Oncology, the First Medical CenterChinese PLA General Hospital; Chinese PLA Key Laboratory of Oncology, Key Laboratory for Tumor Targeting Therapy and Antibody Drugs Ministry of EducationChina
| | - An Wang
- Medical School of Chinese PLABeijingChina
- Department of Oncology, the First Medical CenterChinese PLA General Hospital; Chinese PLA Key Laboratory of Oncology, Key Laboratory for Tumor Targeting Therapy and Antibody Drugs Ministry of EducationChina
| | - Weiwei Dong
- Medical School of Chinese PLABeijingChina
- Department of Oncology, the First Medical CenterChinese PLA General Hospital; Chinese PLA Key Laboratory of Oncology, Key Laboratory for Tumor Targeting Therapy and Antibody Drugs Ministry of EducationChina
| | - Gehan Zhang
- Institute of Translational Medicine, Chinese PLA General HospitalBeijingChina
| | - Yao Li
- Medical School of Chinese PLABeijingChina
- Department of Oncology, the First Medical CenterChinese PLA General Hospital; Chinese PLA Key Laboratory of Oncology, Key Laboratory for Tumor Targeting Therapy and Antibody Drugs Ministry of EducationChina
| | - Lei Zhao
- Institute of Translational Medicine, Chinese PLA General HospitalBeijingChina
| | - Fan Zhang
- Medical School of Chinese PLABeijingChina
- Department of Oncology, the First Medical CenterChinese PLA General Hospital; Chinese PLA Key Laboratory of Oncology, Key Laboratory for Tumor Targeting Therapy and Antibody Drugs Ministry of EducationChina
| | - Yi Hu
- Medical School of Chinese PLABeijingChina
- Department of Oncology, the First Medical CenterChinese PLA General Hospital; Chinese PLA Key Laboratory of Oncology, Key Laboratory for Tumor Targeting Therapy and Antibody Drugs Ministry of EducationChina
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Guo H, Zhang J, Qin C, Yan H, Luo X, Zhou H. Advances and challenges of first-line immunotherapy for non-small cell lung cancer: A review. Medicine (Baltimore) 2024; 103:e36861. [PMID: 38241591 PMCID: PMC10798763 DOI: 10.1097/md.0000000000036861] [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: 08/05/2023] [Accepted: 12/14/2023] [Indexed: 01/21/2024] Open
Abstract
The current use of immune checkpoint inhibitors (ICIs) for the treatment of lung cancer has dramatically changed the clinical strategy for metastatic non-small cell lung cancer (mNSCLC). As a result of great achievements in clinical trials, 6 programmed death-1 inhibitors (sintilimab, camrelizumab, tislelizumab, pembrolizumab, cemiplimab, and nivolumab), 2 programmed death-ligand 1 inhibitors (sugemalimab and atezolizumab), and 1 cytotoxic T lymphocyte-associated antigen-4 inhibitor (ipilimumab) have been approved as first-line treatment for mNSCLC by the US Food and Drug Administration. Recently, research on ICIs has shifted from a large number of second-line to first-line settings in clinical trials. Results from first-line trials have shown that almost all driver-negative mNSCLC are treated with ICIs and significantly prolong patient survival; however, the low response rate and adverse reactions to immunotherapy remain to be addressed. Here, we summarize the use of ICIs, including monotherapy and combination therapy, in the first-line treatment of mNSCLC in recent years and discuss the low response rate and adverse reactions of ICIs as well as the challenges and expectations for the first-line treatment of mNSCLC in the future.
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Affiliation(s)
- Haiyang Guo
- Institute of Surgery, School of Medicine and Life Sciences, Chengdu University of TCM, Chengdu, China
- Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
| | - Jun Zhang
- Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
- Institute of Surgery, Graduate School, Zunyi Medical University, Zunyi, China
| | - Chao Qin
- Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
- Institute of Surgery, Graduate School, Zunyi Medical University, Zunyi, China
| | - Hang Yan
- Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
- Institute of Surgery, Graduate School, Zunyi Medical University, Zunyi, China
| | - Xinyue Luo
- Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
| | - Haining Zhou
- Institute of Surgery, School of Medicine and Life Sciences, Chengdu University of TCM, Chengdu, China
- Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
- Institute of Surgery, Graduate School, Zunyi Medical University, Zunyi, China
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Galle P, Finn RS, Mitchell CR, Ndirangu K, Ramji Z, Redhead GS, Pinato DJ. Treatment-emergent antidrug antibodies related to PD-1, PD-L1, or CTLA-4 inhibitors across tumor types: a systematic review. J Immunother Cancer 2024; 12:e008266. [PMID: 38238030 PMCID: PMC10806538 DOI: 10.1136/jitc-2023-008266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/27/2023] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Increased understanding of how the immune system regulates tumor growth has innovated the use of immunotherapeutics to treat various cancers. The impact of such therapies, including programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, on the production of antidrug antibodies (ADAs) and their impact on outcomes, is poorly understood. This study aims to evaluate the clinical trial evidence on ADA incidence associated with PD-1, PD-L1, and CTLA-4 inhibitors in the treatment of cancer and to assess associations between treatment administered, ADA incidence, and treatment outcomes. METHODS Embase®, Medline®, and EBM Reviews were searched via the OVID® platform on February 15, 2022. Conference proceedings, clinical trial registries, and global regulatory and reimbursement body websites were also searched. Eligible publications included clinical trials enrolling patients receiving cancer treatment with either PD-1, PD-L1, or CTLA-4 reporting outcomes including incidence or prevalence of ADAs and the impact of immunogenicity on treatment safety and efficacy. Reference lists of eligible publications were also searched. The review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and evidence quality assessment was conducted using the appropriate Joanna Briggs Institute Critical Appraisal tool. RESULTS After screening 4160 records and reviewing 97 full publications, a total of 34 publications reporting on 68 trials were included. A further 41 relevant clinical trials were identified on ClinicalTrials.gov and a further 32 from searches of packaging inserts. In total, 141 relevant trials covering 15 different checkpoint inhibitors and 16 different tumor types were included. Across the included trials, atezolizumab was associated with the highest incidence of ADAs (29.6% of 639 patients), followed by nivolumab (11.2% of 2,085 patients). Combination checkpoint inhibitor treatment appeared to increase the rate of ADAs versus monotherapy. Only 17 trials reported on the impact of ADAs on treatment outcomes with mixed results for the impact of ADAs on treatment efficacy, safety, and pharmacokinetics. CONCLUSIONS Checkpoint inhibitors for the treatment of cancer are immunogenic, with the incidence of treatment-emergent ADAs varying between individual therapies. It remains unclear what impact ADAs have on treatment outcomes.
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Affiliation(s)
- Peter Galle
- University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Richard S Finn
- University of California Los Angeles, Los Angeles, California, USA
| | | | | | | | | | - David J Pinato
- Surgery and Cancer, Imperial College London, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
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Xu J, Jiang H, Pan Y, Gu K, Cang S, Han L, Shu Y, Li J, Zhao J, Pan H, Luo S, Qin Y, Guo Q, Bai Y, Ling Y, Yang J, Yan Z, Yang L, Tang Y, He Y, Zhang L, Liang X, Niu Z, Zhang J, Mao Y, Guo Y, Peng B, Li Z, Liu Y, Wang Y, Zhou H. Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial. JAMA 2023; 330:2064-2074. [PMID: 38051328 PMCID: PMC10698618 DOI: 10.1001/jama.2023.19918] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 09/15/2023] [Indexed: 12/07/2023]
Abstract
Importance Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures The primary end point was overall survival time from randomization. Results Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration ClinicalTrials.gov Identifier: NCT03745170.
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Affiliation(s)
- Jianming Xu
- The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Haiping Jiang
- The First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
| | | | - Kangsheng Gu
- The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Shundong Cang
- Henan Provincial People’s Hospital, Zhengzhou, China
| | - Lei Han
- Affiliated Hospital of Jining Medical University, Jining, China
| | | | - Jiayi Li
- The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Junhui Zhao
- Qinghai University Affiliated Hospital, Xining, China
| | - Hongming Pan
- Sir Run Run Shaw Hospital School of Medicine, Zhejiang University, Hangzhou, China
| | - Suxia Luo
- Henan Cancer Hospital, Zhengzhou, China
| | - Yanru Qin
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qunyi Guo
- Taizhou Hospital of Zhejiang Province, Linhai, China
| | - Yuxian Bai
- Harbin Medical University Cancer Hospital, Harbin, China
| | - Yang Ling
- Changzhou Tumor Hospital, Changzhou, China
| | - Jianwei Yang
- Fujian Provincial Cancer Hospital, Fuzhou, China
| | | | - Lei Yang
- Nantong Tumor Hospital, Nantong, China
| | - Yong Tang
- The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China
| | - Yifu He
- Anhui Provincial Cancer Hospital, Hefei, China
| | | | | | - Zuoxing Niu
- Affiliated Cancer Hospital of Shandong First Medical University, Jinan, China
| | | | - Yong Mao
- Affiliated Hospital of Jiangnan University, Wuxi, China
| | | | - Bo Peng
- Innovent Biologics, Inc., Suzhou, China
| | - Ziran Li
- Innovent Biologics, Inc., Suzhou, China
| | - Ying Liu
- Innovent Biologics, Inc., Suzhou, China
| | - Yan Wang
- Innovent Biologics, Inc., Suzhou, China
| | - Hui Zhou
- Innovent Biologics, Inc., Suzhou, China
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Momin N. Balancing safety and efficacy: tuning the biodistribution and pharmacokinetics of cytokine immunotherapies. Curr Opin Biotechnol 2023; 84:102994. [PMID: 37806081 DOI: 10.1016/j.copbio.2023.102994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 06/12/2023] [Accepted: 08/27/2023] [Indexed: 10/10/2023]
Abstract
Modulating the immune system shows promise in treating various conditions such as autoimmune, malignant, inflammatory, and infectious diseases. While immunotherapies can provide significant clinical benefits, they can also trigger debilitating immune-related toxicities. Achieving a balance between safety and efficacy of immunotherapy remains a significant engineering challenge. A complex immune response can be simplified into a sequence of coordinated signals with precise spatial and temporal arrangements. Mimicking or inhibiting these signals with protein immunotherapies relies on engineering them with specific biodistribution and pharmacokinetic properties. This review summarizes principles governing the movement of therapeutic proteins (i.e. biologics), focusing on cytokine immunotherapies injected intravenously or locally, and highlights approaches and considerations to balance their efficacy and safety.
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Affiliation(s)
- Noor Momin
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Center for Precision Engineering for Health, University of Pennsylvania, Philadelphia, PA, USA.
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30
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He L, Chen N, Dai L, Peng X. Advances and challenges of immunotherapies in NK/T cell lymphomas. iScience 2023; 26:108192. [PMID: 38026157 PMCID: PMC10651691 DOI: 10.1016/j.isci.2023.108192] [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] [Indexed: 12/01/2023] Open
Abstract
Natural killer (NK)/T cell lymphoma (NKTCL) is a rare subtype of Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma characterized by poor clinical outcomes. It is more common in East Asian and Latin American countries. Despite the introduction of asparaginase/pegaspargase-based chemotherapy, the prognosis of patients with advanced NKTCL needs to be improved, and few salvage treatment options are available for relapsed/refractory patients who fail chemotherapy. Although many unknowns remain, novel treatment strategies to further improve outcomes are urgently needed. Immunotherapy has emerged and shown favorable antitumor activity in NKTCL, including monoclonal antibodies targeting immune checkpoint inhibitors, other receptors on the cellular membrane, and cellular immunotherapy, which could enhance immune cells attack on tumor cells. In this review, we provide an overview of recent immunotherapy in NKTCL, focusing on programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), chimeric antigen receptor (CAR) T cells, EBV-specific cytotoxic T lymphocytes, immunomodulatory agents, and other targeted agents, as well as the current progress and challenges in the field.
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Affiliation(s)
- Ling He
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Na Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China
- School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan 610500, China
| | - Lei Dai
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China
| | - Xingchen Peng
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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Jiang Z, Chen X, Sun Z, Shen X, Huang Y, Liu J. Toxic Epidermal Necrolysis and Stevens - Johnson Syndrome Following Sintilimab Administration in a Non-Small Cell Lung Cancer Patient: A Case Report. J Inflamm Res 2023; 16:5061-5067. [PMID: 37936597 PMCID: PMC10627061 DOI: 10.2147/jir.s427336] [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: 06/23/2023] [Accepted: 10/25/2023] [Indexed: 11/09/2023] Open
Abstract
Immune checkpoint inhibitors such as monoclonal antibodies have been used recently with greater effect for the management of non-small cell lung cancer (NSCLC). Sintilimab, a fully human IgG4 monoclonal antibody is specific for the immune checkpoint protein programmed cell death receptor-1 (PD-1). It is a common medication adopted for treating Hodgkin's lymphoma and NSCLC. The adverse effects associated with the use of monoclonal antibodies should be closely monitored and in the current report, the use of sintilimab for treating NSCLC led to skin-associated adverse effects such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Genetic testing showed that genes such as KRAS, CREBBP, NTRK1, RAF1, and TP53 were mutated. Initial visible symptom included the formation of a vesicular rash on the skin that had spread to the upper limbs, chest, and dorsum 1 week after the administration of sintilimab. The patient received anti-inflammatory agents to prevent worsening of the rashes and further infections. When the vesicles in back and limbs enlarged and the neck skin began to desquamate, the patient was diagnosed with Stevens-Johnson syndrome and sintilimab-induced toxic epidermal necrolysis. Toxic epidermal necrolysis was diagnosed via clinical symptoms and physical examination. The patient also reported the symptoms of oral mucositis. As soon as the dose of sintilimab was reduced to 20 mg/day, the skin-associated condition of the patient began to improve. Although the lump in the lungs decreased considerably 45 days after initial administration of sintilimab, the medication was stopped from use as soon as the skin-related symptoms improved after its withdrawal. This report suggests that close monitoring, personal care, and proper use of medications such as sintilimab should be implemented to avoid such rare skin-associated toxicities as an adverse effect.
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Affiliation(s)
- Ziyu Jiang
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People’s Republic of China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, People’s Republic of China
| | - Xiaoli Chen
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, People’s Republic of China
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People’s Republic of China
| | - Zhaoshen Sun
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, People’s Republic of China
- Department of Dermatology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People’s Republic of China
| | - Xiaowei Shen
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, People’s Republic of China
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People’s Republic of China
| | - Yaju Huang
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, People’s Republic of China
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People’s Republic of China
| | - Jingbing Liu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People’s Republic of China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, People’s Republic of China
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Zhang L, Wang L, Cheng Q, Lei X, Wu J, Chen N. Lichenoid dermatitis following PD-1 inhibitor-induced toxic epidermal necrolysis: a case report and literature review. Immunotherapy 2023; 15:1249-1256. [PMID: 37585673 DOI: 10.2217/imt-2023-0081] [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] [Indexed: 08/18/2023] Open
Abstract
Immune checkpoint inhibitors such as anti-PD-1 receptor antibodies have been shown to be effective in patients with advanced gastric cancer. However, there is a growing concern about immune-related adverse events. A case of a patient with gastric adenocarcinoma who developed toxic epidermal necrolysis (TEN) induced by sintilimab and subsequently developed lichenoid dermatitis is reported. TEN was diagnosed according to a history of sintilimab use, clinical symptoms and physical examination. During hospitalization, the patient developed recurrent fever caused by bacteremia and recovered from TEN after anti-infection and anti-inflammatory treatments. However, when TEN was controlled, the patient developed the lesional manifestations of lichenoid dermatitis. To date, no cases of lichenoid dermatitis after TEN have been reported following the use of PD-1 inhibitors.
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Affiliation(s)
- Long Zhang
- Department of Dermatology, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Liang Wang
- Department of Dermatology, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Qionghui Cheng
- Department of Dermatology, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Xia Lei
- Department of Dermatology, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Jinjin Wu
- Department of Dermatology, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Nian Chen
- Department of Dermatology, Daping Hospital, Army Medical University, Chongqing, 400042, China
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Okagawa T, Konnai S, Goto S, Sajiki Y, Ganbaatar O, Watari K, Nakamura H, Wang CX, Tachibana T, Kato Y, Kameda Y, Kohara J, Terasaki N, Kubota M, Takeda A, Takahashi H, Suzuki Y, Maekawa N, Murata S, Ohashi K. Development of a high-affinity anti-bovine PD-1 rabbit-bovine chimeric antibody using an efficient selection and large production system. Vet Res 2023; 54:82. [PMID: 37759311 PMCID: PMC10537840 DOI: 10.1186/s13567-023-01213-6] [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: 12/12/2022] [Accepted: 09/02/2023] [Indexed: 09/29/2023] Open
Abstract
Immune checkpoint molecules PD-1/PD-L1 cause T-cell exhaustion and contribute to disease progression in chronic infections of cattle. We established monoclonal antibodies (mAbs) that specifically inhibit the binding of bovine PD-1/PD-L1; however, conventional anti-PD-1 mAbs are not suitable as therapeutic agents because of their low binding affinity to antigen. In addition, their sensitivity for the detection of bovine PD-1 is low and their use for immunostaining PD-1 is limited. To address these issues, we established two anti-bovine PD-1 rabbit mAbs (1F10F1 and 4F5F2) and its chimeric form using bovine IgG1 (Boch1D10F1), which exhibit high binding affinity. One of the rabbit mAb 1D10F1 binds more strongly to bovine PD-1 compared with a conventional anti-PD-1 mAb (5D2) and exhibits marked inhibitory activity on the PD-1/PD-L1 interaction. In addition, PD-1 expression in bovine T cells could be detected with higher sensitivity by flow cytometry using 1D10F1. Furthermore, we established higher-producing cells of Boch1D10F1 and succeeded in the mass production of Boch1D10F1. Boch1D10F1 exhibited a similar binding affinity to bovine PD-1 and the inhibitory activity on PD-1/PD-L1 binding compared with 1D10F1. The immune activation by Boch1D10F1 was also confirmed by the enhancement of IFN-γ production. Finally, Boch1D10F1 was administered to bovine leukemia virus-infected cows to determine its antiviral effect. In conclusion, the high-affinity anti-PD-1 antibody developed in this study represents a powerful tool for detecting and inhibiting bovine PD-1 and is a candidate for PD-1-targeted immunotherapy in cattle.
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Affiliation(s)
- Tomohiro Okagawa
- Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Satoru Konnai
- Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
- Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan.
| | - Shinya Goto
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Yamato Sajiki
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Otgontuya Ganbaatar
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Kei Watari
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Hayato Nakamura
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Cai-Xia Wang
- Department of Bioengineering, Graduate School of Engineering, Osaka City University, Osaka, Japan
| | - Taro Tachibana
- Department of Bioengineering, Graduate School of Engineering, Osaka City University, Osaka, Japan
- Department of Bioengineering, Graduate School of Engineering, Osaka Metropolitan University, Osaka, Japan
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yayoi Kameda
- Division of Bioresources, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Junko Kohara
- Animal Research Center, Agriculture Research Department, Hokkaido Research Organization, Shintoku, Japan
| | | | - Manabu Kubota
- Hokkaido Agricultural Mutual Aid Association, Shibecha, Japan
| | - Akira Takeda
- Hokkaido Agricultural Mutual Aid Association, Shibecha, Japan
| | | | - Yasuhiko Suzuki
- Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
- Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan
- Division of Bioresources, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
- Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan
| | - Naoya Maekawa
- Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Shiro Murata
- Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| | - Kazuhiko Ohashi
- Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
- International Affairs Office, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
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Yin C, Hu B, Yang X, Kou L, Tian B, Wang C, Li S, Liu B, Ge J. Neoadjuvant sintilimab combined with chemotherapy in resectable locally advanced non-small cell lung cancer: case series and literature review. World J Surg Oncol 2023; 21:304. [PMID: 37749594 PMCID: PMC10521519 DOI: 10.1186/s12957-023-03194-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 09/19/2023] [Indexed: 09/27/2023] Open
Abstract
BACKGROUND In recent years, neoadjuvant immunotherapy with chemotherapy has shown increasing promise for locally advanced non-small cell lung cancer (NSCLC). However, to establish its clinical efficacy and safety, it is imperative to amass more real-world clinical data. This retrospective study aims to assess the safety and effectiveness of combing sintilimab, a PD-1 inhibitor, with chemotherapy as a neoadjuvant treatment modality in patients diagnosed with potentially resectable NSCLC. METHODS We retrospectively reviewed patients with stage II-III NSCLC receiving neoadjuvant chemoimmunotherapy in Sichuan Cancer Hospital between February 2021 and February 2023. Sintilimab injection (intravenously,200 mg, iv, d1, q3w) and platinum-based chemotherapy were administered intravenously every 3 weeks, with radical lung cancer resection planned approximately 4-11 weeks after the last dose. The primary endpoint of the study was pathologic complete response (pCR). The secondary endpoints were objective response rate (ORR), and safety. RESULT Thirteen patients were enrolled, they were mostly diagnosed with stage III NSCLC (IIB 15.4% IIIA 38.5%; IIIB 46.2%). Most of them had pathologically confirmed squamous cell carcinoma (69.2%). All patients received sintilimab combined with platinum-based chemotherapy for 2 to 4 cycles. Notably, none of the patients necessitated a reduction in initial dosages or treatment postponement due to intolerable adverse events. Then, all of them underwent surgical operation. Impressively, nine patients (69.2%) achieved a pathologic complete response. The objective response rate (ORR) stood at 46.15%. Nine patients experienced neoadjuvant treatment-related adverse events (TRAEs), with only one patient (7.6%) encountering a grade 4 neoadjuvant TRAE. CONCLUSION Therefore, the current study suggested that neoadjuvant sintilimab plus platinum-based chemotherapy can be a safe approach in increasing the efficiency of treatment and hopefully improving the prognosis of patients with potentially resectable locally advanced NSCLC.
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Affiliation(s)
- Cunli Yin
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610000, China
| | - Bin Hu
- Department Thoracic Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610000, China
| | - Xi Yang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, China
| | - Lingna Kou
- Department of Medical Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610000, China
| | - Bo Tian
- Department Thoracic Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610000, China
| | - Chenghao Wang
- Department Thoracic Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610000, China
| | - Siru Li
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610000, China
| | - Bin Liu
- Department of Medical Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610000, China
| | - Jun Ge
- Department of Medical Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610000, China.
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Liu L, Deng X, Guo S, Yang S. Successful neoadjuvant chemotherapy plus sintilimab for locally advanced cervical cancer: case series and review of the literature. Diagn Pathol 2023; 18:107. [PMID: 37752528 PMCID: PMC10521576 DOI: 10.1186/s13000-023-01394-w] [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: 07/19/2023] [Accepted: 09/17/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND The locally advanced cervical cancer (LACC) of FIGO stage IB3-IIA2 is characterized by large local mass, poor prognosis and survival rate. Tumor response to neoadjuvant chemotherapy for LACC, utilized as a surrogate endpoint, is urgently needed to improve. Given that the antitumor immune response can be suppressed by programed death-1 axis, the treatment paradigm of neoadjuvant chemotherapy combined with immunotherapy has been explored as one of the prognostic treatments in a variety of solid carcinoma. So far, the application of sintilimab, a domestic immune checkpoint inhibitor, combined with neoadjuvant chemotherapy is still limited in LACC, especially in large lesions. CASE DESCRIPTION We present three postmenopausal women diagnosed with FIGO stage IB3-IIA2 cervical squamous cell carcinoma with lesions larger than 5 cm. Demographic, clinical, histopathological, laboratory and imaging data were record. At the completion of the neoadjuvant therapy with paclitaxel plus carboplatin combined with sintilimab, all patients underwent hysterectomy. After neoadjuvant treatment, a pathologic complete response in case 1 and partial responses in case 2 and case 3 were achieved, and neither patient showed any relapse during the follow-up period of 16 to 22 months. CONCLUSIONS This report provide evidence to support the combination of sintilimab with neoadjuvant chemotherapy in cervical cancer, which has yet to be validated in prospective studies. More clinical data are needed to verify the effectiveness of the combined regimens. This literature review also collected studies involving potential predictors of response to NACT and immunotherapy, which would be helpful in stratifying patients for future trials.
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Affiliation(s)
- Linlin Liu
- Department of Gynecology and Obstetrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, People's Republic of China
| | - Xianbo Deng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, People's Republic of China
| | - Shuang Guo
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, People's Republic of China
| | - Shouhua Yang
- Department of Gynecology and Obstetrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, People's Republic of China.
- Department of Gynecology, South China Hospital, Medical School, Shenzhen University, Shenzhen, 518116, People's Republic of China.
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Wang F, Xia T, Li Z, Gao X, Fang X. Current status of clinical trial research and application of immune checkpoint inhibitors for non-small cell lung cancer. Front Oncol 2023; 13:1213297. [PMID: 37727216 PMCID: PMC10505960 DOI: 10.3389/fonc.2023.1213297] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 08/17/2023] [Indexed: 09/21/2023] Open
Abstract
Immunotherapy has emerged as a hot topic in the treatment of non-small cell lung cancer (NSCLC) with remarkable success. Compared to chemotherapy patients, the 5-year survival rate for immunotherapy patients is 3-fold higher, approximately 4%-5% versus 15%-16%, respectively. Immunotherapies include chimeric antigen receptor T-cell (CAR-T) therapy, tumor vaccines, immune checkpoint inhibitors, and so forth. Among them, immune checkpoint inhibitors are in the spotlight. Common immune checkpoint inhibitors (ICIs) currently in clinical use include programmed death receptor-1(PD-1)/programmed death ligand-1(PD-L1) and cytotoxic T lymphocyte-associated antigen 4(CTLA-4). This article focuses on monotherapy and combination therapy of CTLA-4 and PD-1/PD-L1 immune checkpoint inhibitors. In particular, the combination therapy of ICIs includes the combination of ICIs and chemotherapy, the combination therapy of dual ICIs, the combination of ICIs and anti-angiogenic drugs, the combination of ICIs and radiotherapy, and the combination of ICIs inhibitors and tumor vaccines and so forth. This article focuses on the combination therapy of ICIs with chemotherapy, the combination therapy of dual ICIs, and the combination therapy of ICIs with anti-angiogenic drugs. The efficacy and safety of ICIs as single agents in NSCLC have been demonstrated in many trials. However, ICIs plus chemotherapy regimens offer significant advantages in the treatment of NSCLC with little to no dramatic increase in toxicity, while combined dual ICIs significantly reduce the adverse effects (AEs) of chemotherapy. ICIs plus anti-angiogenic agents regimen improves anti-tumor activity and safety and is expected to be the new paradigm for the treatment of advanced NSCLC. Despite some limitations, these agents have achieved better overall survival rates. In this article, we review the current status and progress of research on ICIs in NSCLC in recent years, aiming to better guide the individualized treatment of NSCLC patients.
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Affiliation(s)
- Fuli Wang
- Department of Oncology, Lianyungang Clinical College Affiliated to Bengbu Medical College, Lianyungang, China
- Department of Oncology, Gaochun Hospital Afliated to Jiangsu University, Nanjing, China
| | - Teng Xia
- Department of Oncology, Gaochun Hospital Afliated to Jiangsu University, Nanjing, China
| | - Zhiqiang Li
- Department of Oncology, Lianyungang Clinical College Affiliated to Bengbu Medical College, Lianyungang, China
| | - Xuzhu Gao
- Department of Oncology, Lianyungang Clinical College Affiliated to Bengbu Medical College, Lianyungang, China
- Department of Oncology, Gaochun Hospital Afliated to Jiangsu University, Nanjing, China
| | - Xinjian Fang
- Department of Oncology, Lianyungang Clinical College Affiliated to Bengbu Medical College, Lianyungang, China
- Department of Oncology, Gaochun Hospital Afliated to Jiangsu University, Nanjing, China
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Zeng X, Jia Y, Chen H, Luo Q, Zhao H, Liang G, Chen W, Li Y. A real-world analysis of survival and cost-effectiveness of sintilimab plus bevacizumab biosimilar regimen in patients with advanced hepatocellular carcinoma. J Cancer Res Clin Oncol 2023; 149:9213-9219. [PMID: 37188985 PMCID: PMC10185451 DOI: 10.1007/s00432-023-04775-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 04/10/2023] [Indexed: 05/17/2023]
Abstract
PURPOSE Programmed death-1 (PD-1) inhibitor sintilimab plus bevacizumab has been approved as the first-line treatment for patients with advanced hepatocellular carcinoma (aHCC). However, the clinical benefits of sintilimab plus bevacizumab in a real-world setting in China is insufficiently defined to date. This study aims to evaluate the efficacy and cost-effectiveness of sintilimab plus bevacizumab biosimilar in a real-word cohort of patients with aHCC from China. METHODS We reviewed the clinical data of 112 consecutive patients with aHCC who received sintilimab plus bevacizumab as a first-line treatment in Chongqing University Cancer hospital between July, 2021 and December, 2022. Overall survival, progression-free survival, overall response rate, and adverse event rates were assessed based on the RECIST 1.1. The survival curves were grafted by Kaplan-Meier method. RESULTS Sixty-eight patients with aHCC were included our study. Efficacy evaluation results showed that 8 patients were partial remission, 51 patients were stable and 9 patients showed progression disease. Median overall survival and progression-free survival were 344.00 (168.77-419.23) days and 238.00 (174.56-301.44) days, respectively. Adverse events occurred in 35 patients (51.5%), including 9 patients with grade ≥ 3. The life-year (LY) and quality-adjusted LY (QALY) were 1.97 and 2.92, respectively, with a cost of $35,018. CONCLUSION Our data confirmed the promising efficacy, tolerable toxicity and cost-effectiveness in Chinese patients with aHCC who received sintilimab plus bevacizumab as the first-line therapy regimen in real-world practice.
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Affiliation(s)
- Xianghua Zeng
- Department of Medical Oncology, Chongqing University Cancer Hospital and Chongqing Cancer Institute, Chongqing, 400030, China
| | - Yingxin Jia
- Department of Medical Oncology, Deyang Hospital of Traditional Chinese Medicine, Deyang, 618000, China
| | - Hongmei Chen
- Department of Medical Oncology, Chongqing Ba'nan Hospital of Traditional Chinese Medicine, Chongqing, 400055, China
| | - Qinli Luo
- Health Examination and Oncology Screening Center, Chongqing University Cancer Hospital and Chongqing Cancer Institute, Chongqing, 400030, China
| | - Huakan Zhao
- Department of Medical Oncology, Chongqing University Cancer Hospital and Chongqing Cancer Institute, Chongqing, 400030, China
| | - Guanzhong Liang
- Department of Medical Oncology, Chongqing University Cancer Hospital and Chongqing Cancer Institute, Chongqing, 400030, China
| | - Wen Chen
- Department of Medical Oncology, Chongqing University Cancer Hospital and Chongqing Cancer Institute, Chongqing, 400030, China.
| | - Yongsheng Li
- Department of Medical Oncology, Chongqing University Cancer Hospital and Chongqing Cancer Institute, Chongqing, 400030, China.
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Wei J, Lu X, Liu Q, Fu Y, Liu S, Zhao Y, Zhou J, Chen H, Wang M, Li L, Yang J, Liu F, Zheng L, Yin H, Yang Y, Zhou C, Zeng P, Zhou X, Ding N, Chen S, Zhao X, Yan J, Fan X, Guan W, Liu B. Neoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial. Nat Commun 2023; 14:4904. [PMID: 37580320 PMCID: PMC10425436 DOI: 10.1038/s41467-023-40480-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 07/31/2023] [Indexed: 08/16/2023] Open
Abstract
In this multicenter, single-arm phase 2 trial (ChiCTR1900024428), patients with locally advanced gastric/gastroesophageal junction cancers receive one cycle of sintilimab (anti-PD1) and chemotherapy (S-1 and nab-paclitaxel), followed by 5 weeks of concurrent chemoradiotherapy and sintilimab, and another cycle of sintilimab and chemotherapy thereafter. Surgery is preferably scheduled within one to three weeks, and three cycles of adjuvant sintilimab and chemotherapy are administrated. The primary endpoint is the pathological complete response. Our results meet the pre-specified primary endpoint. Thirteen of 34 (38.2%) enrolled patients achieve pathological complete response (95% CI: 22.2-56.4). The secondary objectives include disease-free survival (DFS), major pathological response, R0 resection rate, overall survival (OS), event-free survival (EFS), and safety profile. The median DFS and EFS were 17.0 (95%CI: 11.1-20.9) and 21.1 (95%CI: 14.7-26.1) months, respectively, while the median OS was not reached, and the 1-year OS rate was 92.6% (95%CI: 50.1-99.5%). Seventeen patients (50.0%) have grade ≥3 adverse events during preoperative therapy. In prespecified exploratory biomarker analysis, CD3+ T cells, CD56+ NK cells, and the M1/M1 + M2-like macrophage infiltration at baseline are associated with pathological complete response. Here, we show the promising efficacy and manageable safety profile of sintilimab in combination with concurrent chemoradiotherapy for the perioperative treatment of locally advanced gastric/gastroesophageal junction adenocarcinoma.
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Affiliation(s)
- Jia Wei
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China
| | - Xiaofeng Lu
- Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Qin Liu
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China
| | - Yao Fu
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Song Liu
- Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Yang Zhao
- Department of Biostatistics, Nanjing Medical University, Nanjing, 210029, China
| | - Jiawei Zhou
- Department of Biostatistics, Nanjing Medical University, Nanjing, 210029, China
| | - Hui Chen
- Medical Affairs, 3D Medicines Inc, Shanghai, 201114, China
| | - Meng Wang
- Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Lin Li
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Ju Yang
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China
| | - Fangcen Liu
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Liming Zheng
- Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Haitao Yin
- Department of Radiotherapy, Xuzhou Central Hospital, Xuzhou, 221009, China
| | - Yang Yang
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China
| | - Chong Zhou
- Department of Radiotherapy, Xuzhou Central Hospital, Xuzhou, 221009, China
| | - Ping Zeng
- Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Xiaoyu Zhou
- Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Naiqing Ding
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China
| | - Shiqing Chen
- Medical Affairs, 3D Medicines Inc, Shanghai, 201114, China
| | - Xiaochen Zhao
- Medical Affairs, 3D Medicines Inc, Shanghai, 201114, China
| | - Jing Yan
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
- Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China
| | - Xiangshan Fan
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Wenxian Guan
- Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
| | - Baorui Liu
- The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
- Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China.
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Zhou N, Li X, Yang Y, Tan S, Zhang S, Huang Q, Gou H. Sintilimab plus nab-paclitaxel as second-line treatment for advanced biliary tract cancer: study protocol for an investigator-initiated phase 2 trial (NapaSinti trial). BMC Cancer 2023; 23:729. [PMID: 37550655 PMCID: PMC10405505 DOI: 10.1186/s12885-023-11188-4] [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: 02/23/2023] [Accepted: 07/18/2023] [Indexed: 08/09/2023] Open
Abstract
BACKGROUND Biliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. However, there is currently no satisfactory second-line regimen for patients without specific genetic mutations. Nanoparticle albumin-bound paclitaxel, also known as nab-paclitaxel (Abraxane, Bristol Myers Squibb), has shown activity in patients with BTC. Studies investigating the immunogenic features of BTC suggested that checkpoint inhibition may lead to antitumor immune responses. In recent years, improved survival has been observed in patients treated with chemotherapy combined with immunotherapy across multiple cancer types, including BTC. This clinical trial aims to evaluate the efficacy and safety of second-line sintilimab in combination with nab-paclitaxel in advanced BTC patients. METHODS The NapaSinti trial is a prospective, nonrandomized, open-label, phase 2 study conducted at a tertiary hospital in Chengdu, China. Eligible patients are those with histologically or cytologically confirmed locally advanced non-resectable or metastatic adenocarcinoma in the biliary tract (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), aged between 18 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who have experienced disease progression after prior gemcitabine- or fluorouracil-based chemotherapy and have not received taxane or immune checkpoint inhibitor treatment. Enrolled patients will receive intravenous administration of sintilimab 200 mg on day 1 and nab-paclitaxel 125 mg/m2 on days 1 and 8, every three weeks. The primary endpoint is the objective response rate (ORR), while the secondary endpoints include overall survival (OS), progression-free survival (PFS), and safety. Exploratory objectives aim to identify biomarkers and molecular signatures for predicting response or prognosis. Using Simon's two-stage design, a total of 63 participants will be enrolled in the study. This trial was initiated in March 2022 in China. DISCUSSION The NapaSinti trial evaluates the efficacy and safety of second-line sintilimab plus nab-paclitaxel for advanced biliary tract cancer. Additionally, the trial provides an opportunity for translational research. TRIAL REGISTRATION Chinese Clinical Trial Registry ChiCTR2100052118. Registered October 19, 2021.
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Affiliation(s)
- Nan Zhou
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No.37 Guo Xue Xiang, 610041, Chengdu, Sichuan, China
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaofen Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No.37 Guo Xue Xiang, 610041, Chengdu, Sichuan, China
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yu Yang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No.37 Guo Xue Xiang, 610041, Chengdu, Sichuan, China
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Sirui Tan
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No.37 Guo Xue Xiang, 610041, Chengdu, Sichuan, China
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Shunyu Zhang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No.37 Guo Xue Xiang, 610041, Chengdu, Sichuan, China
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qiyue Huang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No.37 Guo Xue Xiang, 610041, Chengdu, Sichuan, China
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hongfeng Gou
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No.37 Guo Xue Xiang, 610041, Chengdu, Sichuan, China.
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
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Li H, Mu F, Zou B, Wang L. Pulmonary sarcoidosis-like reactions induced by sintilimab in esophageal cancer: A case report. Medicine (Baltimore) 2023; 102:e34432. [PMID: 37543824 PMCID: PMC10403023 DOI: 10.1097/md.0000000000034432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/07/2023] Open
Abstract
RATIONALE Esophageal cancer is one of the deadliest cancers in the world, with high incidence and mortality rates ranking among the top ten in China. The efficacy of conventional treatments is limited and often accompanied by severe adverse reactions, which results in unsatisfactory outcomes. The mechanism of immune checkpoint inhibitors (ICIs) is to activate cytotoxic T cells to kill tumor cells expressing tumor antigens. The application of ICIs has profoundly changed the mode of cancer treatment. However, the use of ICIs also induces a series of adverse reactions similar to autoimmune reactions, called immune-related adverse events (irAEs). Some ICIs can cause manifestations similar to those in the development of sarcoidosis, which are called sarcoidosis-like reactions or granulomatosis. PATIENT CONCERNS We report a 50-year-old Chinese male patient. DIAGNOSES The patient had been diagnosed with advanced esophageal squamous cell carcinoma , and was confirmed to have pulmonary sarcoidosis-like reactions associated with sintilimab, a human programmed cell death protein 1 (PD-1) inhibitor. INTERVENTIONS The patient was administered corticosteroid treatment. OUTCOMES After receiving steroid treatment, the patient's systemic and pulmonary symptoms improved rapidly. To our knowledge, this is the first report of pulmonary sarcoidosis-like reaction in a patient with esophageal squamous cell carcinoma. The patient then continued to receive 1 year of follow-up antitumor treatment after the appearance of lung pulmonary sarcoidosis-like reactions. The prognosis was good and the patient's condition is currently stable. LESSONS The diagnosis of ICI-induced sarcoidosis often requires comprehensive evaluation through clinical, pathological, and radiological assessment. A subset of patients with sarcoidosis-like reactions may not require treatment unless there is organ dysfunction or severe clinical symptoms, and these reactions generally respond well to treatment. The occurrence of sarcoidosis-like reactions after immunotherapy is positively correlated with the long-term prognosis of cancer patients. However, this hypothesis requires larger prospective studies for validation.
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Affiliation(s)
- Haoqian Li
- Department of Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China
| | - Fengchun Mu
- Department of Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China
| | - Bing Zou
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China
| | - Linlin Wang
- Department of Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China
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Sun HB, Xing WQ, Liu XB, Yang SJ, Chen PN, Liu SL, Li P, Ma YX, Jiang D, Yan S. A multicenter randomized, controlled clinical trial of adjuvant sintilimab for esophageal squamous cell carcinoma. Future Oncol 2023; 19:1777-1784. [PMID: 37737025 DOI: 10.2217/fon-2022-1255] [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: 09/23/2023] Open
Abstract
No adjuvant treatment has been established for patients who remain at high risk of recurrence and incidental pathologic lymph node metastasis for esophageal squamous cell carcinoma (ESCC). In this open-label, multicenter, phase III, randomized controlled trial, ESCC patients who did not achieve pathologic complete response after neoadjuvant chemotherapy plus surgery and clinical T1-2 N0 patients with incidental pathologic lymph node metastasis following initial surgery were randomized at a 2:1 ratio to receive either a sintilimab regimen or observational management (NCT05495152). The primary end point was disease-free survival for all randomized patients. The results of this randomized controlled trial addressed controversy regarding the survival benefits of adjuvant sintilimab treatment for patients with resected locally advanced ESCC. Clinical Trial Registration: NCT05495152 (ClinicalTrials.gov).
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Affiliation(s)
- Hai-Bo Sun
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Wen-Qun Xing
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Xian-Ben Liu
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Shu-Jun Yang
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Pei-Nan Chen
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Shi-Lei Liu
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Peng Li
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Ya-Xing Ma
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Duo Jiang
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Sen Yan
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
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Fang X, Zhong C, Weng S, Hu H, Wang J, Xiao Q, Wang J, Sun L, Xu D, Liao X, Dong C, Zhang S, Li J, Ding K, Yuan Y. Sintilimab plus bevacizumab and CapeOx (BBCAPX) on first-line treatment in patients with RAS mutant, microsatellite stable, metastatic colorectal cancer: study protocol of a randomized, open-label, multicentric study. BMC Cancer 2023; 23:676. [PMID: 37464378 DOI: 10.1186/s12885-023-11139-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 06/30/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND Rat sarcoma viral oncogene homolog (RAS) gene mutation is a common molecular event in colorectal cancer (CRC). The prognosis of mCRC (metastatic colorectal cancer) patients with RAS mutation is poor and capecitabine and oxaliplatin (CapeOx) plus bevacizumab has shown to be one of the standard therapeutic regimens as first line for these patients with objective response rate (ORR) of ~ 50% and median progression-free survival (mPFS) of 8-9 months. Immunotherapy, especially anti-programmed death 1 (PD-1) monoclonal antibody has demonstrated ground-breaking results in deficient mismatch repair (dMMR) / microsatellite instability-high (MSI-H) mCRC patients. However, the response rate of in microsatellite stable (MSS) patients is extremely low. In addition, preclinical studies have demonstrated that anti-Vascular endothelial growth factor (VEGF) agents, such as bevacizumab, can induce tumor vascular normalization and enhance antitumor immunity. Previous study indicated the combination of chemotherapy, anti-VEGF agents (bevacizumab) with immune checkpoint inhibitors may have promising clinical activity in RAS mutant, MSS refractory mCRC patients. Based on these evidences, we will explore the combination of CapeOx with bevacizumab and sintilimab (anti-PD-1 monoclonal antibody) in RAS mutant, MSS mCRC patients as first-line therapy. METHODS This is a randomized, open-label, multicentric clinical trial. In the sintilimab arm, patients will receive sintilimab in combination with CapeOx and bevacizumab. In the control arm, patients will receive CapeOx and bevacizumab. This trial will recruit 494 patients from 20 centers and randomly (1:1) disseminated into two groups. The primary endpoint is the PFS. The secondary endpoints include overall survival, safety, ORR, and disease control rate. DISCUSSION This study may provide new ideas for optimizing oncology treatment planning for RAS mutant, MSS mCRC patients in the first-line set. TRIAL REGISTRATION This study is short for BBCAPX and has been registered at clinicaltrials.gov registry with identifier NCT05171660.
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Affiliation(s)
- Xuefeng Fang
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Chenhan Zhong
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Shanshan Weng
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Hanguang Hu
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Jian Wang
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Qian Xiao
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Jianwei Wang
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Lifeng Sun
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Dong Xu
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Xiujun Liao
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Caixia Dong
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Suzhan Zhang
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Jun Li
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
| | - Kefeng Ding
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
- Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
| | - Ying Yuan
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
- Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
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Charles J, Vrionis A, Mansur A, Mathias T, Shaikh J, Ciner A, Jiang Y, Nezami N. Potential Immunotherapy Targets for Liver-Directed Therapies, and the Current Scope of Immunotherapeutics for Liver-Related Malignancies. Cancers (Basel) 2023; 15:2624. [PMID: 37174089 PMCID: PMC10177356 DOI: 10.3390/cancers15092624] [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: 04/12/2023] [Revised: 05/01/2023] [Accepted: 05/03/2023] [Indexed: 05/15/2023] Open
Abstract
Liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, is increasing in incidence and mortality across the globe. An improved understanding of the complex tumor microenvironment has opened many therapeutic doors and led to the development of novel pharmaceuticals targeting cellular signaling pathways or immune checkpoints. These interventions have significantly improved tumor control rates and patient outcomes, both in clinical trials and in real-world practice. Interventional radiologists play an important role in the multidisciplinary team given their expertise in minimally invasive locoregional therapy, as the bulk of these tumors are usually in the liver. The aim of this review is to highlight the immunological therapeutic targets for primary liver cancers, the available immune-based approaches, and the contributions that interventional radiology can provide in the care of these patients.
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Affiliation(s)
- Jonathan Charles
- Morsani College of Medicine, University of South Florida, 560 Channelside Drive, Tampa, FL 33602, USA; (J.C.); (A.V.); (J.S.)
| | - Andrea Vrionis
- Morsani College of Medicine, University of South Florida, 560 Channelside Drive, Tampa, FL 33602, USA; (J.C.); (A.V.); (J.S.)
| | - Arian Mansur
- Harvard Medical School, Harvard University, Boston, MA 02115, USA;
| | - Trevor Mathias
- School of Medicine, University of Maryland, Baltimore, MD 21201, USA;
| | - Jamil Shaikh
- Morsani College of Medicine, University of South Florida, 560 Channelside Drive, Tampa, FL 33602, USA; (J.C.); (A.V.); (J.S.)
- Department of Radiology, Tampa General Hospital, University of South Florida Health, Tampa General Cir, Tampa, FL 33606, USA
| | - Aaron Ciner
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (A.C.); (Y.J.)
| | - Yixing Jiang
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (A.C.); (Y.J.)
| | - Nariman Nezami
- Division of Vascular and Interventional Radiology, Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Experimental Therapeutics Program, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
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Hu Y, Liu C, Jin S, Yi Z, Wang C, Pan X, Huang H. A case of subclinical immune checkpoint inhibitor-associated myocarditis in non-small cell lung cancer. BMC Pulm Med 2023; 23:119. [PMID: 37060029 PMCID: PMC10103507 DOI: 10.1186/s12890-023-02417-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 04/04/2023] [Indexed: 04/16/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have been widely used in the treatment of cancer. Moreover, immune-related adverse events (irAEs) have become a new clinical challenge. ICI-associated myocarditis is a rare but fatal condition among diverse organ injuries, and early recognition and effective interventions are critical for patients. CASE PRESENTATION In this report, we present the case of a healthy 60-year-old male who was diagnosed with lung squamous cell carcinomas following chemotherapy and received ICIs. The patient presented with asymptomatic cardiac biomarker elevation followed by immune-related myocarditis. Fortunately, the patient achieved a good clinical result after receiving high-dose steroids. The treatment with ICIs was discontinued because of recurrent increases in troponin T. CONCLUSION ICI-mediated associated myocarditis is an uncommon but potentially life-threatening adverse event. The current data suggest that clinicians need to be cautious about reinitiation in low-grade patients; however, further study of the diagnosis and treatment is necessary.
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Affiliation(s)
- Yue Hu
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
- Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
| | - Cuixia Liu
- Department of Respiratory and Critical Care Medicine, Songyang people's Hospital of Zhejiang, Lishui, 323499, Zhejiang, China
| | - Shaojun Jin
- Department of emergency, Zhuji people's Hospital of Zhejiang, Zhuji, 311800, Zhejiang, China
| | - Zihan Yi
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Chao Wang
- Department of Radiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Xiaohong Pan
- Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Huaqiong Huang
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
- Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
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Ke H, Zhang F, Wang J, Xiong L, An X, Tu X, Chen C, Wang Y, Mao B, Guo S, Ju C, He X, Sun R, Zhang L, O'Connor OA, Li QX. HX009, a novel BsAb dual targeting PD1 x CD47, demonstrates potent anti-lymphoma activity in preclinical models. Sci Rep 2023; 13:5419. [PMID: 37012357 PMCID: PMC10070465 DOI: 10.1038/s41598-023-32547-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
Both PD1/PD-L1 and CD47 blockades have demonstrated limited activity in most subtypes of NHL save NK/T-cell lymphoma. The hemotoxicity with anti-CD47 agents in the clinic has been speculated to account for their limitations. Herein we describe a first-in-class and rationally designed bispecific antibody (BsAb), HX009, targeting PD1 and CD47 but with weakened CD47 binding, which selectively hones the BsAb for tumor microenvironment through PD1 interaction, potentially reducing toxicity. In vitro characterization confirmed: (1) Both receptor binding/ligand blockade, with lowered CD47 affinity; (2) functional PD1/CD47 blockades by reporter assays; (3) T-cell activation in Staphylococcal-enterotoxin-B-pretreated PBMC and mixed-lymphocyte-reaction. In vivo modeling demonstrated antitumor activity in Raji-B and Karpass-229-T xenograft lymphomas. In the humanized mouse syngeneic A20 B-lymphoma (huCD47-A20) HuGEMM model, which has quadruple knocked-in hPD1xhPD-L1xhCD47xhSIRPα genes and an intact autologous immune-system, a contribution of effect is demonstrated for each targeted biologic (HX008 targeting PD1 and SIRPα-Fc targeting CD47), which is clearly augmented by the dual targeting with HX009. Lastly, the expression of the immune-checkpoints PD-L1/L2 and CD47 seemed co-regulated among a panel of lymphoma-derived-xenografts, where HX009 maybe more effective in those with upregulated CD47. Our data warrants HX009's further clinical development for treating NHLs.
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Affiliation(s)
- Hang Ke
- Hanx Pharmaceuticals, Inc., Hangzhou, China
| | | | | | | | - Xiaoyu An
- Crown Bioscience, Inc., San Diego, USA
| | | | - Cen Chen
- Hanx Pharmaceuticals, Inc., Hangzhou, China
| | | | | | - Sheng Guo
- Crown Bioscience, Inc., San Diego, USA
| | | | - Xiangfei He
- Shanghai Model Organisms Center, Inc. (SMOC), Shanghai, China
| | - Ruilin Sun
- Shanghai Model Organisms Center, Inc. (SMOC), Shanghai, China
| | - Lei Zhang
- Hanx Pharmaceuticals, Inc., Hangzhou, China
| | - Owen A O'Connor
- Division of Hematology and Oncology, University of Virginia Cancer Center, University of Virginia, Charlottesville, USA
| | - Qi-Xiang Li
- Hanx Pharmaceuticals, Inc., Hangzhou, China.
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Zhang L, Wang W, Ge S, Li H, Bai M, Duan J, Yang Y, Ning T, Liu R, Wang X, Ji Z, Wang F, Zhang H, Ba Y, Deng T. Sintilimab Plus Apatinib and Chemotherapy as Second‑/Third-Line treatment for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: a prospective, Single-Arm, phase II trial. BMC Cancer 2023; 23:211. [PMID: 36872337 PMCID: PMC9985926 DOI: 10.1186/s12885-023-10661-4] [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: 09/10/2022] [Accepted: 02/20/2023] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND The prognosis of patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer remains poor. Given the robust development of immunotherapy and targeted therapy during the last decades, we aimed to investigate if the combination of traditional second-line chemotherapy with sintilimab and apatinib could bring survival benefits for these patients. METHODS In this single-center, single-arm, phase II trial, patients with previously treated advanced gastric or GEJ adenocarcinoma received specific dose level of intravenous paclitaxel or irinotecan (investigator's choice), 200 mg intravenous sintilimab on day 1, and 250 mg oral apatinib once daily continuously in each cycle until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoints were objective response rate and progression-free survival. The secondary endpoints were mainly overall survival and safety. RESULTS From May 2019 to May 2021, 30 patients were enrolled. At the data cutoff date (March 19, 2022), the median follow-up duration was 12.3 months and 53.6% (95% CI, 33.9-72.5%) patients achieved objective response. The median progression-free survival and overall survival were 8.5 months (95% CI, 5.4-11.5) and 12.5 months (95% CI, 3.7-21.3), respectively. Grade 3-4 adverse events included hematological toxicities, elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated alkaline phosphatase, elevated gamma-glutamyl transpeptidase, hyperbilirubinemia and proteinuria. The most frequent grade 3-4 adverse event was neutropenia (13.3%). No serious treatment-related adverse events or treatment-related deaths occurred. CONCLUSION Sintilimab plus apatinib and chemotherapy demonstrates promising anti-tumor activity with manageable safety profile in patients with previously treated advanced gastric or GEJ cancer. TRIAL REGISTRATION ClinicalTrials.gov: NCT05025033, 27/08/2021.
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Affiliation(s)
- Le Zhang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Weixue Wang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Shaohua Ge
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Hongli Li
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Ming Bai
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Jingjing Duan
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Yuchong Yang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Tao Ning
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Rui Liu
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Xia Wang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Zhi Ji
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Feixue Wang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Haiyang Zhang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Yi Ba
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China.
| | - Ting Deng
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China.
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47
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Chuprin J, Buettner H, Seedhom MO, Greiner DL, Keck JG, Ishikawa F, Shultz LD, Brehm MA. Humanized mouse models for immuno-oncology research. Nat Rev Clin Oncol 2023; 20:192-206. [PMID: 36635480 PMCID: PMC10593256 DOI: 10.1038/s41571-022-00721-2] [Citation(s) in RCA: 130] [Impact Index Per Article: 65.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/12/2022] [Indexed: 01/14/2023]
Abstract
Immunotherapy has emerged as a promising treatment paradigm for many malignancies and is transforming the drug development landscape. Although immunotherapeutic agents have demonstrated clinical efficacy, they are associated with variable clinical responses, and substantial gaps remain in our understanding of their mechanisms of action and specific biomarkers of response. Currently, the number of preclinical models that faithfully recapitulate interactions between the human immune system and tumours and enable evaluation of human-specific immunotherapies in vivo is limited. Humanized mice, a term that refers to immunodeficient mice co-engrafted with human tumours and immune components, provide several advantages for immuno-oncology research. In this Review, we discuss the benefits and challenges of the currently available humanized mice, including specific interactions between engrafted human tumours and immune components, the development and survival of human innate immune populations in these mice, and approaches to study mice engrafted with matched patient tumours and immune cells. We highlight the latest advances in the generation of humanized mouse models, with the aim of providing a guide for their application to immuno-oncology studies with potential for clinical translation.
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Affiliation(s)
- Jane Chuprin
- Program in Molecular Medicine, The University of Massachusetts Chan Medical School, Worcester, MA, USA
- Department of Molecular, Cell and Cancer Biology, The University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Hannah Buettner
- Program in Molecular Medicine, The University of Massachusetts Chan Medical School, Worcester, MA, USA
- Department of Surgery, The University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Mina O Seedhom
- Program in Molecular Medicine, The University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Dale L Greiner
- Program in Molecular Medicine, The University of Massachusetts Chan Medical School, Worcester, MA, USA
| | | | | | | | - Michael A Brehm
- Program in Molecular Medicine, The University of Massachusetts Chan Medical School, Worcester, MA, USA.
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48
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Yao G, Huang J, Zhang Q, Hu D, Yuan F, Han G. Excellent response of refractory triple-negative breast cancer to sintilimab plus chemotherapy: a case report. Immunotherapy 2023; 15:221-228. [PMID: 36789554 DOI: 10.2217/imt-2022-0104] [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: 02/16/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high propensity for invasion and a high incidence of lymph node metastasis. Systemic chemotherapy is considered the primary treatment for patients with TNBC; however, immune checkpoint inhibitors in addition to chemotherapy have been associated with better outcomes. Sintilimab, an anti-PD-1 antibody, was developed in China. Herein, the authors report a 49-year-old woman diagnosed with TNBC with extensive lung and sternal metastases. Treatment with sintilimab plus paclitaxel and carboplatin was found highly effective after failure of first-line chemotherapy. This combinational therapy can be considered for the treatment of TNBC after necessary investigations and clinical trials.
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Affiliation(s)
- Guojun Yao
- Radiotherapy Center of Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Junping Huang
- Oncology department of HuBei Jianghan Oilfield General Hospital, China
| | - Qu Zhang
- Radiotherapy Center of Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Desheng Hu
- Radiotherapy Center of Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Feng Yuan
- Breast Cancer Center of Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Guang Han
- Radiotherapy Center of Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
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49
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Zhou Y, Shen H, Wu M, Wang J, Wu Z, Fu F, Liu Y, Lu J, Yao Y, Luo N, Zhou S, Tan KS, Chen B, Wang D. Pharmacology, pharmacokinetics, and toxicity characterization of a novel anti-CD73 therapeutic antibody IBI325 for cancer immunotherapy. Int J Biol Macromol 2023; 229:158-167. [PMID: 36587633 DOI: 10.1016/j.ijbiomac.2022.12.258] [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: 09/04/2022] [Revised: 10/12/2022] [Accepted: 12/22/2022] [Indexed: 12/31/2022]
Abstract
It is an intriguing approach to target the ecto-5'-nucleotidase CD73 to confer synergetic beneficial survival in cancer patients, along with clinically established immunotherapy targets. In this study, a fully human, subnanomolar affinity CD73 antibody IBI325 was developed using the yeast display platform. Compared with Oleclumab, IBI325 was equivalent in hCD73 affinity and more potent in cell-bound and soluble CD73 enzymatic inhibition, and no hook effects were observed. Correspondingly, adenosine monophosphate-mediated immune suppression was reversed by IBI325, and significant T cell proliferation and release of cytokines were observed. Also, IBI325 enhanced the T cell recall response by inducing interferon-γ secretion. The antitumor efficacy of IBI325 was investigated in a hPBMC-reconstituted NOG mouse model, and a hCD73 knock-in mouse model. Consequently, IBI325 induced a significant tumor regression by inducing intratumoral immune cell expansion, and a combo therapy of IBI325 and aPD-1 was superior in efficacy than aCD73 or aPD-1 monotherapy. Additionally, the binding epitopes of CD73 to IBI325 were distinct from previously reported aCD73 therapeutics. IBI325 displayed acceptable pharmacokinetics and sufficient tolerable safety profiles to support clinical development. In conclusion, the pharmacology, pharmacokinetics, and toxicity profiles of IBI325 with complete CD73 inhibition were characterized, and encouraging preclinical outcomes were reported.
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Affiliation(s)
- Ying Zhou
- College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu, China; Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, China
| | - Haoran Shen
- College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu, China; Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, China
| | - Min Wu
- College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu, China; Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, China
| | - Jie Wang
- Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, China
| | - Zhihai Wu
- Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, China
| | - Fenggen Fu
- Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, China
| | - Yang Liu
- Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, China
| | - Jia Lu
- Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, China
| | - Ying Yao
- Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, China
| | - Nana Luo
- Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, China
| | - Shuaixiang Zhou
- Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, China
| | - Keai Sinn Tan
- Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, China
| | - Bingliang Chen
- Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, China.
| | - Dongfang Wang
- Innovent Biologics (Suzhou) Co., Ltd., 168 Dongping Street, Suzhou Industrial Park, Suzhou 215123, Jiangsu Province, China.
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50
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Liu S, Meng Y, Liu L, Lv Y, Wei F, Yu W, Wang L, Zhang X, Ren X, Sun Q. Rational pemetrexed combined with CIK therapy plus anti-PD-1 mAbs administration sequence will effectively promote the efficacy of CIK therapy in non-small cell lung cancer. Cancer Gene Ther 2023; 30:277-287. [PMID: 36352092 DOI: 10.1038/s41417-022-00543-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 09/24/2022] [Accepted: 10/03/2022] [Indexed: 11/10/2022]
Abstract
Cytokine-induced killer (CIK) cells are heterogeneous cells composed mainly of CD3+CD56+ T cells. As an important treatment method of adoptive therapy, it has shown promising efficacy in many clinical trials, especially in combination with multidrug therapy. However, the maximal antitumor efficacy of CIK therapy in the combined administration of multidrug and CIK therapies and which administration scheme can maximize the antitumor efficacy of CIK therapy are still remain unclear. In this study, we observed that pemetrexed administration prior to the injection of CIK cells maximizes the efficacy of CIK therapy. Anti-PD-1 mAbs should be administered prior to CIK cell injection to maximize the efficacy of the therapy. However, administering anti-PD-1 mAbs after CIK cell injection significantly affects the binding rate of anti-PD-1 mAbs to the PD-1 receptor on CIK cells, affecting the efficacy of the antitumor therapy. In conclusion, our study observed that a rational administration sequence of pemetrexed combined with CIK therapy and anti-PD-1 mAbs significantly promotes the efficacy of CIK therapy, providing an experimental basis for the combination therapy mode and regimen of CIK therapy in clinical practice. We hope that this study can provide patients with lung adenocarcinoma with a prolonged survival time.
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Affiliation(s)
- Shaochuan Liu
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yuan Meng
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Liang Liu
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yingge Lv
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Feng Wei
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Wenwen Yu
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Limei Wang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Xiying Zhang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.,Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Xiubao Ren
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China. .,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China. .,Tianjin's Clinical Research Center for Cancer, Tianjin, China. .,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China. .,Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. .,Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
| | - Qian Sun
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China. .,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China. .,Tianjin's Clinical Research Center for Cancer, Tianjin, China. .,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China. .,Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
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