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Tian Y, Wang S, Ren S, Lin X, Song L, Zhang L, Wang Z. Targeting suppressive feedback of adenosine immunometabolic pathway by tumor cell membranes-coated nanocapsules for chemo-photothermal therapy and enhanced immunotherapy. CHEMICAL ENGINEERING JOURNAL 2025; 515:163579. [DOI: 10.1016/j.cej.2025.163579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2025]
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2
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Liu D, Liu L, Zhao X, Zhang X, Chen X, Che X, Wu G. A comprehensive review on targeting diverse immune cells for anticancer therapy: Beyond immune checkpoint inhibitors. Crit Rev Oncol Hematol 2025; 210:104702. [PMID: 40122356 DOI: 10.1016/j.critrevonc.2025.104702] [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: 02/10/2025] [Revised: 03/02/2025] [Accepted: 03/07/2025] [Indexed: 03/25/2025] Open
Abstract
Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, primary resistance and acquired resistance continue to limit their efficacy for many patients. To address resistance and enhance the anti-tumor activity within the tumor immune microenvironment (TIME), numerous therapeutic strategies targeting both innate and adaptive immune cells have emerged. These include combination therapies with ICIs, chimeric antigen receptor T-cell (CAR-T), chimeric antigen receptor macrophages (CAR-Ms) or chimeric antigen receptor natural killer cell (CAR-NK) therapy, colony stimulating factor 1 receptor (CSF1R) inhibitors, dendritic cell (DC) vaccines, toll-like receptor (TLR) agonists, cytokine therapies, and chemokine inhibition. These approaches underscore the significant potential of the TIME in cancer treatment. This article provides a comprehensive and up-to-date review of the mechanisms of action of various innate and adaptive immune cells within the TIME, as well as the therapeutic strategies targeting each immune cell type, aiming to deepen the understanding of their therapeutic potential.
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Affiliation(s)
- Dequan Liu
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Lei Liu
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Xinming Zhao
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Xiaoman Zhang
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Xiaochi Chen
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
| | - Xiangyu Che
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
| | - Guangzhen Wu
- Department of Urology, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
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Srinivasan S, Narayan A, Dhamne C, Chichra A, Khemani P, Dhariwal N, Ranjan R, Shah S, Shet T, Gollamudi VRM, Roy Moulik N, Banavali SD, Narula G. Combination of fixed low-dose nivolumab and bendamustine in children with high-risk relapsed/refractory classical Hodgkin lymphoma. Br J Haematol 2025. [PMID: 40394816 DOI: 10.1111/bjh.20148] [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: 01/28/2025] [Accepted: 05/01/2025] [Indexed: 05/22/2025]
Abstract
A retrospective study of 18 pediatric patients with high-risk relapsed/refractory classical Hodgkin lymphoma demonstrated that a fixed low-dose combination of nivolumab and bendamustine achieved an 88% complete response rate, with 1-year progression-free survival (PFS) of 88.2% and overall survival (OS) of 94.4%.
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Affiliation(s)
- Shyam Srinivasan
- Department of Paediatric Oncology, Tata Memorial Hospital/ACTREC, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Aditya Narayan
- Department of Paediatric Oncology, Tata Memorial Hospital/ACTREC, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Chetan Dhamne
- Department of Paediatric Oncology, Tata Memorial Hospital/ACTREC, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Akanksha Chichra
- Department of Paediatric Oncology, Tata Memorial Hospital/ACTREC, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Poonam Khemani
- Homi Bhabha National Institute, Mumbai, India
- Department of Paediatric Oncology, Homi Bhabha Cancer Hospital (HBCH), Varanasi, India
| | - Nidhi Dhariwal
- Homi Bhabha National Institute, Mumbai, India
- Department of Paediatric Oncology, Homi Bhabha Cancer Hospital and Research Centre (HBCHRC), Mullanpur, India
| | - Raghwesh Ranjan
- Homi Bhabha National Institute, Mumbai, India
- Department of Paediatric Oncology, Homi Bhabha Cancer Hospital (HBCH), Varanasi, India
| | - Sneha Shah
- Homi Bhabha National Institute, Mumbai, India
- Department of Nuclear Medicine, Tata Memorial Hospital/ACTREC, Mumbai, India
| | - Tanuja Shet
- Homi Bhabha National Institute, Mumbai, India
- Department of Pathology, Tata Memorial Hospital/ACTREC, Mumbai, India
| | - Venkata Rama Mohan Gollamudi
- Department of Paediatric Oncology, Tata Memorial Hospital/ACTREC, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Nirmalya Roy Moulik
- Department of Paediatric Oncology, Tata Memorial Hospital/ACTREC, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Shripad D Banavali
- Department of Paediatric Oncology, Tata Memorial Hospital/ACTREC, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Gaurav Narula
- Department of Paediatric Oncology, Tata Memorial Hospital/ACTREC, Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
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4
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Shang Y, Pang Y, Liu T, Wang W. Application of mass cytometry in the immune microenvironment of breast cancer. Med Oncol 2025; 42:215. [PMID: 40388018 DOI: 10.1007/s12032-025-02770-w] [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: 02/08/2025] [Accepted: 04/29/2025] [Indexed: 05/20/2025]
Abstract
The rapid development of immunotherapy has shown preliminary clinical efficacy and significant anti-tumor effects in some cancer patients. Although immunotherapy has been approved for breast cancer, some breast cancer patients still do not benefit from it due to issues such as immunotherapy insensitivity and resistance. Mass cytometry, as a mature single-cell proteomic analysis method, with its high-throughput capabilities, has been widely used in the analysis of tumor immune microenvironments and immune cell subpopulations. Using mass cytometry to analyze the immune microenvironment of breast cancer and explore new immunotherapy targets can help improve the current status of breast cancer immunotherapy and develop personalized treatment plans for more patients. This review surveys the recent advancements in analyzing the single-cell components of breast cancer using mass cytometry technology and reviews the immune microenvironment of breast cancer as well as potential targets for immunotherapy. These results provide new insights for the subsequent research of the immune microenvironment of breast cancer and targeted immunotherapy.
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Affiliation(s)
- Yuefeng Shang
- Department of Radiation Oncology, Tumor Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
- Department of Breast Surgery, Tumor Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Yuheng Pang
- Department of Radiation Oncology, Tumor Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
- Department of Breast Surgery, Tumor Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Tong Liu
- Department of Radiation Oncology, Tumor Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
- Department of Breast Surgery, Tumor Hospital of Harbin Medical University, Harbin, Heilongjiang, People's Republic of China
| | - Wenjing Wang
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, No.8, Xi Tou Tiao, Youanmen Wai, Fengtai District, Beijing, 100069, People's Republic of China.
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5
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Li R, Zhang G, Tao Q, Wu Z, Liu X, Wang R, Liu L, Niu Y, Du K, Wu R, Du F, Zheng X, Li Y, Shi X. Revealing the prognostic potential of natural killer cell-related genes in hepatocellular carcinoma: the key role of NRAS. Discov Oncol 2025; 16:807. [PMID: 40383831 PMCID: PMC12086133 DOI: 10.1007/s12672-025-02200-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 03/21/2025] [Indexed: 05/20/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy associated with high morbidity and mortality rates worldwide. To improve the prognosis of HCC, early diagnosis is crucial. However, to date, little is known about the role of natural killer cell-related genes (NKCRGs) in predicting the prognosis of hepatocellular carcinoma patients. In this study, we identified 24 differentially expressed NKCRGs in HCC specimens from the TCGA dataset, including 22 upregulated genes and 2 downregulated genes. Functional enrichment analysis revealed that these genes were mainly involved in immune response pathways and various cancer-related pathways. Univariate analysis identified 21 prognostic NKCRGs, with eight genes (PAK1, MAP2K2, MAPK3, PLCG1, SHC1, HRAS, NRAS, and MICB) confirmed to be involved in HCC prognosis through Venn diagram analysis. A prognostic model was developed using LASSO-Cox regression, incorporating four genes (MAP2K2, SHC1, HRAS, and NRAS). The model's risk score was significantly associated with overall survival (OS) in both the TCGA and ICGC cohorts. Patients with high-risk scores had poorer OS, as demonstrated by Kaplan-Meier curves and ROC analyses. The risk score was not significantly correlated with gender or age but was higher in patients with advanced tumor grades and stages. Immune status analysis using ssGSEA showed higher enrichment scores for various immune cells and pathways in the high-risk group. Additionally, the risk score was positively correlated with the immune score, indicating its potential role in tumor microenvironment modulation. Expression analysis revealed that HRAS, SHC1, MAP2K2, and NRAS were upregulated in HCC tissues, with higher expressions of HRAS, MAP2K2, and NRAS associated with shorter OS. Knockdown experiments confirmed that silencing NRAS suppressed the proliferation of HCC cells, highlighting its potential as a therapeutic target. Overall, our findings suggest that the identified NKCRGs, particularly NRAS, play crucial roles in HCC progression and could serve as valuable prognostic markers and therapeutic targets.
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Affiliation(s)
- Ruixi Li
- Department of Hepatobiliary and Pancreatic Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China
| | - Guangquan Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China
| | - Qiang Tao
- Department of Hepatobiliary and Pancreatic Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China
| | - Ziyun Wu
- The First Clinical Medical College of Nanchang University, Nanchang, 330031, China
| | - Xiaoping Liu
- The First Clinical Medical College of Nanchang University, Nanchang, 330031, China
| | - Rongrong Wang
- The First Clinical Medical College of Nanchang University, Nanchang, 330031, China
| | - Lei Liu
- Department of Clinical Pharmacy, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China
| | - Yiran Niu
- The First Clinical Medical College of Nanchang University, Nanchang, 330031, China
| | - Kaile Du
- The First Clinical Medical College of Nanchang University, Nanchang, 330031, China
| | - Runpeng Wu
- The First Clinical Medical College of Nanchang University, Nanchang, 330031, China
| | - Fei Du
- Department of Hepatobiliary and Pancreatic Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China
| | - Xiyan Zheng
- Department of Hepatobiliary and Pancreatic Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China
| | - Yingliang Li
- Department of Breast Disease Center, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
| | - Xianjie Shi
- Department of Hepatobiliary and Pancreatic Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518033, China.
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Dennehy C, Conroy MR, Forde PM. Immunotherapy for resectable lung cancer. Cancer 2025; 131:e35849. [PMID: 40334018 PMCID: PMC12057804 DOI: 10.1002/cncr.35849] [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: 09/16/2024] [Revised: 03/20/2025] [Accepted: 03/24/2025] [Indexed: 05/09/2025]
Abstract
Lung cancer remains a significant global health challenge, demanding innovative treatment strategies. Immune checkpoint blockade has revolutionized cancer care, leading to improved survival across advanced malignancies and has now become a standard therapy for earlier stage, resectable lung cancer. This review article consolidates the current landscape and future prospects of neoadjuvant and perioperative immunotherapy in lung cancer. The authors outline key findings from clinical trials in resectable lung cancer, including early efficacy, safety profiles, and emerging impact on disease recurrence, and overall survival. Additionally, this review elucidates the challenges encountered, including patient selection criteria, optimal treatment schedules, immune-related adverse events, and impact on surgery. This comprehensive analysis amalgamates current evidence with future directions, providing a roadmap for clinicians, researchers, and stakeholders to navigate the dynamic realm of immunotherapy for surgically resectable lung cancer.
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Affiliation(s)
- Colum Dennehy
- Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Michael R. Conroy
- Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Patrick M. Forde
- Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreMarylandUSA
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Deshmukh SS, Chaudhari KS, Basu A, Sonpavde GP. Current update on pharmacological strategies of penile cancer. Expert Opin Pharmacother 2025; 26:863-878. [PMID: 40210449 DOI: 10.1080/14656566.2025.2492335] [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: 01/08/2025] [Revised: 03/18/2025] [Accepted: 04/08/2025] [Indexed: 04/12/2025]
Abstract
INTRODUCTION Penile cancer considered an orphan malignancy - due to its low incidence - makes research and clinical development challenging. The limited understanding of molecular biology and genetic landscape adds to the complexity of developing effective therapies. AREAS COVERED This review takes a closer look at how penile cancer treatment has evolved - from traditional modes like surgery and radiation to now vaccines - over the period of time. Breakthroughs in immunotherapy offer a ray of hope alongside treatments like adoptive T-cell therapies (ATCT), anti-angiogenic agents, Antibody-Drug Conjugates (ADCs), and Bispecific Antibodies (BsAbs). EXPERT OPINION The integration of immunotherapy and targeted therapy has demonstrated promising results, particularly in patients with advanced or metastatic disease. While these advancements bring hope, more research is needed to refine treatment strategies to benefit patients from these novel approaches.
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Affiliation(s)
- Sameer S Deshmukh
- Division of Hematology/Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center at UAB, Birmingham, AL, USA
| | - Kaustubh S Chaudhari
- Department of Medicine, Dr Vaishampayan Memorial Government Medical College, Solapur, India
| | - Arnab Basu
- Division of Hematology/Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center at UAB, Birmingham, AL, USA
| | - Guru P Sonpavde
- Division of Hematology/Oncology, Department of Medicine, AdventHealth Central Florida, Orlando, FL, USA
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8
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Wang J, Chen Q, Shan Q, Liang T, Forde P, Zheng L. Clinical development of immuno-oncology therapeutics. Cancer Lett 2025; 617:217616. [PMID: 40054657 PMCID: PMC11930610 DOI: 10.1016/j.canlet.2025.217616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 03/03/2025] [Accepted: 03/05/2025] [Indexed: 03/15/2025]
Abstract
Immuno-oncology (IO) is one of the fastest growing therapeutic areas within oncology. IO agents work indirectly via the host's adaptive and innate immune system to recognize and eradicate tumor cells. Despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product category. Current Food and Drug Administration (FDA)-approved classes of IO agents include: immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy (CAR-T), bi-specific T-cell engager (BiTE) antibody therapy, T-cell receptor (TCR) engineered T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, cytokine therapy, cancer vaccine therapy, and oncolytic virus therapy. Cancer immunotherapy has made progress in multiple cancer types including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma; however, several cancers remain refractory to immunotherapy. Future directions of IO include exploration in the neoadjuvant/perioperative setting, combination strategies, and optimizing patient selection through improved biomarkers.
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Affiliation(s)
- Jianxin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Qi Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Qiang Shan
- Department of General Surgery, Haining People's Hospital, Haining, 314400, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Patrick Forde
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Mays Cancer Center at the University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Lei Zheng
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Mays Cancer Center at the University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
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9
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Tsukita Y, Umezawa R, Nakagawa T, Anbai A, Makiguchi T, Tanaka H, Horii Y, Suzuki A, Morita R, Nogawa H, Yokouchi H, Kimura N, Jingu K, Inoue A, Sugiura H, Miyauchi E. Phase 2 Trial of Combination Radiotherapy and Pembrolizumab Plus Chemotherapy in Patients With Previously Untreated Metastatic NSCLC: NJLCG 1902. JTO Clin Res Rep 2025; 6:100817. [PMID: 40225955 PMCID: PMC11992379 DOI: 10.1016/j.jtocrr.2025.100817] [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: 10/02/2024] [Revised: 02/02/2025] [Accepted: 02/24/2025] [Indexed: 04/15/2025] Open
Abstract
Introduction Treatment strategies that enhance the efficacy of immunotherapy are desired. Radiotherapy can enhance immunity, but the utility of adding radiotherapy to immunotherapy plus platinum-doubled chemotherapy in patients with metastatic NSCLC has not been explored. Methods This multicenter, single-arm phase 2 trial evaluated the efficacy and safety of combining radiotherapy with pembrolizumab plus chemotherapy in patients with previously untreated metastatic NSCLC. Patients begin receiving pembrolizumab plus platinum-doublet chemotherapy within 1 week of starting radiotherapy (30 Gy in 10 fractions). The primary end point was the 12-month progression-free survival (PFS) rate. The secondary end points included PFS, overall survival, and toxicity profiles. Results Forty patients were enrolled. In total, 37 and 38 patients were analyzed for efficacy and safety, respectively. The 12-month PFS rate was 44.3% (90% confidence interval [CI]: 30.3-57.3), which met the primary end point. The median PFS was 8.4 months (95% CI: 5.7-22.2), and the median overall survival was 30.1 months (95% CI: 22.3-not reached). Grade 3 or 4 adverse events occurred in 25 patients (65.8%), and one treatment-related death was reported. Pneumonitis was reported in 10 patients (26.3%), including two cases of grade 3 pneumonitis and one case of grade 5. Conclusions Adding radiotherapy to pembrolizumab plus platinum-doublet chemotherapy led to promising efficacy in patients with previously untreated metastatic NSCLC. Although caution should be exercised with regard to pneumonitis, adverse events were tolerable. Further research is needed to confirm the efficacy and safety of this strategy.
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Affiliation(s)
- Yoko Tsukita
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Rei Umezawa
- Department of Radiation Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Taku Nakagawa
- Department of Thoracic Surgery, Omagari Kosei Medical Center, Daisen, Japan
| | - Akira Anbai
- Department of Radiology, Omagari Kosei Medical Center, Daisen, Japan
| | - Tomonori Makiguchi
- Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Hisashi Tanaka
- Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Yosuke Horii
- Division of Pulmonary Medicine, Department of Internal Medicine, Iwate Medical University School of Medicine, Morioka, Japan
| | - Aya Suzuki
- Department of Respiratory Medicine, Miyagi Cancer Center, Natori, Japan
| | - Ryo Morita
- Department of Respiratory Medicine, Akita Kousei Medical Center, Akita, Japan
| | - Hitomi Nogawa
- Department of Respiratory Medicine, Yamagata Prefectural Central Hospital, Yamagata, Japan
| | - Hiroshi Yokouchi
- Department of Respiratory Medicine, NHO Hokkaido Cancer Center, Sapporo, Japan
| | - Nozomu Kimura
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Keiichi Jingu
- Department of Radiation Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akira Inoue
- Department of Palliative Medicine, Tohoku University School of Medicine, Sendai, Japan
| | - Hisatoshi Sugiura
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Eisaku Miyauchi
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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Lai G, Xie B, Zhang C, Zhong X, Deng J, Li K, Liu H, Zhang Y, Liu A, Liu Y, Fan J, Zhou T, Wang W, Huang A. Comprehensive analysis of immune subtype characterization on identification of potential cells and drugs to predict response to immune checkpoint inhibitors for hepatocellular carcinoma. Genes Dis 2025; 12:101471. [PMID: 40092490 PMCID: PMC11907441 DOI: 10.1016/j.gendis.2024.101471] [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: 10/17/2023] [Revised: 04/12/2024] [Accepted: 11/02/2024] [Indexed: 03/19/2025] Open
Abstract
Immunosubtyping enables the segregation of immune responders from non-responders. However, numerous studies failed to focus on the integration of cellular heterogeneity and immunophenotyping in the prediction of hepatocellular carcinoma (HCC) patients' response to immune checkpoint inhibitors (ICIs). We categorized HCC patients into various immune subtypes based on feature scores linked to ICI response. Single-cell sequencing technology was to investigate the cellular heterogeneity of different immune subtypes and acquire significant ICI response-associated cells. Candidate drugs were identified using a blend of various drug databases and network approaches. HCC patients were divided into two distinct immune subtypes based on characterization scores of 151 immune-related gene sets. Patients in both subtypes showed varying overall survival, immunity levels, biological activities, and TP53 mutation rates. Subtype 1-related natural killer cells showed a positive correlation with immune-promoting scores but a negative correlation with immune-suppressing scores. Notably, docetaxel sensitivity in HCC patients rose as the levels of subtype 1-related natural killer cells increased. Our study demonstrated that immune subtypes have cellular heterogeneity in predicting response to ICIs. A combination of subtype 1-associated natural killer cells and docetaxel may offer new hope for ICI treatment in HCC.
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Affiliation(s)
- Guichuan Lai
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Biao Xie
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Cong Zhang
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Xiaoni Zhong
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Jielian Deng
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Kangjie Li
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Hui Liu
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Yuan Zhang
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Anbin Liu
- Department of Applied Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Yi Liu
- Department of Applied Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Jie Fan
- Department of Epidemiology, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Tianyi Zhou
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Wei Wang
- Department of Applied Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Ailong Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
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11
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Bess SN, Smart GK, Muldoon TJ. Quantifying treatment response to a macrophage-targeted therapy in combination with immune checkpoint inhibitors after exposure to conventional chemotherapy. Front Immunol 2025; 16:1565953. [PMID: 40356923 PMCID: PMC12066502 DOI: 10.3389/fimmu.2025.1565953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Accepted: 04/04/2025] [Indexed: 05/15/2025] Open
Abstract
Background Conventional chemotherapeutic agents, such as 5-fluorouracil (5-FU), can exert anti-tumor effects through immunogenic cell death (ICD) induction. Researchers have found hallmarks that quantify ICD (such as the translocation of HMGB1 and calreticulin). Although chemotherapeutic agents can induce ICD, they increase the expression of immune checkpoints, limiting their effectiveness. Studies have emphasized the importance of investigating the heterogeneous responses of cells co-localized in a solid tumor (macrophages, tumor cells, etc.) to ICD induction. However, these studies were performed in vivo, which limits the collection of information on cell-cell interactions due to model complexity. Methods In this study, we used a multicellular spheroid model in conjunction with single spheroid imaging to understand the structural and metabolic changes of a simulated solid tumor model. In addition to using the spheroid model, conventional 2D co-culture monolayers were used to quantify ICD hallmarks and changes in macrophage functional behavior while correlating immune responses after exposure to the combinatory regimen of immune checkpoint inhibitors and an ICD inducer. Results Results indicate that the combination of two immune checkpoint inhibitors in addition to a chemotherapy agent reduced spheroid growth (~46%) and reduced M2 macrophage expression and cellular proliferation while modulating cellular metabolism, ICD hallmarks, and phagocytic function. Conclusions Overall, this study not only quantified microregional metabolic and structural changes in a simulated spheroid model but also quantified changes in ICD hallmarks and macrophage functional behavior. It was also found that correlations between spheroid structure and ICD hallmarks through immunofluorescence markers could exist after exposure to the combinatory regimen of immune checkpoint inhibitors and an ICD inducer.
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Affiliation(s)
| | | | - Timothy J. Muldoon
- Department of Biomedical Engineering, University of Arkansas,
Fayetteville, AR, United States
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12
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Huang X, Ji M, Shang X, Zhang H, Zhang X, Zhou J, Yin T. Smart on-demand drug release strategies for cancer combination therapy. J Control Release 2025; 383:113782. [PMID: 40294796 DOI: 10.1016/j.jconrel.2025.113782] [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: 01/20/2025] [Revised: 04/06/2025] [Accepted: 04/24/2025] [Indexed: 04/30/2025]
Abstract
In cancer therapy, enhancing therapeutic indices and patient compliance has been a central focus in recent drug delivery technology development. However, achieving a delicate balance between improving anti-tumor efficacy and minimizing toxicity to normal tissues remains a significant challenge. With the advent of smart on-demand drug release strategies, new opportunities have emerged. These strategies represent a promising approach to drug delivery, enabling precise control over the release of therapeutic agents in a programmed and spatiotemporal manner. Recent studies have focused on designing delivery systems capable of releasing multiple therapeutic agents sequentially, while achieving spatial resolution in vivo. Smart on-demand drug release strategies have demonstrated considerable potential in tumor combination therapy for achieving precision drug delivery and controlled release by responding to specific physiological signals or external physical stimuli in the tumor microenvironment. These strategies not only improve tumor targeting and reduce toxicity to healthy tissues but also enable sequential release in combination therapy, allowing multiple drugs to be released in a specific spatiotemporal order to enhance synergistic treatment effects. In this paper, we systematically reviewed the current research progress of smart on-demand drug release drug delivery strategies in anti-tumor combination therapy. We highlighted representative integrated drug delivery systems and discussed the challenges associated with their clinical application. Additionally, potential future research directions are proposed to further advance this promising field.
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Affiliation(s)
- Xiaolin Huang
- Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Mengfei Ji
- Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Xinyu Shang
- Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Hengchuan Zhang
- Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Xin Zhang
- Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
| | - Jianping Zhou
- Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
| | - Tingjie Yin
- Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
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13
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Sun Y, Deng Z, Sun H, Wei X, Wang L, Wang S, Gao A, Sun Y, Li J. Prognostic impact of the timing of immunotherapy in first-line immunochemotherapy for patients with advanced lung adenocarcinoma: A propensity score-matched analysis. Int J Cancer 2025. [PMID: 40259531 DOI: 10.1002/ijc.35447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 03/20/2025] [Accepted: 03/26/2025] [Indexed: 04/23/2025]
Abstract
Immunochemotherapy combinations have been the standard first-line therapy for advanced lung adenocarcinoma (LUAD) without driver mutations, wherein concurrent chemotherapy and immunotherapy are conventionally anchored in the established dosing regimen. A few studies have suggested that the timing of immunotherapy in combinations may have a significant impact on the efficacy. However, this issue has not been addressed in an advanced LUAD cohort. We aimed to investigate the prognostic significance of the timing of immunotherapy in first-line immunochemotherapy combinations for patients with advanced LUAD. We retrospectively analyzed 508 patients with advanced LUAD without driver mutations who received immunochemotherapy as initial systemic treatment. The patients were divided into two groups-the induction and non-induction groups-with induction defined as receiving chemotherapy alone before concurrent immunochemotherapy. The bias between different groups was minimized using propensity score matching (PSM). We found both the PFS and OS of the patients in the induction group were significantly longer than those in the non-induction group before (PFS: p < 0.0001, OS: p < 0.0001) and after PSM (PFS: p = 0.0045, OS: p = 0.00073). After adjusting for confounders, induction chemotherapy was still a significant favorable factor for both PFS (p = 0.001) and OS (p = 0.001). In subsequent analyses, we found that both ≥2-cycles induction (PFS: p = 0.000, OS: p = 0.000) and 1-cycle induction (PFS: p = 0.013, OS: p = 0.002) were superior to non-induction and these differences were still significant after PSM. Our findings highlight the notable benefits of induction chemotherapy for patients with advanced LUAD treated with first-line immunochemotherapy combinations.
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Affiliation(s)
- Yanxin Sun
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
- Phase I Clinical Trail Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Zhenzhen Deng
- Phase I Clinical Trail Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Haifeng Sun
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
- Phase I Clinical Trail Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Xiaojuan Wei
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Leirong Wang
- Phase I Clinical Research Center, Shandong University Cancer Center, Jinan, Shandong, China
| | - Shuyun Wang
- Phase I Clinical Trail Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Aiqin Gao
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yuping Sun
- Phase I Clinical Trail Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Juan Li
- Phase I Clinical Trail Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
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Orooji N, Babaei S, Fadaee M, Abbasi-Kenarsari H, Eslami M, Kazemi T, Yousefi B. Novel therapeutic approaches for non-small cell lung cancer: an updated view. J Drug Target 2025:1-16. [PMID: 40186594 DOI: 10.1080/1061186x.2025.2489986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 03/24/2025] [Accepted: 04/01/2025] [Indexed: 04/07/2025]
Abstract
Non-small cell lung cancer (NSCLC) continues to be one of the leading causes of cancer-related mortality globally. Most patients who undergo surgical procedures may encounter distant metastasis or local recurrence, necessitating supplementary treatments such as radiation therapy, chemotherapy, or targeted therapy as adjuvant alternatives. Recent advancements in molecular biology and immunotherapy have paved the way for innovative therapeutic approaches that target specific genetic mutations and promote the immune response against tumour cells. This review explores emerging therapies, including targeted therapies such as tyrosine kinase inhibitors (TKIs) for actionable mutations (e.g., EGFR, ALK, ROS1), as well as the role of immune checkpoint inhibitors (ICIs) that employ the body's immune system to combat cancer. Additionally, we discuss the potential of exosome therapies, as well as promising nanotherapeutic options for the treatment of NSCLC. This study attempts to provide a thorough overview of the changing landscape of NSCLC treatment and its implications for enhancing patient outcomes by presenting these innovative techniques.
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Affiliation(s)
- Niloufar Orooji
- Department of Immunology, School of Medicine, Semnan University of Medical Science, Semnan, Iran
| | - Shabnam Babaei
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Manouchehr Fadaee
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hajar Abbasi-Kenarsari
- Department of Immunology, Faculty of Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Majid Eslami
- Department of Bacteriology and Virology, Semnan University of Medical Sciences, Semnan, Iran
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Tohid Kazemi
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Department of Immunology, School of Medicine, Semnan University of Medical Science, Semnan, Iran
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
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Guan X, Shen Y, Zhao C, Li X, Li X, Lu D, Wang L, Liu L, Wu S, Huang B, Guo L, Xu H. Cascade-Responsive Nanoprodrug Disrupts Immune-Fibroblast Communications for Potentiated Cancer Mechanoimmunotherapy. Adv Healthc Mater 2025; 14:e2500176. [PMID: 40079115 DOI: 10.1002/adhm.202500176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/02/2025] [Indexed: 03/14/2025]
Abstract
The abnormal tumor mechanical microenvironment due to specific cancer-associated fibroblasts (CAFs) subset and low tumor immunogenicity caused by inefficient conversion of active chemotherapeutic agents are two key obstacles that impede patients with desmoplastic tumors from achieving stable and complete immune responses. Herein, it is demonstrated that FAP-α+CAFs-induced stromal stiffness accelerated tumor progression by precluding cytotoxic T lymphocytes. Subsequently, a cascade-responsive nanoprodrug capable of re-educating FAP-α+CAFs and amplifying tumor immunogenicity for potentiated cancer mechanoimmunotherapy is ingeniously designed. Benefiting from the active targeted release of angiotensin II receptor antagonist (losartan) guided by FAP-α cleavable peptide and the efficient conversion of topoisomerase I inhibitor (7-Ethyl-10-hydroxycamptothecin) prodrug under high glutathione/esterase within tumor cells, this regimen created an immune-activated landscape that retarded primary tumor growth and counteracted resistance to immune checkpoint inhibitor in mice with triple-negative breast cancer. This nanoprodrug-assisted mechanoimmunotherapy can serve as a universal strategy for conferring efficient tumoricidal immunity in "immune excluded" desmoplastic tumor interventions.
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Affiliation(s)
- Xin Guan
- Department of Ultrasound, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361000, P. R. China
| | - Yuting Shen
- Department of Ultrasound, Institiute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Chongke Zhao
- Department of Ultrasound, Institiute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Xiao Li
- Department of Ultrasound, Institiute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Xiaolong Li
- Department of Ultrasound, Institiute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Dan Lu
- Department of Ultrasound, Institiute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Lifan Wang
- Department of Ultrasound, Institiute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Linna Liu
- Department of Ultrasound, Institiute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Shengbo Wu
- Department of Ultrasound, Zhejiang Hospital, Hangzhou, 310013, P. R. China
| | - Bin Huang
- Department of Ultrasound, Zhejiang Hospital, Hangzhou, 310013, P. R. China
| | - Lehang Guo
- Department of Medical Ultrasound and Center of Minimally Invasive Treatment for Tumor, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, P. R. China
| | - Huixiong Xu
- Department of Ultrasound, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361000, P. R. China
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Ji X, Wang G, Pan D, Xu S, Lei X. Efficacy and safety of pembrolizumab in advanced gastric and gastroesophageal junction cancer: a systematic review and meta-analysis. BMC Gastroenterol 2025; 25:173. [PMID: 40087572 PMCID: PMC11908035 DOI: 10.1186/s12876-025-03754-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 03/03/2025] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND Pembrolizumab, a PD-1 inhibitor, has shown potential for treating advanced gastric and gastroesophageal junction (GEJ) cancer. This meta-analysis evaluates its efficacy and safety, alone or combined with chemotherapy, in this population. METHODS A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. Databases including PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science were searched up to October 31, 2024. Twelve studies comprising 4,069 patients were included. The primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes included objective response rate (ORR), adverse events (AEs), and grade ≥ 3 AEs. Effect sizes were calculated using mean differences (MDs) and odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS Pembrolizumab combined with chemotherapy significantly improved OS (MD = 1.92 months; 95% CI: 0.94 to 2.91) and ORR (MD = 11.05%; 95% CI: 6.29 to 15.82) compared to chemotherapy alone. Pembrolizumab monotherapy did not show a significant effect on OS (MD = 0.24 months; 95% CI: -1.15 to 1.63) and was associated with a significant reduction in PFS (MD = -2.28 months; 95% CI: -2.85 to -1.71) compared to chemotherapy alone. For safety, pembrolizumab monotherapy significantly reduced the risk of AEs (OR = 0.68; 95% CI: 0.57 to 0.81) and grade ≥ 3 AEs (OR = 0.39; 95% CI: 0.30 to 0.51) compared to chemotherapy. Pembrolizumab combined with chemotherapy did not significantly alter the risk of AEs (OR = 1.01; 95% CI: 0.90 to 1.13) or grade ≥ 3 AEs (OR = 1.12; 95% CI: 0.99 to 1.27) compared to chemotherapy alone. CONCLUSION Pembrolizumab combined with chemotherapy improves survival and response rates with a manageable safety profile in advanced gastric and GEJ cancers. Monotherapy shows limited efficacy, highlighting the need for combination strategies and patient selection.
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Affiliation(s)
- Xiaoying Ji
- Department of Pharmacy, Yiwu Central Hospital, Yiwu, Zhejiang, 322000, China
| | - Guoping Wang
- Department of Pharmacy, Yiwu Central Hospital, Yiwu, Zhejiang, 322000, China
| | - Dandan Pan
- Department of Pharmacy, Yiwu Central Hospital, Yiwu, Zhejiang, 322000, China
| | - Shanxia Xu
- Quzhou Zhong Da Lang Yuan Nursing Home, Quzhou, Zhejiang, 324000, China
| | - Xinming Lei
- The Quzhou Afliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, Zhejiang, 324000, China.
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17
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Gao Y, Zhang L, Yan M, Sun Z, Zhao H, Zhao L. Development of a prognostic model for patients with extensive-stage small cell lung cancer undergoing immunotherapy and chemotherapy. Front Immunol 2025; 16:1561333. [PMID: 40124379 PMCID: PMC11926142 DOI: 10.3389/fimmu.2025.1561333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 02/25/2025] [Indexed: 03/25/2025] Open
Abstract
Purpose In this study, we aimed to develop a predictive model for patients receiving chemotherapy and immunotherapy for extensive-stage small cell lung cancer. Methods We retrospectively analyzed 112 extensive-stage small cell lung cancer patients treated with first-line immunotherapy and chemotherapy. The relevant clinical data were collected to evaluate the changes during the treatment. The best subset regression, univariate analysis, and LASSO regression with cross-validation were applied for variable selection and model establishment. The nomograms for 1- and 2-year survival probabilities were established, and the calibration curve was utilized to evaluate the correspondence between actual and predicted survival. The model prediction capacity was assessed using decision curve analysis, calibration curves, and receiver operating characteristic curves. Moreover, five-fold cross-validation was conducted for internal validation. According to risk score, the patients were assigned to high- and low-risk groups, and survival curves were generated for each group. Results The LASSO regression model was established based on the variables such as age, ECOG, metastatic sites, NLR, and immunotherapy cycles. This predictive model displayed robust performance, evidenced by the Area Under the Curve of 0.887 and concordance index of 0.759. The nomogram effectively predicted 1- and 2-year survival probabilities and demonstrated a high degree of calibration. The decision curve analysis displayed that the model possessed superior predictive capability. The risk stratification for patients with high- and low-risk categories facilitated more individualized survival assessment. Conclusion The study successfully developed a prognostic model for extensive-stage small cell lung cancer patients undergoing immunotherapy and chemotherapy, demonstrating the good accuracy and predictability.
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Affiliation(s)
- Yunbin Gao
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
- Department of Oncology, Jining No. 1 People’s Hospital, Jining, Shandong, China
| | - Lixia Zhang
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Meng Yan
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
| | - Zongwen Sun
- Department of Oncology, Jining No. 1 People’s Hospital, Jining, Shandong, China
| | - Haibo Zhao
- Department of Oncology, Jining No. 1 People’s Hospital, Jining, Shandong, China
| | - Lujun Zhao
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
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18
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de Zawadzki A, Leeming DJ, Sanyal AJ, Anstee QM, Schattenberg JM, Friedman SL, Schuppan D, Karsdal MA. Hot and cold fibrosis: The role of serum biomarkers to assess immune mechanisms and ECM-cell interactions in human fibrosis. J Hepatol 2025:S0168-8278(25)00148-5. [PMID: 40056933 DOI: 10.1016/j.jhep.2025.02.039] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 02/18/2025] [Accepted: 02/23/2025] [Indexed: 05/24/2025]
Abstract
Fibrosis is a pathological condition characterised by excessive accumulation of extracellular matrix (ECM) components, particularly collagens, leading to tissue scarring and organ dysfunction. In fibrosis, an imbalance between collagen synthesis (fibrogenesis) and degradation (fibrolysis) results in the deposition of fibrillar collagens disrupting the structural integrity of the ECM and, consequently, tissue architecture. Fibrosis is associated with a wide range of chronic diseases, including cirrhosis, kidney fibrosis, pulmonary fibrosis, and autoimmune diseases. Recently, the concept of "hot" and "cold" fibrosis has emerged, referring to the immune status within fibrotic tissues and the nature of fibrogenic signalling. Hot fibrosis is characterised by active immune cell infiltration and inflammation, while cold fibrosis is associated with auto- and paracrine myofibroblast activation, immune cell exclusion and quiescence. In this article, we explore the relationship between hot and cold fibrosis, the role of various types of collagens and their biologically active fragments in modulating the immune system, and how serological ECM biomarkers can help improve our understanding of the disease-relevant interactions between immune and mesenchymal cells in fibrotic tissues. Additionally, we draw lessons from immuno-oncology research in solid tumours to shed light on potential strategies for fibrosis treatment and highlight the advantage of having a "hot fibrotic environment" to treat fibrosis by enhancing collagen degradation through modulation of the immune system.
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Affiliation(s)
| | - Diana J Leeming
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - Arun J Sanyal
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health and Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Quentin M Anstee
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK; Newcastle NIHR Biomedical Research Center, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, UK
| | - Jörn M Schattenberg
- Department of Internal Medicine II, Saarland University Medical Centre, Homburg, Germany
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Detlef Schuppan
- Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Harvard Medical School, MA, USA
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Bedi D, Hassan M, Yirsaw A, Vikas B, Datta P, Samuel T. The immunopeptidome of colon cancer cells treated with topoisomerase inhibiting drug reveals differential as well as common endogenous protein sampling and display of MHC I-associated peptides. Mol Cell Oncol 2025; 12:2471640. [PMID: 40051755 PMCID: PMC11881837 DOI: 10.1080/23723556.2025.2471640] [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: 01/16/2024] [Revised: 08/05/2024] [Accepted: 02/20/2025] [Indexed: 03/09/2025]
Abstract
Immunotherapy options for microsatellite stable (MSS) colorectal cancer are currently very limited. The lack of detectably unique or altered immunogens in the tumor microenvironment may be a factor. Radiation and chemotherapy may enhance immunotherapy by increasing cancer cell visibility through Major Histocompatibility Complex I (MHC I) expression. To investigate this, we treated MSS and microsatellite-instable (MSI) colon cancer cells with a topoisomerase inhibitor and analyzed MHC I-associated peptides. Treatment increased peptide numbers by 5% in RKO (MSI) cells and 83% in SW620 (MSS) cells, with 40-50% of peptides being exclusive to treatment. Additionally, clustering analysis revealed a set of peptides with uniquely conserved residues displayed only in treated MSS SW620 cells. Gene Ontology analysis of MHC I-displayed proteins revealed a treatment-induced increase in extracellular vesicle- and nuclear-derived proteins, alongside reduced cytosolic protein sampling. Overall, we present evidence for treatment-inducible differential display of peptides, some of which may affect interactions and functions of immune cells. Given the multitude of factors that modulate the effects of increased MHC I expression and associated peptides, further studies are needed to elucidate the pathophysiological implications of these changes.
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Affiliation(s)
- Deepa Bedi
- Departments of Pathobiology and Biomedical Sciences, Tuskegee University, College of Veterinary Medicine and Center for Biomedical Research, Tuskegee, AL, USA
| | - Mohammed Hassan
- Departments of Pathobiology and Biomedical Sciences, Tuskegee University, College of Veterinary Medicine and Center for Biomedical Research, Tuskegee, AL, USA
| | - Alehegne Yirsaw
- Departments of Pathobiology and Biomedical Sciences, Tuskegee University, College of Veterinary Medicine and Center for Biomedical Research, Tuskegee, AL, USA
| | - Biba Vikas
- Departments of Pathobiology and Biomedical Sciences, Tuskegee University, College of Veterinary Medicine and Center for Biomedical Research, Tuskegee, AL, USA
| | - Pran Datta
- University of Alabama at Birmingham, Birmingham, AL, USA
| | - Temesgen Samuel
- Departments of Pathobiology and Biomedical Sciences, Tuskegee University, College of Veterinary Medicine and Center for Biomedical Research, Tuskegee, AL, USA
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20
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Cammarota A, Woodford R, Smyth EC. Targeting HER2 in Gastroesophageal Cancer: A New Appetite for an Old Plight. Drugs 2025; 85:361-383. [PMID: 39843758 DOI: 10.1007/s40265-024-02132-2] [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: 11/21/2024] [Indexed: 01/24/2025]
Abstract
The incidence of gastroesophageal cancers is rising, driven, in part, by an increasing burden of risk factors of obesity and gastroesophageal reflux. Despite efforts to address these risk factors, and a growing interest in methods of population screening, the bulk of these tumours are unresectable at diagnosis. In this setting, effective systemic treatments are paramount to improve survival and quality of life. Early and accurate identification of oncogenic drivers, such as human epidermal growth factor receptor 2 (HER2), present in 5-30% of gastroesophageal adenocarcinomas (GEAs), is integral to guide choice of therapies due to the clear predictive implications that arise from overexpression of this receptor. After trastuzumab, the first anti-HER2 agent with approved use in HER2-positive GEA, the addition of pembrolizumab to first-line trastuzumab-chemotherapy and trastuzumab deruxtecan in the refractory space have more recently changed practice. Yet, the response to these agents has been vastly different across patients with HER2-positive disease, underpinning the need for reliable biomarkers of response. Emergent data have suggested that levels of HER2 expression on tissue or liquid biopsies may predict response to first-generation HER2 therapies while HER2 heterogeneity, receptor changes, co-occurring molecular alterations and oncogenic genomic and metabolic reprogramming may be implicated in resistance. A robust knowledge of the mechanisms of resistance and response to HER2-directed therapies is necessary to inform novel strategies of HER2-targeting and guide choice combinations with other biomarker-directed therapies, to improve outcomes from a new generation of clinical trials in HER2-positive GEA. Understanding and close examination of previous failures in this space form an important part of this assessment, as does correlative biomarker and translational work pertaining to the role of HER2 and dynamic changes that result through treatment exposure. In this review, we aim to provide an overview of strategies for HER2 targeting, summarising both the successes and disappointments in this therapeutic landscape and discuss existing challenges and future perspectives on development in this highly morbid tumour type.
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Affiliation(s)
- Antonella Cammarota
- Sarah Cannon Research Institute UK, 93 Harley St, London, UK
- Department of Medical Sciences, Humanitas University, Via Rita Levi Montalcini, Pieve Emanuele, Milan, Italy
| | - Rachel Woodford
- Sarah Cannon Research Institute UK, 93 Harley St, London, UK
- National Health and Medical Research Council Clinical Trials Centre (NHMRC CTC), University of Sydney, Parramatta Road, Camperdown, Australia
| | - Elizabeth C Smyth
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.
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Tang B, Xiao J, Chi Z, Duan R, Cui C, Si L, Liu Y, Hu X, Liu Z, Xiang P, Li S, Yan X, Zhou L, Li J, Li Y, Yu X, Dai X, Li X, Guo J, Sheng X. Phase Ib study of anti-PD-L1 monoclonal antibody socazolimab in combination with nab-paclitaxel as first-line therapy for advanced urothelial carcinoma. Oncologist 2025; 30:oyae260. [PMID: 39418340 PMCID: PMC11883152 DOI: 10.1093/oncolo/oyae260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 04/20/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND PD-1/PD-L1 immune checkpoint inhibitors (ICIs) have demonstrated activity in the post-platinum and platinum-ineligible settings for advanced urothelial carcinoma (aUC). As only around 50% of patients with aUC can tolerate platinum-containing treatment, treatments combining first-line ICIs with non-platinum drugs are urgently needed. Therefore, we assessed the safety and efficacy of the anti-PD-L1 monoclonal antibody Socazolimab in combination with nab-paclitaxel as first-line therapy in aUC (NCT04603846). METHODS This was a multi-center, single-arm, phase Ib study that enrolled patients with treatment-naive aUC. Patients received Socazolimab (5 mg/kg) and nab-paclitaxel (260 mg/m2) Q3w. The primary endpoint was safety and tolerability of the combination regimen. Second endpoints were the objective response rate (ORR) and progression-free survival. RESULTS Between September, 2020 and September, 2021, 20 patients with urothelial carcinoma were enrolled, arising from renal pelvis (5), bladder (8), and ureter (7). After a median follow-up of 17 months, the median number of treatment cycles was 12. No patients had dose limiting toxicity. All patients had treatment-related adverse events (TRAEs), most of which were grade 1 or 2. The common TRAEs (≥20%) were peripheral neurotoxicity, alopecia, rash, increased ALT, weight loss, weakness, pruritus, increased AST, increased γGT, increased ALP, neutropenia, emesis, and anorexia. Nine patients (45%) developed grade 3 TRAEs including peripheral neurotoxicity (30.0%), increased ALT (10.0%), and increased γGT (5.0%). Two patients (10%) discontinued treatment because of grade 3 mouth ulcer (n = 1) and grade 2 lung fibrosis (n = 1). No grade 4-5 TRAEs were observed. Among the 17 patients who had received at least one tumor assessment, ORR was 58.8% (95% CI, 32.9%-81.6%) and the median progression-free survival was 8.3 months (95% CI, 5.2-19.5). The median duration of response was 13.3 months (95% CI, 2.0-20.1), and the overall survival was 19.5 months (95% CI, 11.2-not reached). CONCLUSION Socazolimab combined with nab-paclitaxel has shown good safety and promising antitumor activity as first-line therapy in patients with advanced urothelial carcinoma.
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Affiliation(s)
- Bixia Tang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Soft Tissue Sarcoma, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Jun Xiao
- Department of Urology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
| | - Zhihong Chi
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Soft Tissue Sarcoma, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Rong Duan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Chuanliang Cui
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Lu Si
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Soft Tissue Sarcoma, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Yixun Liu
- Department of Urology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
| | - Xuechun Hu
- Department of Urology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
| | - Zhi Liu
- Department of Urology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
| | - Ping Xiang
- Department of Urology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
| | - Siming Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Xieqiao Yan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Li Zhou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Juan Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Yujie Li
- Zhaoke (Guangzhou) Oncology Pharmaceutical Limited, Guangzhou 511400, People’s Republic of China
| | - Xiaohui Yu
- Zhaoke (Guangzhou) Oncology Pharmaceutical Limited, Guangzhou 511400, People’s Republic of China
| | - Xiangrong Dai
- Zhaoke (Guangzhou) Oncology Pharmaceutical Limited, Guangzhou 511400, People’s Republic of China
| | - Xiaoyi Li
- Zhaoke (Guangzhou) Oncology Pharmaceutical Limited, Guangzhou 511400, People’s Republic of China
| | - Jun Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
| | - Xinan Sheng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China
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Misawa K, Bhat H, Adusumilli PS, Hou Z. Combinational CAR T-cell therapy for solid tumors: Requisites, rationales, and trials. Pharmacol Ther 2025; 266:108763. [PMID: 39617146 PMCID: PMC11848936 DOI: 10.1016/j.pharmthera.2024.108763] [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: 09/06/2024] [Revised: 11/18/2024] [Accepted: 11/26/2024] [Indexed: 12/10/2024]
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has achieved potent antitumor efficacy in hematological malignancies; however, because of limitations in CAR T-cell recruitment, infiltration, activation, and functional persistence in the tumor, its efficacy in solid tumors has been suboptimal. To overcome these challenges, combinational strategies that include chemotherapy, radiation therapy, or immune checkpoint inhibitor agent therapy with CAR T-cell therapy are being investigated. The established functional characteristics of the abovementioned therapies provide a rationale for the use of a combinational approach with CAR T cells. Chemotherapy reshapes the peritumoral stroma, decreases the immunosuppressive cell population, and promotes a proinflammatory milieu, all of which allow for increased recruitment, infiltration, and accumulation of CAR T cells. Radiation therapy promotes a chemokine gradient, which augments tumor infiltration by CAR T cells and further increases expression of tumor-associated antigens, allowing for increased activation of CAR T cells. Immune checkpoint inhibitor agent therapy inactivates T-cell exhaustion pathways-most notably, the PD1/PDL1 pathway-thereby improving the functional persistence of CAR T cells and promoting endogenous immunity. In this review, we discuss the requisites and rationales for combinational therapy, and we review 25 ongoing phase I and II clinical trials, of which 4 use chemotherapy, 3 use radiation therapy, 11 use immunotherapy, and 7 use another agent. While safety, efficacy, and improved outcomes are the primary goals of these ongoing studies, the knowledge gained from them will help pave the way for subsequent studies focused on optimizing combinational regimens and identifying predictive biomarkers.
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Affiliation(s)
- Kyohei Misawa
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Hina Bhat
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
| | - Prasad S Adusumilli
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
| | - Zhaohua Hou
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
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23
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Lin J, Li W, Zhang X, Zhou K, Yang Y, Cheng S, Sun R, Dang C, Diao D. Thromboembolic events associated with immune checkpoint inhibitors in cancer patients: A Bayesian network meta-analysis. Thromb Res 2025; 246:109243. [PMID: 39721224 DOI: 10.1016/j.thromres.2024.109243] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 12/17/2024] [Accepted: 12/19/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs), which offer previously unknown therapeutic advantages, have revolutionized cancer treatment. However, the risk of thromboembolic events (TEEs) associated with ICIs remains unclear. The aim of this network meta-analysis (NMA) was to evaluate the incidence of TEEs in cancer patients receiving different treatment regimens. METHODS We searched for randomized clinical trials (RCTs) between January 2021 and December 2023 without restricting the cancer type. The percentages of TEEs were systematically extracted. An NMA was performed comparing atezolizumab, cemiplimab, durvalumab, ipilimumab, nivolumab, pembrolizumab, conventional therapy (which consists mainly of chemotherapy, targeted therapy, placebo, and their combinations), two ICI drugs, one ICI drug combined with conventional therapy, and two ICI drugs combined with conventional therapy. Additionally, subgroup analysis was conducted based on cancer type. RESULTS Eighty-three RCTs involving 54,736 patients were included. Patients receiving ICIs demonstrated comparable risks of arterial thromboembolism (ATE), deep vein thrombosis (DVT), myocardial infarction (MI), and cerebrovascular accidents (CVAs). Nivolumab (OR 0.39, 95 % CI 0.19 to 0.80) and two ICI drugs (OR 0.52, 95 % CI 0.29 to 0.89) had the lowest risk of venous thromboembolism (VTE) compared to two ICI drugs with conventional therapy. The risk of pulmonary embolism (PE) was greater for ipilimumab (OR 4.09, 95 % CI 1.13 to 15.51) than for nivolumab. For melanoma in the subgroup analysis, nivolumab significantly reduced the risk of VTE (OR 0.07, 95 % CI 0.00 to 0.76) compared to two ICI drugs. Among the single-ICI regimens, durvalumab was associated with the highest incidence of ATE, MI, and CVAs; ipilimumab had the highest incidence of VTE and PE; and pembrolizumab had the highest incidence of DVT. The combination of one ICI drug with conventional therapy was associated with a significantly greater risk of TEEs (except for MI) than the combination of two ICI drugs. CONCLUSIONS Various ICI regimens in cancer patients exhibit clinically significant differences in the risks of TEEs. Nivolumab exhibited a favorable safety profile regarding VTE, while ipilimumab had the highest risk of both VTE and PE. Different ICI regimens require tailored risk management strategies to reduce TEEs.
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Affiliation(s)
- Jinhe Lin
- Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Wenxing Li
- Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Xin Zhang
- Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Kai Zhou
- Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Yanqi Yang
- Department of Pathology, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Shaoli Cheng
- Basic Medical Experiment Teaching Center, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Ruifang Sun
- Department of Pathology, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Chengxue Dang
- Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
| | - Dongmei Diao
- Department of Oncology Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
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24
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Abushanab AK, Mustafa MT, Mousa MT, Albanawi RF, Alkhalaileh RM, Alqudah GN, Abu Zaina RF, Abu Sitta ZA, Almasri IM, Abuquteish D. Immune checkpoint inhibitors plus taxane-based chemotherapy for patients with advanced/metastatic NSCLC: a systematic review and meta-analysis across different PD-L1 expression levels. Expert Rev Anticancer Ther 2025; 25:167-179. [PMID: 39874440 DOI: 10.1080/14737140.2025.2460537] [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: 10/18/2024] [Revised: 01/13/2025] [Accepted: 01/21/2025] [Indexed: 01/30/2025]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are currently the primary approach for managing NSCLC. However, numerous combination therapies are currently under investigation. Our goal is to investigate the overall efficacy and safety of ICIs and taxane-based chemotherapy. METHODS We conducted a systematic review and meta-analysis, searching web databases for relevant literature. We limited our eligibility to phase II/III randomized clinical trials involving advanced/metastatic NSCLC patients. RESULTS We performed a meta-analysis encompassing nineteen studies derived from sixteen RCTs. For patients with sq-NSCLC PD-L1 ≥ 50%, using ICIs plus taxane significantly improve PFS and OS with HR of 0.58 (95% CI, 0.45-0.74, p < 0.0001) and 0.41 (95% CI, 0.33-0.50, p < 0.00001), respectively. For patients with non-sq NSCLC PD-L1 1-49%, the analysis revealed significant improvement of OS and PFS with HR of 0.64 (95% CI, 0.47-0.88, p = 0.005) and 0.62 (95% CI, 0.47-0.81, p = 0.0004), respectively. For TRAEs of all grades, ICIs plus taxane resulted with no significant difference compared to control group with risk ratio (RR) 1.00 (95% CI 0.99-1.02). CONCLUSION The analysis revealed significant improvement in efficacy of ICIs with taxane in advanced/metastatic NSCLC patients compared with ICI/taxane monotherapy.Registration: PROSPERO (CRD42023447532).
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Dua Abuquteish
- Department of Microbiology, Pathology and Forensic Medicine, Faculty of Medicine, The Hashemite University, Zarqa, Jordan
- Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan
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25
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Li J, Luo Y, Fu Q, Tang S, Zhang P, Frazer IH, Liu X, Wang T, Ni G. Caerin 1.1/1.9-mediated antitumor immunity depends on IFNAR-Stat1 signalling of tumour infiltrating macrophage by autocrine IFNα and is enhanced by CD47 blockade. Sci Rep 2025; 15:3789. [PMID: 39885296 PMCID: PMC11782643 DOI: 10.1038/s41598-025-87687-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 01/21/2025] [Indexed: 02/01/2025] Open
Abstract
Previously, we demonstrated that natural host-defence peptide caerin 1.1/caerin 1.9 (F1/F3) increases the efficacy of anti-PD-1 and therapeutic vaccine, in a HPV16 + TC-1 tumour model, but the anti-tumor mechanism of F1/F3 is still unclear. In this study, we explored the impact of F1/F3 on the tumor microenvironment in a transplanted B16 melanoma model, and further investigated the mechanism of action of F1/F3 using monoclonal antibodies to deplete relevant cells, gene knockout mice and flow cytometry. We show that F1/F3 is able to inhibit the growth of melanoma B16 tumour cells both in vitro and in vivo. Depletion of macrophages, blockade of IFNα receptor, and Stat1 inhibition each abolishes F1/F3-mediated antitumor responses. Subsequent analysis reveals that F1/F3 increases the tumour infiltration of inflammatory macrophages, upregulates the level of IFNα receptor, and promotes the secretion of IFNα by macrophages. Interestingly, F1/F3 upregulates CD47 level on tumour cells; and blocking CD47 increases F1/F3-mediated antitumor responses. Furthermore, F1/F3 intratumor injection, CD47 blockade, and therapeutic vaccination significantly increases the survival time of B16 tumour-bearing mice. These results indicate that F1/F3 may be effective to improve the efficacy of ICB and therapeutic vaccine-based immunotherapy for human epithelial cancers and warrants consideration for clinical trials.
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Affiliation(s)
- Junjie Li
- Key Laboratory of Cancer Immunotherapy of Guangdong Tertiary Education, Guangdong CAR-T Treatment Related Adverse Reaction Key Laboratory, The First Affiliated Hospital/Clinical Medical School, Guangdong Pharmaceutical University, Guangzhou, 510080, China
- Zhongao Biomedical Technology (Guangdong) Co., Ltd, Zhongshan, 528403, Guangdong, China
| | - Yuandong Luo
- Medical School of Guizhou University, Guiyang, 550000, Guizhou, China
| | - Quanlan Fu
- Medical School of Guizhou University, Guiyang, 550000, Guizhou, China
| | - Shuxian Tang
- Cancer Research Institute, Foshan First People's Hospital, Foshan, 528000, Guangdong, China
| | - Pingping Zhang
- Cancer Research Institute, Foshan First People's Hospital, Foshan, 528000, Guangdong, China
| | - Ian H Frazer
- Diamantia Institute, Translational Research Institute, University of Queensland, Woolloongabba, Brisbane, QLD, 4002, Australia
| | - Xiaosong Liu
- Key Laboratory of Cancer Immunotherapy of Guangdong Tertiary Education, Guangdong CAR-T Treatment Related Adverse Reaction Key Laboratory, The First Affiliated Hospital/Clinical Medical School, Guangdong Pharmaceutical University, Guangzhou, 510080, China
- Cancer Research Institute, Foshan First People's Hospital, Foshan, 528000, Guangdong, China
| | - Tianfang Wang
- Centre for Bioinnovation, University of the Sunshine Coast, Maroochydore BC, QLD, 4558, Australia.
- School of Science, Technology and Engineering, University of the Sunshine Coast, Maroochydore BC, QLD, 4558, Australia.
| | - Guoying Ni
- Key Laboratory of Cancer Immunotherapy of Guangdong Tertiary Education, Guangdong CAR-T Treatment Related Adverse Reaction Key Laboratory, The First Affiliated Hospital/Clinical Medical School, Guangdong Pharmaceutical University, Guangzhou, 510080, China.
- Cancer Research Institute, Foshan First People's Hospital, Foshan, 528000, Guangdong, China.
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26
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Lv X, Sun X, Gao Y, Song X, Hu X, Gong L, Han L, He M, Wei M. Targeting RNA splicing modulation: new perspectives for anticancer strategy? J Exp Clin Cancer Res 2025; 44:32. [PMID: 39885614 PMCID: PMC11781073 DOI: 10.1186/s13046-025-03279-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 01/07/2025] [Indexed: 02/01/2025] Open
Abstract
The excision of introns from pre-mRNA is a crucial process in the expression of the majority of genes. Alternative splicing allows a single gene to generate diverse mRNA and protein products. Aberrant RNA splicing is recognized as a molecular characteristic present in almost all types of tumors. Therefore, identifying cancer-specific subtypes from aberrant processing offers new opportunities for therapeutic development. Numerous splicing modulators, each utilizing different mechanisms, have been developed as promising anticancer therapies, some of which are in clinical trials. In this review, we summarize the splice-altered signatures of cancer cell transcriptomes and the contributions of splicing aberrations to tumorigenesis and progression. Especially, we discuss current and emerging RNA splicing-targeted strategies for cancer therapy, including pharmacological approaches and splice-switching antisense oligonucleotides (ASOs). Finally, we address the challenges and opportunities in translating these findings into clinical practice.
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Affiliation(s)
- Xuemei Lv
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110122, P. R. China
- Central Laboratory, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China
| | - Xiaoyu Sun
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110122, P. R. China
| | - Yang Gao
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110122, P. R. China
| | - Xinyue Song
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110122, P. R. China
| | - Xiaoyun Hu
- Scientific Experimental Center, School of Pharmacy, China Medical University, Shenyang, 110122, P. R. China
| | - Lang Gong
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110122, P. R. China
| | - Li Han
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110122, P. R. China.
- Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Shenyang, China.
| | - Miao He
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110122, P. R. China.
- Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Shenyang, China.
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110122, P. R. China.
- Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Shenyang, China.
- Shenyang Kangwei Medical Laboratory Analysis Co. LTD, Shenyang, China.
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Glaviano A, Lau HSH, Carter LM, Lee EHC, Lam HY, Okina E, Tan DJJ, Tan W, Ang HL, Carbone D, Yee MYH, Shanmugam MK, Huang XZ, Sethi G, Tan TZ, Lim LHK, Huang RYJ, Ungefroren H, Giovannetti E, Tang DG, Bruno TC, Luo P, Andersen MH, Qian BZ, Ishihara J, Radisky DC, Elias S, Yadav S, Kim M, Robert C, Diana P, Schalper KA, Shi T, Merghoub T, Krebs S, Kusumbe AP, Davids MS, Brown JR, Kumar AP. Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition. J Hematol Oncol 2025; 18:6. [PMID: 39806516 PMCID: PMC11733683 DOI: 10.1186/s13045-024-01634-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 11/11/2024] [Indexed: 01/16/2025] Open
Abstract
The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.
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Affiliation(s)
- Antonino Glaviano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Hannah Si-Hui Lau
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Lukas M Carter
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - E Hui Clarissa Lee
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Hiu Yan Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Elena Okina
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Donavan Jia Jie Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- School of Chemical and Life Sciences, Singapore Polytechnic, Singapore, 139651, Singapore
| | - Wency Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- School of Chemical and Life Sciences, Singapore Polytechnic, Singapore, 139651, Singapore
| | - Hui Li Ang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Daniela Carbone
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Michelle Yi-Hui Yee
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
| | - Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Xiao Zi Huang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Lina H K Lim
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
- Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, 117456, Singapore
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Ruby Yun-Ju Huang
- School of Medicine and Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan
- Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore
| | - Hendrik Ungefroren
- First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), Campus Lübeck, 23538, Lübeck, Germany
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, UMC, Vrije Universiteit, HV Amsterdam, 1081, Amsterdam, The Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana Per La Scienza, 56017, San Giuliano, Italy
| | - Dean G Tang
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
- Experimental Therapeutics (ET) Graduate Program, University at Buffalo & Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Tullia C Bruno
- Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Mads Hald Andersen
- National Center for Cancer Immune Therapy, Department of Oncology, Herlev and Gentofte Hospital, Herlev, Denmark
| | - Bin-Zhi Qian
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, The Human Phenome Institute, Zhangjiang-Fudan International Innovation Center, Fudan University, Shanghai, China
| | - Jun Ishihara
- Department of Bioengineering, Imperial College London, London, W12 0BZ, UK
| | - Derek C Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Salem Elias
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Saurabh Yadav
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Minah Kim
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Caroline Robert
- Department of Cancer Medicine, Inserm U981, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France
- Faculty of Medicine, University Paris-Saclay, Kremlin Bicêtre, Paris, France
| | - Patrizia Diana
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Kurt A Schalper
- Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, USA
| | - Tao Shi
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Taha Merghoub
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Department of Medicine, Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, NY, USA
| | - Simone Krebs
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anjali P Kusumbe
- Tissue and Tumor Microenvironment Group, MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Matthew S Davids
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jennifer R Brown
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
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Ji K, Jia H, Liu Z, Yu G, Wen R, Zhang T, Peng Z, Man W, Tian Y, Wang C, Ling Q, Zhang W, Zhou L, Liu M, Zhu B. New insight in immunotherapy and combine therapy in colorectal cancer. Front Cell Dev Biol 2025; 12:1453630. [PMID: 39839672 PMCID: PMC11747282 DOI: 10.3389/fcell.2024.1453630] [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: 06/24/2024] [Accepted: 12/18/2024] [Indexed: 01/23/2025] Open
Abstract
The advent of immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC) treatment marks a major breakthrough. These therapies have proven safer and more effective than traditional radiotherapy and targeted treatments. Immunotherapies like pembrolizumab, nivolumab, and ipilimumab have pioneered new treatment avenues, potentially improving patient outcomes and quality of life. Additionally, advances in immunotherapy have prompted detailed research into CRC therapies, especially those integrating ICIs with conventional treatments, providing new hope for patients and shaping future research and practice. This review delves into the mechanisms of various ICIs and evaluates their therapeutic potential when combined with radiotherapy, chemotherapy, and targeted therapies in clinical settings. It also sheds light on the current application and research involving ICIs in CRC treatment.
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Affiliation(s)
- Kai Ji
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
- Department of Colorectal Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Hang Jia
- Department of Colorectal Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zixuan Liu
- Department of Colorectal Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Guanyu Yu
- Department of Colorectal Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Rongbo Wen
- Department of Colorectal Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Tianshuai Zhang
- Department of Colorectal Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhiying Peng
- Department of Colorectal Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Wenjiang Man
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
- Department of Colorectal Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yucheng Tian
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
- Department of Colorectal Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Can Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
- Department of Colorectal Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Qianlong Ling
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
| | - Wei Zhang
- Department of Colorectal Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Leqi Zhou
- Department of Colorectal Surgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China
| | - Mulin Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
| | - Bing Zhu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
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Trepka KR, Olson CA, Upadhyay V, Zhang C, Turnbaugh PJ. Pharma[e]cology: How the Gut Microbiome Contributes to Variations in Drug Response. Annu Rev Pharmacol Toxicol 2025; 65:355-373. [PMID: 39107044 PMCID: PMC11864876 DOI: 10.1146/annurev-pharmtox-022724-100847] [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: 08/09/2024]
Abstract
Drugs represent our first, and sometimes last, line of defense for many diseases, yet despite decades of research we still do not fully understand why a given drug works in one patient and fails in the next. The human gut microbiome is one of the missing puzzle pieces, due to its ability to parallel and extend host pathways for drug metabolism, along with more complex host-microbiome interactions. Herein, we focus on the well-established links between the gut microbiome and drugs for heart disease and cancer, plus emerging data on neurological disease. We highlight the interdisciplinary methods that are available and how they can be used to address major remaining knowledge gaps, including the consequences of microbial drug metabolism for treatment outcomes. Continued progress in this area promises fundamental biological insights into humans and their associated microbial communities and strategies for leveraging the microbiome to improve the practice of medicine.
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Affiliation(s)
- Kai R Trepka
- Department of Microbiology & Immunology, University of California, San Francisco, California, USA;
| | - Christine A Olson
- Department of Microbiology & Immunology, University of California, San Francisco, California, USA;
| | - Vaibhav Upadhyay
- Department of Medicine, University of California, San Francisco, California, USA
- Department of Microbiology & Immunology, University of California, San Francisco, California, USA;
| | - Chen Zhang
- Department of Microbiology & Immunology, University of California, San Francisco, California, USA;
| | - Peter J Turnbaugh
- Chan Zuckerberg Biohub San Francisco, San Francisco, California, USA
- Department of Microbiology & Immunology, University of California, San Francisco, California, USA;
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30
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Chang C, Cai Z, Cheng K, Shen C, Zhang B, Chen Z, Yin Y, Cao D. Efficacy and safety of S-1 plus oxaliplatin combined with apatinib and camrelizumab as neoadjuvant therapy for patients with locally advanced gastric or gastroesophageal junction adenocarcinoma: a protocol for a single-arm phase II trial. Updates Surg 2025; 77:165-174. [PMID: 39738886 DOI: 10.1007/s13304-024-02052-6] [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: 08/12/2023] [Accepted: 11/27/2024] [Indexed: 01/02/2025]
Abstract
Gastric cancer, as the fifth most diagnosed malignancy and the fourth leading cause of cancer-related death globally, remains a significant health concern. The potential effect of the programmed death-1 (PD-1) inhibitor, when used alongside chemotherapy and antiangiogenic agents in neoadjuvant therapy for gastric cancer, has yet to be explored in the published literature. This study aims to evaluate the efficacy and safety of the S-1 plus oxaliplatin (SOX) regimen when combined with apatinib and camrelizumab (SOXAC) as neoadjuvant therapy for patients with locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. A single-arm, open-label, single-center phase II clinical trial has been designed to evaluate the safety and efficacy of the SOXAC regimen as neoadjuvant therapy for patients diagnosed with locally advanced gastric or GEJ adenocarcinoma (cT2-3N + M0 or T4NxM0). Eligible patients are to receive 2 cycles of SOXAC and 1 cycle of SOX regimen with camrelizumab (SOXC) as neoadjuvant therapy prior to radical surgery, and 3 cycles of SOXC as postoperative adjuvant therapy. The primary endpoint is major pathological remission (MPR), while secondary endpoints include pathological complete response (pCR) rate, R0 resection rate, objective response rate (ORR), operation-related outcomes, and safety. The SOX regimen remains a leading choice for neoadjuvant chemotherapy in Eastern countries. Recent studies suggest that combining chemotherapy, targeted agents, and immune checkpoint inhibitors can enhance the antitumor immune response. This phase II clinical trial seeks to assess the safety and efficacy of the SOXAC regimen as neoadjuvant therapy for patients with locally advanced resectable gastric or GEJ adenocarcinoma, while also exploring the correlation between biomarkers and efficacy.Trial Registration Chinese Clinical Trial Registry (ChiCTR): ChiCTR2200062285 ( https://www.chictr.org.cn/ ).
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Affiliation(s)
- Chen Chang
- Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center and State Key Laboratory of Biological Therapy, West China Hospital, Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Zhaolun Cai
- Gastric Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Ke Cheng
- Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center and State Key Laboratory of Biological Therapy, West China Hospital, Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Chaoyong Shen
- Gastric Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Bo Zhang
- Gastric Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Zhixin Chen
- Gastric Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Yuan Yin
- Gastric Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China.
| | - Dan Cao
- Division of Abdominal Tumor, Department of Medical Oncology, Cancer Center and State Key Laboratory of Biological Therapy, West China Hospital, Sichuan University, No.37 Guoxue Alley, Chengdu, 610041, Sichuan, China.
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31
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Zhang X, Shen J, Huang M, Li R. Efficacy and safety of adding immune checkpoint inhibitors to first-line standard therapy for recurrent or advanced cervical cancer: a meta-analysis of phase 3 clinical trials. Front Immunol 2024; 15:1507977. [PMID: 39712004 PMCID: PMC11659232 DOI: 10.3389/fimmu.2024.1507977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 11/20/2024] [Indexed: 12/24/2024] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) combined with standard therapy (ST) have emerged as a novel treatment strategy for recurrent or advanced cervical cancer (r/a CC). However, the available data from phase 3 clinical trials have yielded mixed results. This study aims to evaluate the therapeutic efficacy and safety of adding ICIs to ST in the treatment of r/a CC. Methods Data from four phase 3 clinical trials (KEYNOTE-826, CALLA, BEATcc, and ENGOT-cx11/GOG-3047/KEYNOTE-A18), involving 2,857 patients, were analyzed. Meta-analyses were conducted to combine hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), odds ratios (ORs) for the objective response rate (ORR), and relative risks (RRs) for adverse events (AEs). Results The addition of ICIs to ST significantly improved PFS (HR, 0.67; 95% CI, 0.60-0.75), OS (HR, 0.66; 95% CI, 0.58-0.75), and ORR (OR, 1.48; 95% CI, 1.13-1.94) compared to ST alone. However, there was a modest increase in grade 3-5 AEs (RR, 1.08; 95% CI, 1.03-1.13) with the combined therapy. Conclusion This meta-analysis indicates that the combination of ICIs with ST in the treatment of r/a CC not only demonstrates superior efficacy over ST alone but also maintains a comparable toxicity profile, offering strong evidence for an effective and relatively safe treatment approach for managing this disease. Systematic Review Registration https://www.crd.york.ac.uk/prospero/, identifier CRD42024593895.
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Affiliation(s)
- Xinmiao Zhang
- College of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
- Department of Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jinhai Shen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China
- Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Mengfan Huang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China
- Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Rongxia Li
- College of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
- Department of Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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32
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Hu J, Zhang J, Wan S, Zhang P. Neoadjuvant immunotherapy for non-small cell lung cancer: Opportunities and challenges. CHINESE MEDICAL JOURNAL PULMONARY AND CRITICAL CARE MEDICINE 2024; 2:224-239. [PMID: 39834585 PMCID: PMC11742355 DOI: 10.1016/j.pccm.2024.11.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Indexed: 01/22/2025]
Abstract
Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for resectable non-small cell lung cancer. Numerous trials have explored the use of ICIs, either as monotherapy or in combination with other therapies, in the neoadjuvant setting for stage I-III non-small cell lung cancer. Most trials have demonstrated neoadjuvant immunotherapy to be safe and to have remarkable efficacy, with a high pathological response rate and significantly improved event-free survival. This review summarizes the findings of Phase I-III clinical trials investigating various neoadjuvant regimens, including ICI monotherapy, ICI therapy combined with chemotherapy, ICI plus anti-angiogenic therapy, dual ICI therapy, and ICI therapy in combination with radiotherapy or chemoradiotherapy. We discuss the benefits and outcomes associated with each approach. Despite the results being promising, several unresolved issues remain, including identification of reliable biomarkers, the appropriate duration of therapy, the optimal treatment regimen for tumors with high programmed cell death ligand 1 (PD-L1) expression, the false-negative pathological complete response rate, and the role of digital pathology in assessing the response to treatment. Resistance to immunotherapy, in particular, remains a significant barrier to effective use of ICIs. Given the critical influence of the tumor microenvironment (TME) on the response to treatment, we examine the characteristics of the TME in both responsive and resistant tumors as well as the dynamic changes that occur in the TME in response to neoadjuvant immunotherapy. We also summarize the mechanisms underlying T cell responses following neoadjuvant immunotherapy and provide a perspective on strategies to enhance the understanding of tumor heterogeneity, therapy-driven TME remodeling, and overcoming resistance to therapy. Finally, we propose future directions for advancements in personalized neoadjuvant immunotherapy.
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Affiliation(s)
- Junjie Hu
- School of Medicine, Tongji University, Shanghai 200092, China
| | - Jing Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Shiyue Wan
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
| | - Peng Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
- The 1st School of Medicine, the 1st Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Department of Thoracic Surgery, The First Affiliated Hospital of Shihezi University Medical College, Shihezi, Xinjiang 832000, China
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Tasis A, Papaioannou NE, Grigoriou M, Paschalidis N, Loukogiannaki C, Filia A, Katsiki K, Lamprianidou E, Papadopoulos V, Rimpa CM, Chatzigeorgiou A, Kourtzelis I, Gerasimou P, Kyprianou I, Costeas P, Liakopoulos P, Liapis K, Kolovos P, Chavakis T, Alissafi T, Kotsianidis I, Mitroulis I. Single-Cell Analysis of Bone Marrow CD8+ T Cells in Myeloid Neoplasms Reveals Pathways Associated with Disease Progression and Response to Treatment with Azacitidine. CANCER RESEARCH COMMUNICATIONS 2024; 4:3067-3083. [PMID: 39485042 PMCID: PMC11616010 DOI: 10.1158/2767-9764.crc-24-0310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 09/13/2024] [Accepted: 10/29/2024] [Indexed: 11/03/2024]
Abstract
Immunophenotypic analysis identified a BM CD57+CXCR3+ subset of CD8+ T cells associated with response to AZA in patients with MDS and AML. Single-cell RNA sequencing analysis revealed that IFN signaling is linked to the response to treatment, whereas TGF-β signaling is associated with treatment failure, providing insights into new therapeutic approaches.
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Affiliation(s)
- Athanasios Tasis
- Translational Research and Laboratory Medicine Unit, First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
- Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
| | - Nikos E. Papaioannou
- Laboratory of Immune Regulation, Center of Basic Sciences, Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - Maria Grigoriou
- Translational Research and Laboratory Medicine Unit, First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
- Laboratory of Autoimmunity and Inflammation, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - Nikolaos Paschalidis
- Laboratory of Autoimmunity and Inflammation, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - Catherine Loukogiannaki
- Laboratory of Autoimmunity and Inflammation, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - Anastasia Filia
- Translational Research and Laboratory Medicine Unit, First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
- Laboratory of Autoimmunity and Inflammation, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - Kyriaki Katsiki
- Translational Research and Laboratory Medicine Unit, First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
| | - Eleftheria Lamprianidou
- Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
| | - Vasileios Papadopoulos
- Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
| | - Christina Maria Rimpa
- Translational Research and Laboratory Medicine Unit, First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
- Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioannis Kourtzelis
- Hull York Medical School, York Biomedical Research Institute, University of York, York, United Kingdom
| | | | - Ioannis Kyprianou
- Molecular Hematology-Oncology, Karaiskakio Foundation, Nicosia, Cyprus
| | - Paul Costeas
- Molecular Hematology-Oncology, Karaiskakio Foundation, Nicosia, Cyprus
| | - Panagiotis Liakopoulos
- Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
| | - Konstantinos Liapis
- Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
| | - Petros Kolovos
- Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany
- National Center for Tumor Diseases, Partner Site Dresden, Dresden, Germany
| | - Themis Alissafi
- Laboratory of Immune Regulation, Center of Basic Sciences, Biomedical Research Foundation Academy of Athens, Athens, Greece
- Laboratory of Biology, School of Medicine, Athens, Greece
| | - Ioannis Kotsianidis
- Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
| | - Ioannis Mitroulis
- Translational Research and Laboratory Medicine Unit, First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
- Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany
- National Center for Tumor Diseases, Partner Site Dresden, Dresden, Germany
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Landre T, Chouaïd C, Sadaoui N, Bouharati D, Taleb C. Clinical benefit of anti-PD-1/PD-L1 plus chemotherapy in first-line treatment for patients over the age of 65 or 75 with metastatic non-small cell lung cancer (NSCLC). J Chemother 2024; 36:675-681. [PMID: 38303601 DOI: 10.1080/1120009x.2024.2308978] [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: 10/25/2023] [Revised: 01/16/2024] [Accepted: 01/17/2024] [Indexed: 02/03/2024]
Abstract
Anti-PD-1/PD-L1 plus chemotherapy (CT) is considered the standard of care in first line treatment of metastatic NSCLC. However, the clinical benefit of this combination in older patients is controversial. We performed a meta-analysis of phase III randomized trials that compared PD-1/PD-L1 inhibitor plus CT with CT alone in first line of treatment for older patients with advanced NSCLC. Subgroups of patients over 65 and over 75 were analyzed. The outcomes included overall survival (OS) and progression-free survival (PFS). A fixedeffect model was used. We analyzed ten trials with an anti-PD-1 (camrelizumab, cemiplimab, nivolumab, pembrolizumab, tislelizumab or toripalimab) and six trials with an anti-PD-L1 (atezolizumab, durvalumab or sugemalimab), including 3666 patients over the age of 65 (41%) and 282 patients over the age of 75 (<10%). For patients over 65 years of age, anti-PD- 1/PD-L1 + CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.79 [0.72-0.86]; p < 0.00001) and P FS (0.63 [0.58-0.68]; p < 0.00001) compared to CT alone. Survival benefits occurred in both anti-PD-1 and anti-PD-L1 trials. For patients over 75 years of age, OS benefit was not statistically significant (0.88 [0.67-1.16]; p = 0.37). For patients over the age of 65 with untreated NSCLC, the anti-PD-1/PD-L1 combination with CT, compared with CT alone, is associated with significantly improved OS and PFS. Due to the low number of patients, it is difficult to conclude for those over 75.
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Affiliation(s)
- Thierry Landre
- Department of Ucog, Hôpital René Muret - AP HP, Sevran, France
| | - Christos Chouaïd
- Department of Pneumology, CH intercommunal Créteil, France
- Inserm U955, UPEC, IMRB, Créteil, France
| | - Nassyma Sadaoui
- Department of Geriatric, Hôpital René Muret - AP HP, Sevran, France
| | - Djamila Bouharati
- Department of Geriatric Oncology, Hôpital René Muret - AP HP, Sevran, France
| | - Chérifa Taleb
- Department of Ucog, Hôpital René Muret - AP HP, Sevran, France
- Department of Geriatric, Hôpital René Muret - AP HP, Sevran, France
- Department of Geriatric Oncology, Hôpital René Muret - AP HP, Sevran, France
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Lin Y, Shen W, Ye J, Luo H, Zhang X, Xu Y, Lin Q, Liu W, Zhang Y, Xu Y, Jiang W, Zhao L, Liu A, Wu L, Ge H, Xie C, Zhao K, Chen J, Wang L, Liu Q. Effectiveness and safety of first-line pembrolizumab plus chemotherapy in patients with advanced/recurrent or metastatic esophageal squamous cell carcinoma in China: a real-world multicenter study. Ther Adv Med Oncol 2024; 16:17588359241297092. [PMID: 39563718 PMCID: PMC11574897 DOI: 10.1177/17588359241297092] [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: 07/29/2024] [Accepted: 10/14/2024] [Indexed: 11/21/2024] Open
Abstract
Background There are currently limited real-world data on the effectiveness and safety of first-line pembrolizumab combined with chemotherapy in patients with advanced/recurrent or metastatic esophageal squamous cell carcinoma (ESCC) in China. This study was conducted to address this knowledge gap. Methods This multicenter retrospective cohort study was conducted at 17 hospitals in China and included adults (⩾18 years) with stage IV primary ESCC, or recurring 6 months after radical radiotherapy/surgery-based combination therapy, who had received first-line pembrolizumab plus chemotherapy. Data were collected from electronic medical records. Endpoints included objective response rate (ORR), disease control rate (DCR) progression-free survival (PFS), overall survival (OS), and safety. Subgroup analyses were conducted to identify patient characteristics and treatment patterns associated with treatment response. Results In total, 202 patients who had received treatment from 2018 to 2023 were included: 125 (61.9%) newly diagnosed and 77 (38.1%) with recurrence, 181 (89.1%) were male. Pembrolizumab was most commonly combined with paclitaxel + platinum (69.8%) or fluorouracil + platinum (19.3%). After a median follow-up of 22.6 months (95% confidence interval (CI) 20.1-25.4), the ORR and DCR were 60.9% and 87.6% and the median PFS and OS were 10.8 months (95% CI 9.1-13.5) and 17.3 months (95% CI 14.9-19.9), respectively. OS was similar in patients with treatment-naïve and recurrent disease. Among the combination chemotherapy regimens, paclitaxel + platinum was associated with the longest median OS (18.2 months, 95% CI 16.1-22.5). Favorable survival outcomes were observed in patients with oligometastases. No new safety signals were observed. Conclusion These real-world data indicate that the first-line treatment with pembrolizumab plus chemotherapy is effective and safe in Chinese patients with advanced ESCC and show that paclitaxel + platinum is the most commonly used and most effective partner chemotherapy in China.
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Affiliation(s)
- Yu Lin
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center Fujian Hospital, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Wenbin Shen
- Radiotherapy Department of Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jinjun Ye
- Department of Radiotherapy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - Honglei Luo
- Department of Radiation Oncology, Huai'an First People's Hospital, Huai'an, China
| | - Xizhi Zhang
- Department of Oncology, The Northern Jiangsu People's Hospital, Yangzhou, China
| | - Yuanji Xu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center Fujian Hospital, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Qin Lin
- Department of Radiotherapy, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Wenyang Liu
- Department of Radiotherapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yingying Zhang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Yujin Xu
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Wei Jiang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Lina Zhao
- Department of Radiation Oncology, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - Anwen Liu
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Lei Wu
- Department of Radiation Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Hong Ge
- Department of Radiation Oncology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Conghua Xie
- Department of Pulmonary Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Kuaile Zhao
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Junqiang Chen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center Fujian Hospital, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, 420 Fuma Road, Jin'an District, Fuzhou 350014, China
| | - Luhua Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 113 Baohe Road, Longgang District, Shenzhen 518116, China
| | - Qi Liu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
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Rousseau A, Géraud A, Geiss R, Farcet A, Spano JP, Hamy AS, Gougis P. Safety of solid oncology drugs in older patients: a narrative review. ESMO Open 2024; 9:103965. [PMID: 39481329 PMCID: PMC11567126 DOI: 10.1016/j.esmoop.2024.103965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/19/2024] [Accepted: 09/23/2024] [Indexed: 11/02/2024] Open
Abstract
The older population represents ∼50%-60% of the population of newly diagnosed patients with cancer. Due to physiological and pathological aging and the increased presence of comorbidities and frailty factors, this population is at higher risk of serious toxicity from anticancer drugs and, consequently, often under-treated. Despite the complexity of these treatments, a good knowledge of the pharmacology of anticancer drugs and potentially risky situations can limit the emergence of potentially lethal toxicities in this population. This review focuses on optimizing systemic oncology treatments for older patients, emphasizing the unique characteristics of each therapeutic class and the necessity for a precautionary approach for this vulnerable population.
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Affiliation(s)
- A Rousseau
- Department of Medical Oncology, Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France
| | - A Géraud
- Department of Medical Oncology, Institut Paoli-Calmette, Marseille, France
| | - R Geiss
- Department of Medical Oncology, Institut Curie, Université Paris Cité, Paris, France
| | - A Farcet
- Department of Medical Oncology, Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France
| | - J-P Spano
- Department of Medical Oncology, Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France
| | - A-S Hamy
- Department of Medical Oncology, Institut Curie, Université Paris Cité, Paris, France; Residual Tumor and Response to Treatment, RT2Lab, INSERM, U932 Cancer & Immunity, Institut Curie, Université Paris Sciences Lettres, Paris, France
| | - P Gougis
- Department of Medical Oncology, Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France; Residual Tumor and Response to Treatment, RT2Lab, INSERM, U932 Cancer & Immunity, Institut Curie, Université Paris Sciences Lettres, Paris, France; Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Paris (AP-HP), Centre d'Investigation Clinique (CIC-1901), Pharmacology Department, Pitié-Salpêtrière Hospital, Paris, France.
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Chen X, Zhang D, Ou H, Su J, Wang Y, Zhou F. Bulk and single-cell RNA sequencing analyses coupled with multiple machine learning to develop a glycosyltransferase associated signature in colorectal cancer. Transl Oncol 2024; 49:102093. [PMID: 39217850 PMCID: PMC11402624 DOI: 10.1016/j.tranon.2024.102093] [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: 01/21/2024] [Revised: 07/10/2024] [Accepted: 08/11/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND This study aims to identify key glycosyltransferases (GTs) in colorectal cancer (CRC) and establish a robust prognostic signature derived from GTs. METHODS Utilizing the AUCell, UCell, singscore, ssgsea, and AddModuleScore algorithms, along with correlation analysis, we redefined genes related to GTs in CRC at the single-cell RNA level. To improve risk model accuracy, univariate Cox and lasso regression were employed to discover a more clinically subset of GTs in CRC. Subsequently, the efficacy of seven machine learning algorithms for CRC prognosis was assessed, focusing on survival outcomes through nested cross-validation. The model was then validated across four independent external cohorts, exploring variations in the tumor microenvironment (TME), response to immunotherapy, mutational profiles, and pathways of each risk group. Importantly, we identified potential therapeutic agents targeting patients categorized into the high-GARS group. RESULTS In our research, we classified CRC patients into distinct subgroups, each exhibiting variations in prognosis, clinical characteristics, pathway enrichments, immune infiltration, and immune checkpoint genes expression. Additionally, we established a Glycosyltransferase-Associated Risk Signature (GARS) based on machine learning. GARS surpasses traditional clinicopathological features in both prognostic power and survival prediction accuracy, and it correlates with higher malignancy levels, providing valuable insights into CRC patients. Furthermore, we explored the association between the risk score and the efficacy of immunotherapy. CONCLUSION A prognostic model based on GTs was developed to forecast the response to immunotherapy, offering a novel approach to CRC management.
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Affiliation(s)
- Xin Chen
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China; Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, PR China; Hubei Clinical Cancer Study Center, Zhongnan Hospital, Wuhan University, PR China
| | - Dan Zhang
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China; Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, PR China; Hubei Clinical Cancer Study Center, Zhongnan Hospital, Wuhan University, PR China
| | - Haibin Ou
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China; Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, PR China; Hubei Clinical Cancer Study Center, Zhongnan Hospital, Wuhan University, PR China
| | - Jing Su
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China; Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, PR China; Hubei Clinical Cancer Study Center, Zhongnan Hospital, Wuhan University, PR China
| | - You Wang
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China; Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, PR China; Hubei Clinical Cancer Study Center, Zhongnan Hospital, Wuhan University, PR China.
| | - Fuxiang Zhou
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China; Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital, Wuhan University, Wuhan, PR China; Hubei Clinical Cancer Study Center, Zhongnan Hospital, Wuhan University, PR China.
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Zang J, Shahatiaili A, Cai MC, Jin D, Shen P, Qian L, Zhang L, Zhang T, Wu Y, Yang F, Wu Z, Hou Y, Bai Y, Xia J, Cheng L, Zhang R, Zhuang G, Chen H. Genomic Profiling and Immune Phenotyping of Neuroendocrine Bladder Cancer. Clin Cancer Res 2024; 30:4920-4931. [PMID: 39226396 DOI: 10.1158/1078-0432.ccr-24-1277] [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: 04/22/2024] [Revised: 06/15/2024] [Accepted: 08/27/2024] [Indexed: 09/05/2024]
Abstract
PURPOSE Neuroendocrine bladder cancer (NEBC) poses a formidable clinical challenge and attracts keen interests to explore immunotherapy as a viable treatment option. However, a comprehensive immunogenomic landscape has yet to be thoroughly investigated. EXPERIMENTAL DESIGN Leveraging a long-term cohort of natural NEBC cases, we employed a multimodal approach integrating genomic (n = 19), transcriptomic (n = 3), single-cell RNA sequencing (n = 1), and IHC analyses (n = 34) to meticulously characterize the immunogenicity and immunotypes of primary NEBC tumors. Information on clinical, pathologic, medical imaging, and treatment aspects was retrospectively retrieved and analyzed. RESULTS Our study unveiled that despite a considerable mutational burden, NEBC was typically immunologically inactive, as manifested by the "immune-excluded" or "immune-desert" microenvironment. Interestingly, a subset of mixed NEBC with concurrent urothelial bladder cancer histology displayed an "immune-infiltrated" phenotype with prognostic relevance. When compared with urothelial bladder cancer, NEBC lesions were distinguished by a denser cellular composition and augmented peritumoral extracellular matrix, which might collectively impede lymphatic infiltration. As a result, single-agent immune checkpoint inhibitors demonstrated limited efficacy against NEBC, whereas pharmacologic immunostimulation with combination chemotherapy conferred a more favorable response. CONCLUSIONS These new insights derived from genomic profiling and immune phenotyping pave the way for rational immunotherapeutic interventions in patients with NEBC, with the potential to ultimately reduce mortality from this otherwise fatal disease.
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Affiliation(s)
- Jingyu Zang
- State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Akezhouli Shahatiaili
- State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mei-Chun Cai
- State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Di Jin
- State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Peiye Shen
- State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Qian
- State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lu Zhang
- State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tianxiang Zhang
- State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuchen Wu
- State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fan Yang
- Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zheng Wu
- State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanli Hou
- State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongrui Bai
- State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Xia
- Department of Pathology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, Department of Surgery (Urology), Brown University Warren Alpert Medical School, the Legorreta Cancer Center at Brown University, and Brown University Health, Providence, RI
| | - Ruiyun Zhang
- State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guanglei Zhuang
- State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haige Chen
- State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Lu Z, Li Y, Hu W, Cao Y, Lv X, Jia X, Shen S, Zhao J, Xu C. Radiomics nomogram combined with clinical factors for predicting pathological complete response in resectable esophageal squamous cell carcinoma. Front Oncol 2024; 14:1347650. [PMID: 39544301 PMCID: PMC11560869 DOI: 10.3389/fonc.2024.1347650] [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: 12/01/2023] [Accepted: 10/03/2024] [Indexed: 11/17/2024] Open
Abstract
Introduction Predicting the efficacy of neoadjuvant immunochemotherapy (NICT) for esophageal squamous cell carcinoma (ESSC) prior to surgery can minimize unnecessary surgical interventions and facilitate personalized treatment strategies. Our goal is to develop and validate an image-based radiomic model using preoperative computed tomography (CT) scans and clinical data to predict pathological complete response (pCR) in resectable ESSC following neoadjuvant immunotherapy. Methods We retrospectively collected data from patients diagnosed with ESCC at the First Affiliated Hospital of Soochow University between January 2018 and May 2023, who received preoperative neoadjuvant immunochemotherapy. Eligible patients were randomly divided into training and validation sets. Radiomic features extracted from preprocessed CT images were used to develop a radiomic model, incorporating Radiomic score (Rad-score) and clinical factors through multivariate logistic regression analysis. The model's performance was assessed for calibration, discrimination, and clinical utility in an independent validation cohort. Results We enrolled a total of 105 eligible participants who were randomly divided into two groups: a training set (N=74) and a validation set (N=31). After data dimension reduction and feature selection, we identified 11 radiomic features, which collectively formed the Rad-score. Rad-score had an area under the curve (AUC) of 0.83 (95% CI 0.72-0.93) in the training set and 0.78 (95% CI 0.60-0.95) in the validation set. Multivariate analysis revealed that radiological response and Neutrophil-Lymphocyte Ratio (NLR) were independent predictors of pCR, with p-values of 0.0026 and 0.0414, respectively. We developed and validated a nomogram combining Rad-score and clinical features, achieving AUCs of 0.90 (95% CI 0.82-0.98) in the training set and 0.85 (95% CI 0.70-0.99) in the validation set. The Delong test confirmed the nomogram's superiority over pure radiomic and clinical models. Decision curve analysis (DCA) and integrated discrimination improvement (IDI) assessment supported the clinical value and superiority of the combined model. Conclusion The nomogram, which integrates Rad-score and clinical features, offers a precise and reliable method for predicting pCR status in ESCC patients who have undergone neoadjuvant immunochemotherapy. This tool aids in tailoring treatment strategies to individual patients.
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Affiliation(s)
| | | | | | | | | | | | | | - Jun Zhao
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow
University, Suzhou, China
| | - Chun Xu
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow
University, Suzhou, China
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Liu Y, Deng Y, Yang C, Naranmandura H. Double-Faced Immunological Effects of CDK4/6 Inhibitors on Cancer Treatment: Challenges and Perspectives. Bioengineering (Basel) 2024; 11:1084. [PMID: 39593745 PMCID: PMC11591775 DOI: 10.3390/bioengineering11111084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 10/23/2024] [Accepted: 10/24/2024] [Indexed: 11/28/2024] Open
Abstract
Cyclin-dependent kinases (CDKs) are generally involved in the progression of cell cycle and cell division in normal cells, while abnormal activations of CDKs are deemed to be a driving force for accelerating cell proliferation and tumorigenesis. Therefore, CDKs have become ideal therapeutic targets for cancer treatment. The U.S FDA has approved three CDK4/6 inhibitors (CDK4/6is) for the treatment of patients with hormone receptor-positive (HR+) or human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer, and these drugs showed impressive results in clinics. Besides cell-cycle arrest, there is growing evidence that CDK4/6is exert paradoxical roles on cancer treatment by altering the immune system. Indeed, clinical data showed that CDK4/6is could change the immune system to exert antitumor effects, while these changes also caused tumor resistance to CDK4/6i. However, the molecular mechanism for the regulation of the immune system by CDK4/6is is unclear. In this review, we comprehensively discuss the paradoxical immunological effects of CDK4/6is in cancer treatment, elucidating their anticancer mechanisms through immunomodulatory activity and induction of acquired drug resistance by dysregulating the immune microenvironment. More importantly, we suggest a few strategies including combining CDK4/6is with immunotherapy to overcome drug resistance.
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Affiliation(s)
- Yongqin Liu
- Department of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
- Department of Hematology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Yiying Deng
- Department of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
- Department of Hematology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Chang Yang
- Department of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
- Department of Hematology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Hua Naranmandura
- Department of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
- Department of Hematology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
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Wang Y, Zhao Y, Zhang G, Lin Y, Fan C, Wei H, Chen S, Guan L, Liu K, Yu S, Fu L, Zhang J, Yuan Y, He J, Cai H. Pan-cancer and single-cell analysis reveal dual roles of lymphocyte activation gene-3 (LAG3) in cancer immunity and prognosis. Sci Rep 2024; 14:24203. [PMID: 39406840 PMCID: PMC11480387 DOI: 10.1038/s41598-024-74808-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 09/30/2024] [Indexed: 10/19/2024] Open
Abstract
Lymphocyte activating gene-3 (LAG3) is a distinctive T cell co-receptor that is expressed on the surface of lymphocytes. It plays a special inhibitory immune checkpoint role due to its unique domain and signaling pattern. Our aim is to explore the correlation between LAG3 in cancers and physiological processes related to a range of cancers, as well as build LAG3-related immunity and prognostic models. By comprehensively using of datasets and methods from TCGA, GTE-x and GEO databases, cBioPortal, HPA, Kaplan-Meier Plotter, Spearman, CellMinerTM, we delved deeper into the potential impact of the LAG3 in cancer development. These include expression differences, Localization of tumor cell subsets, immune infiltration, matrix infiltration, gene mutations, DNA methylation, signaling pathways and prognosis. Furthermore, we explored LAG3 interactions with different drugs. LAG3 is highly expressed in ACC (p < 0.001), BRCA (p < 0.001), DLBC (p < 0.001), ESCA (p < 0.001), GBM (p < 0.001), HNSC (p < 0.001), KIRC (p < 0.001), LGG (p < 0.001), LUAD (p < 0.01), LUSC (p < 0.001), PAAD (p < 0.001), PCPG (p < 0.01), SKCM (p < 0.001), STAD (p < 0.001), TGCT (p < 0.001) and THCA (p < 0.05), while lowly expressed in COAD (p < 0.001), LIHC (p < 0.05), OV (p < 0.001), PRAD (p < 0.001), READ (p < 0.001), UCEC (p < 0.001) and UCS (p < 0.001). High expression of LAG3 correlates with longer overall survival (OS) in BLCA (HR = 0.67, p < 0.05), CESC (HR = 0.3, p < 0.001), HNSC (HR = 0.67, p < 0.01), LUSC (HR = 0.71, p < 0.05), OV (HR = 0.65, p < 0.01), STAD (HR = 0.68, p < 0.05), and UCEC (HR = 0.57, p < 0.01). Conversely, in KIRC (HR = 1.85, p < 0.001), KIRP (HR = 2.81, p < 0.001), and THYM (HR = 8.92, p < 0.001), high LAG3 expression corresponds to shorter OS. Comprehensive results for recurrence-free survival (RFS) indicate that LAG3 acts as a protective factor in BLCA, CESC, OV, and UCEC. Moreover, LAG3 is widely expressed in tumor-associated lymphocytes, positively correlating with tumor immune scores and stromal scores, and significantly present in the C2 immune subtype across various tumors. High LAG3 expression correlates with increased immune infiltration. LAG3 shows associations with MSI, TMB, and the MMR system, participating in multiple signaling pathways including the T cell receptor pathway. It also demonstrates positive correlations with sensitivity to eleven different drugs. Unlike traditional inhibitory immune checkpoints, LAG3 exhibits dual roles in clinical and immune prognostication across pan-cancers, making it a significant predictive factor. In some cancers, LAG3 serves as a risk factor, indicating adverse clinical outcomes. Conversely, in BLCA, CESC, OV, and UCEC, LAG3 acts as a protective factor associated with longer patient survival. LAG3 demonstrates strong associations within tumor immunity, participating in a range of immune and inflammatory signaling pathways. Elevated levels of LAG3 are linked not only to T cell exhaustion but also to increased immune infiltration and polarization towards M1 macrophages.
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Affiliation(s)
- Yongfeng Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, China
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, 730000, Gansu, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, 204 Donggang West Road, Lanzhou, 730000, Gansu, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu, China
| | - Yanzong Zhao
- School of Stomatology, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Guangming Zhang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Yifeng Lin
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Chunling Fan
- School of Life Science, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Hui Wei
- School of Stomatology, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Shude Chen
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Ling Guan
- School of Stomatology, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Kan Liu
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Shenhan Yu
- School of Stomatology, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Liangyin Fu
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, China
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, 730000, Gansu, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, 204 Donggang West Road, Lanzhou, 730000, Gansu, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu, China
| | - Jing Zhang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Yuan Yuan
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, 204 Donggang West Road, Lanzhou, 730000, Gansu, China.
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu, China.
| | - Jin He
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, China.
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, 730000, Gansu, China.
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, 204 Donggang West Road, Lanzhou, 730000, Gansu, China.
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu, China.
| | - Hui Cai
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, China.
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, 730000, Gansu, China.
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, 204 Donggang West Road, Lanzhou, 730000, Gansu, China.
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu, China.
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Shang X, Xie Y, Yu J, Zhang C, Zhao G, Liang F, Liu L, Zhang W, Li R, Yu W, Yue J, Chen C, Duan X, Ma Z, Chen Z, Xiong Y, Yang F, Xiao J, Zhang R, Liu P, Cheng Y, Cao F, Guo F, Liu G, Meng B, Zhou D, Sun Y, Ren X, Yu J, Hao J, Jiang H. A prospective study of neoadjuvant pembrolizumab plus chemotherapy for resectable esophageal squamous cell carcinoma: The Keystone-001 trial. Cancer Cell 2024; 42:1747-1763.e7. [PMID: 39406186 DOI: 10.1016/j.ccell.2024.09.008] [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: 11/18/2023] [Revised: 06/13/2024] [Accepted: 09/16/2024] [Indexed: 11/15/2024]
Abstract
In this phase II study, 47 patients with locally advanced, resectable esophageal squamous cell carcinoma (ESCC) received three cycles of pembrolizumab plus chemotherapy, followed by Da Vinci robot-assisted surgery. The primary endpoints were safety and major pathological response (MPR). Key secondary endpoints included complete pathological response (pCR) and survival. No grade ≥3 adverse events or surgical delays occurred during neoadjuvant therapy. Among 46 patients studied for efficacy, the MPR and pCR rates were 72% and 41%, respectively. After a median follow-up of 27.2 months, the 2-year overall survival (OS) and disease-free survival (DFS) rates were 91% and 89%, respectively. Expansion of TRGC2+ NKT cells in peripheral blood correlated with neoadjuvant treatment effectiveness, which was validated by in vitro organoid experiments and external cancer datasets, and its functional classification and mechanism of action were further explored. These findings show preoperative pembrolizumab plus chemotherapy is a promising therapeutic strategy for resectable ESCC.
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Affiliation(s)
- Xiaobin Shang
- Department of Minimally Invasive Esophageal Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yongjie Xie
- The Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jinpu Yu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Chen Zhang
- Department of Minimally Invasive Esophageal Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Gang Zhao
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Fei Liang
- Department of Biostatistics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Liang Liu
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Weihong Zhang
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Runmei Li
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Wenwen Yu
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jie Yue
- Department of Minimally Invasive Esophageal Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Chuangui Chen
- Department of Minimally Invasive Esophageal Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Xiaofeng Duan
- Department of Minimally Invasive Esophageal Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Zhao Ma
- Department of Minimally Invasive Esophageal Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Zuoyu Chen
- Department of Minimally Invasive Esophageal Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yanjuan Xiong
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Fan Yang
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jianyu Xiao
- Department of Radiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Rui Zhang
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Pengpeng Liu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yanan Cheng
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Fuliang Cao
- Department of Endoscopy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Feng Guo
- Department of Endoscopy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Guoyan Liu
- Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Bin Meng
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Dejun Zhou
- Department of Endoscopy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yan Sun
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Xiubao Ren
- Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China; Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
| | - Jun Yu
- The Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
| | - Jihui Hao
- The Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
| | - Hongjing Jiang
- Department of Minimally Invasive Esophageal Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
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43
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Zhang XD, Xu XY, Zhong YS, Zhang ZY, Jin LH, Luo JC, Ye F, Ni JH, Chen J, Chen GZ, Qian JC, Liu ZG. New drug combination regimen based on pharmacokinetic characteristics-Erdafitinib combined with sertraline or duloxetine. Biomed Pharmacother 2024; 179:117414. [PMID: 39260324 DOI: 10.1016/j.biopha.2024.117414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/28/2024] [Accepted: 09/04/2024] [Indexed: 09/13/2024] Open
Abstract
The aim of this study is to investigate novel strategies for reducing adverse reactions caused by erdafitinib through a drug combination based on its pharmacokinetic characteristics. The spectrum and characterizations of drugs that can inhibit the metabolism of erdafitinib are examined both in vitro and in vivo. The efficacy of combination regimens are then evaluated using subcutaneous xenograft tumor models. The results demonstrated that sertraline and duloxetine, out of more than 100 screened drugs, inhibited the metabolism of erdafitinib through mixed and non-competitive inhibition, respectively. This inhibition primarily occurred via the CYP2C9 and CYP2D6 pathways. The primary alleles of CYP2C9 and CYP2D6 not only determine the metabolic characteristics of erdafitinib but also influence the strength of drug-drug interactions. Co-administration of sertraline or duloxetine with erdafitinib in rats and mice resulted in nearly a three-fold increase in the blood exposure of erdafitinib and its major metabolite M6. When sertraline or duloxetine was combined with 1/3 of the erdafitinib dosage, the anti-proliferative and pro-apoptotic effects on SNU-16 xenografts were comparable to those of the original full dose of erdafitinib. However, the combination regimen significantly mitigated hyperphosphatemia, retinal damage, intestinal villus damage, and gut microbiome dysbiosis. This study utilized pharmacokinetic methods to propose a new formulation of erdafitinib combined with sertraline or duloxetine. The findings suggest that this combination has potential for clinical co-administration based on a database analysis, thereby providing a novel strategy for anti-tumor treatment with fibroblast growth factor receptor (FGFR) inhibitors.
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Affiliation(s)
- Xiao-Dan Zhang
- Department of Behavioral Medicine, Wenzhou Seventh People's Hospital, Wenzhou, Zhejiang, China; Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiao-Yu Xu
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yun-Shan Zhong
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhe-Yan Zhang
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Le-Hao Jin
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jian-Chao Luo
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Feng Ye
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jin-Huan Ni
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jing Chen
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Gao-Zhi Chen
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jian-Chang Qian
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Zhi-Guo Liu
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
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Liu JJ, Pan ZD, Yue YL, Wang SS, Chen J, Jiang H, Zhang BH, Wu MY, Yuan YS, Bian YL, Yin HY, Wang L, Li JY, Gilly J, Xie YQ, Zhu JW. T cell-redirecting antibody for treatment of solid tumors via targeting mesothelin. Acta Pharmacol Sin 2024; 45:2186-2198. [PMID: 38858494 PMCID: PMC11420237 DOI: 10.1038/s41401-024-01316-6] [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: 02/22/2024] [Accepted: 05/15/2024] [Indexed: 06/12/2024]
Abstract
T cell engaging bispecific antibodies (TCBs) have recently become significant in cancer treatment. In this study we developed MSLN490, a novel TCB designed to target mesothelin (MSLN), a glycosylphosphatidylinositol (GPI)-linked glycoprotein highly expressed in various cancers, and evaluated its efficacy against solid tumors. CDR walking and phage display techniques were used to improve affinity of the parental antibody M912, resulting in a pool of antibodies with different affinities to MSLN. From this pool, various bispecific antibodies (BsAbs) were assembled. Notably, MSLN490 with its IgG-[L]-scFv structure displayed remarkable anti-tumor activity against MSLN-expressing tumors (EC50: 0.16 pM in HT-29-hMSLN cells). Furthermore, MSLN490 remained effective even in the presence of non-membrane-anchored MSLN (soluble MSLN). Moreover, the anti-tumor activity of MSLN490 was enhanced when combined with either Atezolizumab or TAA × CD28 BsAbs. Notably, a synergistic effect was observed between MSLN490 and paclitaxel, as paclitaxel disrupted the immunosuppressive microenvironment within solid tumors, enhancing immune cells infiltration and improved anti-tumor efficacy. Overall, MSLN490 exhibits robust anti-tumor activity, resilience to soluble MSLN interference, and enhanced anti-tumor effects when combined with other therapies, offering a promising future for the treatment of a variety of solid tumors. This study provides a strong foundation for further exploration of MSLN490's clinical potential.
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Affiliation(s)
- Jun-Jun Liu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Zhi-di Pan
- Jecho Institute, Shanghai, 200240, China
| | - Ya-Li Yue
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | | | - Jie Chen
- Jecho Institute, Shanghai, 200240, China
| | - Hua Jiang
- Jecho Laboratories, Inc., Frederick, MD, 21704, USA
- Jecho Biopharmaceuticals Co., Ltd, Tianjin, 300450, China
| | - Bao-Hong Zhang
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Ming-Yuan Wu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yun-Sheng Yuan
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yan-Lin Bian
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | | | - Lei Wang
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Jun-Yan Li
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - John Gilly
- Jecho Biopharmaceuticals Co., Ltd, Tianjin, 300450, China
| | - Yue-Qing Xie
- Jecho Institute, Shanghai, 200240, China.
- Jecho Laboratories, Inc., Frederick, MD, 21704, USA.
| | - Jian-Wei Zhu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
- Jecho Institute, Shanghai, 200240, China.
- Jecho Laboratories, Inc., Frederick, MD, 21704, USA.
- Jecho Biopharmaceuticals Co., Ltd, Tianjin, 300450, China.
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Zeng L, Zhu Y, Cui X, Chi J, Uddin A, Zhou Z, Song X, Dai M, Cristofanilli M, Kalinsky K, Wan Y. Tuning Immune-Cold Tumor by Suppressing USP10/B7-H4 Proteolytic Axis Reinvigorates Therapeutic Efficacy of ADCs. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2400757. [PMID: 39206932 PMCID: PMC11516061 DOI: 10.1002/advs.202400757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 08/04/2024] [Indexed: 09/04/2024]
Abstract
Tuning immune-cold tumor hot has largely attracted attention to improve cancer treatment, including immunotherapy and antibody-drug conjugates (ADCs). Utilizing multiomic analyses and experimental validation, this work identifies a pivotal role for the USP10/B7-H4 proteolytic axis in mediating the interplay between tumor immune responses and ADC efficacy, particularly for sacituzumab govitecan (SG) in treating triple negative breast cancers (TNBCs). Mechanistically, the inhibition of autocrine motility factor receptor (AMFR)-mediated ubiquitylation of B7-H4 by the deubiquitinase USP10 leads to the stabilization of B7-H4, which suppresses tumor immune activity and reduces SG treatment effectiveness. Pharmacological inhibition of USP10 promotes the degradation of B7-H4, enhancing tumor immunogenicity and consequently improving the tumor-killing efficacy of SG. In preclinical TNBC models, suppression of USP10/B7-H4 proteolytic axis is effective in increasing SG killing efficacy and reducing tumor growth, especially for the tumors with the USP10high/B7-H7high signature. Collectively, these findings uncover a novel strategy for targeting the immunosuppressive molecule B7-H4 for cancer therapy.
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Affiliation(s)
- Lidan Zeng
- Department of Pharmacology and Chemical BiologyEmory University School of MedicineAtlantaGA30322USA
- Winship Cancer InstituteEmory University School of MedicineAtlantaGA30322USA
| | - Yueming Zhu
- Department of Pharmacology and Chemical BiologyEmory University School of MedicineAtlantaGA30322USA
- Winship Cancer InstituteEmory University School of MedicineAtlantaGA30322USA
| | - Xin Cui
- Department of Pharmacology and Chemical BiologyEmory University School of MedicineAtlantaGA30322USA
- Winship Cancer InstituteEmory University School of MedicineAtlantaGA30322USA
| | - Junlong Chi
- Department of Pharmacology and Chemical BiologyEmory University School of MedicineAtlantaGA30322USA
- DGP graduate programNorthwestern University Feinberg School of MedicineChicagoIL60611USA
| | - Amad Uddin
- Department of Pharmacology and Chemical BiologyEmory University School of MedicineAtlantaGA30322USA
- Winship Cancer InstituteEmory University School of MedicineAtlantaGA30322USA
| | - Zhuan Zhou
- Department of SurgeryUT Southwestern Medical CenterDallasTX75390USA
| | - Xinxin Song
- Department of SurgeryUT Southwestern Medical CenterDallasTX75390USA
| | - Mingji Dai
- Department of Pharmacology and Chemical BiologyEmory University School of MedicineAtlantaGA30322USA
- Department of ChemistryCollege of Arts and ScienceEmory UniversityAtlantaGA30322USA
| | | | - Kevin Kalinsky
- Winship Cancer InstituteEmory University School of MedicineAtlantaGA30322USA
- Department of Hematology and Medical OncologyEmory University School of MedicineAtlantaGA30322USA
| | - Yong Wan
- Department of Pharmacology and Chemical BiologyEmory University School of MedicineAtlantaGA30322USA
- Winship Cancer InstituteEmory University School of MedicineAtlantaGA30322USA
- Department of Hematology and Medical OncologyEmory University School of MedicineAtlantaGA30322USA
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Zhang D, Wang M, Liu G, Li X, Yu W, Hui Z, Ren X, Sun Q. Novel FABP4 +C1q + macrophages enhance antitumor immunity and associated with response to neoadjuvant pembrolizumab and chemotherapy in NSCLC via AMPK/JAK/STAT axis. Cell Death Dis 2024; 15:717. [PMID: 39353883 PMCID: PMC11445384 DOI: 10.1038/s41419-024-07074-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 09/07/2024] [Accepted: 09/12/2024] [Indexed: 10/03/2024]
Abstract
Immune checkpoint inhibitors (ICIs) immunotherapy facilitates new approaches to achieve precision cancer treatment. A growing number of patients with non-small cell lung cancer (NSCLC) have benefited from treatment with neoadjuvant ICIs combined with chemotherapy. However, the mechanisms and associations between the therapeutic efficacy of neoadjuvant pembrolizumab and chemotherapy (NAPC) and macrophage subsets are still unclear. We performed single-cell RNA sequencing (scRNA-seq) and identified a novel FABP4+C1q+ macrophage subtype, which exhibited stronger proinflammatory cytokine production and phagocytic ability. This subtype was found to be more abundant in tumor tissues and lymph nodes of major pathological response (MPR) patients compared to non-MPR patients, and was associated with a good efficacy of NAPC. Multiplex fluorescent immunohistochemical (mIHC) staining was subsequently used to verify our findings. Further mechanistic studies indicated that FABP4 and C1q regulate the expression of proinflammatory cytokines synergistically. In addition, FABP4 and C1q promote fatty acid synthesis, enhance anti-apoptosis ability and phagocytic ability of macrophage via the interaction of AMPK/JAK/STAT axis. This study provides novel insights into the underlying mechanisms and predictive biomarkers of NAPC. Our findings contribute to improving the prognosis of patients with NSCLC by potentially guiding more precise patient selection and treatment strategies. NOVELTY & IMPACT STATEMENTS: We identified a group of macrophages (FABP4+C1q+ macrophages) related to the therapeutic efficacy of neoadjuvant chemoimmunotherapy. FABP4+C1q+ macrophages highly expressed proinflammatory cytokines-related genes and had a strong cytokine production and phagocytic ability. We believe that our study provides a novel insight into the synergistic mechanism of neoadjuvant ICI combined with chemotherapy and may lead to improved clinical outcomes in patients with NSCLC in the future.
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Affiliation(s)
- Dong 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
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Min 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
| | - Gen 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
| | - Xin Li
- 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
| | - Zhenzhen Hui
- 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
| | - 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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47
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Huang Z, Xu L, Wu Z, Xiong X, Luo L, Wen Z. CDC25B Is a Prognostic Biomarker Associated With Immune Infiltration and Drug Sensitivity in Hepatocellular Carcinoma. Int J Genomics 2024; 2024:8922878. [PMID: 39371450 PMCID: PMC11455594 DOI: 10.1155/2024/8922878] [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: 05/16/2024] [Accepted: 09/09/2024] [Indexed: 10/08/2024] Open
Abstract
Cell division cycle 25B (CDC25B), a member of the CDC25 phosphatase family, plays a key role in cell cycle regulation. Studies have suggested its carcinogenic potential in various cancers, but the role of CDC25B in the development of hepatocellular carcinoma (HCC) remains poorly understood. The aim of this study was to clarify the role of CDC25B in HCC using bioinformatics and experiments. CDC25B expression data of HCC cancer tissues and paracancerous normal samples were obtained from The Cancer Gene Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and the relationship between CDC25B expression and the prognosis and degree of tumor differentiation of HCC patients was analyzed. CDC25B expression was verified in clinical HCC tissue samples using fluorescence quantitative polymerase chain reaction (q-PCR) and protein immunoblotting (Western blot). Gene set enrichment analysis (GSEA) was used to identify signaling pathways enriched in CDC25B expression, and differential genes (DEGs) were used to screen out coexpressed hub genes and construct protein-protein interaction (PPI) networks. 5-Ethynyl-2'-deoxyuridine (EDU) staining was used to compare the proliferation and differentiation ability of the HCC cell line (HCC-LM3) after knockdown of CDC25B. Finally, we investigated the mutation of CDC25B in HCC and the relationship between CDC25B expression and tumor cell infiltration of lymphocytes and some immune checkpoints as well as drug sensitivity. CDC25B was overexpressed in HCC tissues and correlated with poor prognosis and the degree of tumor differentiation in patients with HCC. The GSEA and PPI networks together revealed significantly upregulated signaling pathways, as well as functions, associated with the development of HCC when CDC25B was overexpressed. The EDU assay demonstrated that the ability of cells to differentiate value addedly was markedly reduced following the downregulation of CDC25B expression in HCC-LM3s. CDC25B was also involved in the formation of the tumor microenvironment (TME) and immune processes in HCC, and the high expression of CDC25B made patients less sensitive to some drugs. CDC25B can be used as a biomarker and immunotherapeutic target for poor prognosis and partial drug sensitivity in HCC, providing new ideas for HCC treatment.
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Affiliation(s)
- Zixiang Huang
- Department of GastroenterologyThe Second Affiliated Hospital of Jiangxi Medical CollegeNanchang University, Nanchang, China
| | - Liangzhi Xu
- Department of Hepatobiliary SurgeryEzhou Central Hospital, Ezhou, Hubei, China
| | - Zhengqiang Wu
- Department of GastroenterologyThe Second Affiliated Hospital of Jiangxi Medical CollegeNanchang University, Nanchang, China
| | - Xiaofeng Xiong
- Department of GastroenterologyThe Second Affiliated Hospital of Jiangxi Medical CollegeNanchang University, Nanchang, China
| | - Linfei Luo
- Department of GastroenterologyThe Second Affiliated Hospital of Jiangxi Medical CollegeNanchang University, Nanchang, China
| | - Zhili Wen
- Department of GastroenterologyThe Second Affiliated Hospital of Jiangxi Medical CollegeNanchang University, Nanchang, China
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48
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Yao Y, Chen YF, Zhang Q. Optimized patient-specific immune checkpoint inhibitor therapies for cancer treatment based on tumor immune microenvironment modeling. Brief Bioinform 2024; 25:bbae547. [PMID: 39451158 PMCID: PMC11503752 DOI: 10.1093/bib/bbae547] [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: 04/28/2024] [Revised: 08/12/2024] [Accepted: 10/11/2024] [Indexed: 10/26/2024] Open
Abstract
Enhancing patient response to immune checkpoint inhibitors (ICIs) is crucial in cancer immunotherapy. We aim to create a data-driven mathematical model of the tumor immune microenvironment (TIME) and utilize deep reinforcement learning (DRL) to optimize patient-specific ICI therapy combined with chemotherapy (ICC). Using patients' genomic and transcriptomic data, we develop an ordinary differential equations (ODEs)-based TIME dynamic evolutionary model to characterize interactions among chemotherapy, ICIs, immune cells, and tumor cells. A DRL agent is trained to determine the personalized optimal ICC therapy. Numerical experiments with real-world data demonstrate that the proposed TIME model can predict ICI therapy response. The DRL-derived personalized ICC therapy outperforms predefined fixed schedules. For tumors with extremely low CD8 + T cell infiltration ('extremely cold tumors'), the DRL agent recommends high-dosage chemotherapy alone. For tumors with higher CD8 + T cell infiltration ('cold' and 'hot tumors'), an appropriate chemotherapy dosage induces CD8 + T cell proliferation, enhancing ICI therapy outcomes. Specifically, for 'hot tumors', chemotherapy and ICI are administered simultaneously, while for 'cold tumors', a mid-dosage of chemotherapy makes the TIME 'hotter' before ICI administration. However, in several 'cold tumors' with rapid resistant tumor cell growth, ICC eventually fails. This study highlights the potential of utilizing real-world clinical data and DRL algorithm to develop personalized optimal ICC by understanding the complex biological dynamics of a patient's TIME. Our ODE-based TIME dynamic evolutionary model offers a theoretical framework for determining the best use of ICI, and the proposed DRL agent may guide personalized ICC schedules.
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Affiliation(s)
- Yao Yao
- School of Data Science, City University of Hong Kong, Kowloon, Hong Kong SAR 00001, China
| | - Youhua Frank Chen
- Department of Management Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR 00001, China
| | - Qingpeng Zhang
- Musketeers Foundation Institute of Data Science, The University of Hong Kong, Pokfulam, Hong Kong SAR 00001, China
- Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR 00001, China
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49
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Feng L, Luo B, Li B, Gou M, Luo Y, Liu G, Ye X, Xu J, Fan Y, You Z. Gold Nano Frameworks with Mesopores for Synergistic Immune-Thermal Therapy in Hepatic Carcinoma: A Paradigm Shift in Immune Checkpoint Blockade. ACS APPLIED MATERIALS & INTERFACES 2024; 16:45901-45916. [PMID: 39169670 DOI: 10.1021/acsami.4c06833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
Immune checkpoint blockade (ICB) therapy, while showing promise in various cancers, exhibits limited effectiveness in hepatic carcinoma due to the tumor's immunosuppressive microenvironment (TME) and challenges associated with immune cell infiltration. Efforts to transform the "cold" TME into an "inflamed" state, notably through chemo-immunotherapy, have sparked interest due to their potential to induce immunogenic cell death and augment the infiltration of cytotoxic T lymphocytes (CTLs). Nonetheless, the efficacy of chemo-immunotherapy is often compromised by suboptimal pharmacokinetics, poor tumor accumulation, and off-target toxicity. Herein, in response, we introduce an innovative, milder thermal therapeutic approach leveraging gold nano frameworks with mesopores for the targeted delivery of the immunostimulant imiquimod and NIR-II photothermal therapy. This strategy employs targeted molecule modifications to ensure precise tumor targeting, guided by photoacoustic imaging. Subsequent to mild thermal treatment, there is a release of immunogenic proteins (CRT and HSP90), enhancing tumor immunogenicity. Assisted by imiquimod, substantial CTL infiltration occurs, accompanied by pro-inflammatory factor release (TNF-α, IL-6), transforming M2 macrophages into the M1 phenotype. Ultimately, the proposed strategy combines PD-L1/PD-1 blockade, imiquimod and mild thermal treatment to synergistically enhance tumor immunogenicity, remodel the TME, and restrain hepatic carcinoma, making strides in ICB synergistic immune-thermal therapy.
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Affiliation(s)
- Lei Feng
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Bin Luo
- Department of Gastrointestinal Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
| | - Bei Li
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Maling Gou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yuting Luo
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Geng Liu
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xiwen Ye
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jianrong Xu
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yaotian Fan
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Zhen You
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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50
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Zhang XC, Zhou YW, Wei GX, Luo YQ, Qiu M. Locoregional therapies combined with immune checkpoint inhibitors for liver metastases. Cancer Cell Int 2024; 24:302. [PMID: 39217341 PMCID: PMC11365172 DOI: 10.1186/s12935-024-03484-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) have achieved remarkable success in clinical research and practice. Notably, liver metastasis is not sensitive to ICIs. Liver locoregional therapies can cause irreversible damage to tumor cells and release tumor antigens, thereby providing a rationale for immunotherapy treatments in liver metastasis. The combination therapy of ICIs with locoregional therapies is a promising option for patients with liver metastasis. Preclinical studies have demonstrated that combining ICIs with locoregional therapies produces a significantly synergistic anti-tumor effect. However, the current evidence for the efficacy of ICIs combined with locoregional therapies remains insufficient. Therefore, we review the literature on the mechanisms of locoregional therapies in treating liver metastasis and the clinical research progress of their combination with ICIs.
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Affiliation(s)
- Xing-Chen Zhang
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, 610041, Sichuan Province, China
| | - Yu-Wen Zhou
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, 610041, Sichuan Province, China
| | - Gui-Xia Wei
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Yi-Qiao Luo
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Meng Qiu
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, 610041, Sichuan Province, China.
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