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Li W, Xiao L, Li H, Cui W. Global research trends of immunosenescence and immunotherapy: A bibliometric study. Hum Vaccin Immunother 2025; 21:2469403. [PMID: 39992200 PMCID: PMC11853558 DOI: 10.1080/21645515.2025.2469403] [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: 10/10/2024] [Revised: 01/31/2025] [Accepted: 02/15/2025] [Indexed: 02/25/2025] Open
Abstract
Immunosenescence refers to the gradual decline in immune system function with age, increasing susceptibility to infections and cancer in the elderly. The advent of novel immunotherapies has revolutionized the field of cancer treatment. However, the majority of patients exhibit poor re-sponses to immunotherapy, with immunosenescence likely playing a significant role. In recent years, significant progress has been made in understanding the interplay between immunosenescence and immunotherapy. Our research aims to explore the prospects and development trends in the field of immunosenescence and immunotherapy using a bibliometric analysis. Relevant articles were collected from the Web of Science Core Collection (WoSCC) (retrieved on July 20, 2024). Primary bibliometric characteristics were analyzed using the R package "Biblio-metrix," and keyword co-occurrence analysis and visualization were conducted using VOSviewer. A total of 213 English-language original research and review articles spanning 35 years were re-trieved for bibliometric analysis. There was a surge in publications in this field starting in 2017. The United States and China contributed the most articles. Frontiers in Immunology was the most productive journal, while the University of California System was the highest contributing institution. Besse Benjamin from France emerged as the most influential researcher in this field. Popular keywords included "nivolumab," "T cells," "dendritic cells," and "regulatory T cells." The "immunosenescence-associated secretory phenotype" has become a new hotspot, with immune checkpoint inhibitors remaining a central theme in this domain. The field of immunosenescence and immunotherapy is entering a phase of rapid development and will continue to hold significant value in future research.
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Affiliation(s)
- Wendi Li
- Department of Clinical Laboratory, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lin Xiao
- Department of Clinical Laboratory, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haiyang Li
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Cui
- Department of Clinical Laboratory, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Kuusisalo S, Iivanainen S, Koivunen JP. Association of anti-PD-(L)1 treatment duration to efficacy in advanced solid tumors: a single center retrospective study. Ann Med 2025; 57:2476729. [PMID: 40091413 PMCID: PMC11915729 DOI: 10.1080/07853890.2025.2476729] [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: 02/05/2024] [Revised: 11/28/2024] [Accepted: 02/17/2025] [Indexed: 03/19/2025] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are a standard of care in multiple cancers. Only a minority benefits, thus, optimal use and treatment duration remain indistinct. While biomarkers albeit PD-L1 are scarce, declined performance status and cancer-related systemic inflammation detected by blood inflammatory markers such as C-reactive protein (CRP) have been linked to inferior prognosis. MATERIALS AND METHODS We investigated the association of limited anti-PD-(L)1 treatment duration to therapy efficacy in melanoma and non-small cell lung cancer (NSCLC) patients who received therapy in a non-curative setting in Oulu University Hospital 2014-2022. Baseline prognostic factors (e.g. ECOG, CRP, and PD-L1 for NSCLC) were collected. Progression-free (PFS), overall (OS), and IO-free survival were analyzed using the Kaplan-Meier and Cox regression methods. RESULTS 126 patients (NSCLC, n = 72; melanoma, n = 54) were included. Majority (n = 101) were treated in the first line. Objective response rate was 34.9%. The median (m) anti-PD-(L)1 treatment duration was 3.42 months (mo). The mPFS and mOS were 6.8 mo (CI 95% 4.4-9.3) and 19.1 mo (CI 95% 13.3-24.9). Of the baseline factors, ECOG and CRP retained their significance in multivariate analysis for PFS (HR 0.34, CI 95% 0.19-0.59; HR 0.34, CI 95% 0.22-054) and OS (HR 0.38, CI 95% 0.20-0.71; HR 0.29, CI 95% 0.17-0.49). No difference was observed in PFS (HR 1.40, CI 95% 0.68-2.90) or OS (HR 0.69, CI 95% 0.29-1.65) according to treatment duration (3-6mo vs. > 6 mo). Long median IO-free survival (10.2 months; CI 95%, 4.1-16.3) was detected. CONCLUSION We characterized an anti-PD-(L)1 treated advanced NSCLC and melanoma cohort in which treatment benefit occurs irrespective of treatment duration and long-term benefit is observed off-treatment.
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Affiliation(s)
- Saara Kuusisalo
- Department of Medical Oncology and Radiotherapy and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Sanna Iivanainen
- Department of Medical Oncology and Radiotherapy and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Jussi P. Koivunen
- Department of Medical Oncology and Radiotherapy and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
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Kawachi H, Yamada T, Tamiya M, Negi Y, Kijima T, Goto Y, Nakao A, Shiotsu S, Tanimura K, Takeda T, Okada A, Harada T, Date K, Chihara Y, Hasegawa I, Tamiya N, Katayama Y, Nishioka N, Morimoto K, Iwasaku M, Tokuda S, Shimose T, Takayama K. Clinical impact of cancer cachexia on the outcome of patients with non-small cell lung cancer with PD-L1 tumor proportion scores of ≥50% receiving pembrolizumab monotherapy versus immune checkpoint inhibitor with chemotherapy. Oncoimmunology 2025; 14:2442116. [PMID: 39681395 PMCID: PMC11651275 DOI: 10.1080/2162402x.2024.2442116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 12/09/2024] [Accepted: 12/10/2024] [Indexed: 12/18/2024] Open
Abstract
This retrospective, multicenter cohort study aimed to determine whether cancer cachexia serves as a biomarker for determining the most effective treatment for patients having non-small-cell lung cancer (NSCLC) with high programmed death ligand 1 (PD-L1) expression treated with immune checkpoint inhibitors (ICIs) alone or combined with chemotherapy (ICI/chemotherapy). We included 411 patients with advanced NSCLC with a PD-L1 tumor proportion score of ≥50%. The patients were treated with pembrolizumab monotherapy or ICI/chemotherapy. Cancer cachexia was defined as a weight loss of >5% of the total body weight or a body mass index of <20 kg/m2 coupled with an additional weight loss of >2% within 6 months before starting treatment. Eighty-five (21%) patients met the cancer cachexia criteria. Overall survival (OS) was significantly shorter in patients with cachexia than in those without cachexia in both the pembrolizumab monotherapy group (17.2 vs. 35.8 months, p < 0.001) and the ICI/chemotherapy group (27.0 months vs. not reached, p = 0.044). However, after stratifying by cancer cachexia status, no significant difference in OS was observed between the pembrolizumab monotherapy and chemoimmunotherapy groups, regardless of cachexia. In conclusion, ICI/chemotherapy offers limited benefits for NSCLC patients with high PD-L1 expression and concurrent cancer cachexia. Considering the frailty associated with cachexia, ICI monotherapy may be preferred to ICI/chemotherapy for these patients. New interventions that can better address the negative prognostic impact of cachexia in patients treated using ICIs with or without chemotherapy remain warranted.
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MESH Headings
- Humans
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/complications
- Carcinoma, Non-Small-Cell Lung/mortality
- Carcinoma, Non-Small-Cell Lung/pathology
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Cachexia/etiology
- Male
- Female
- Lung Neoplasms/drug therapy
- Lung Neoplasms/complications
- Lung Neoplasms/mortality
- Lung Neoplasms/pathology
- Aged
- Middle Aged
- Immune Checkpoint Inhibitors/therapeutic use
- Immune Checkpoint Inhibitors/adverse effects
- Immune Checkpoint Inhibitors/administration & dosage
- Retrospective Studies
- B7-H1 Antigen/antagonists & inhibitors
- B7-H1 Antigen/metabolism
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Aged, 80 and over
- Adult
- Prognosis
- Treatment Outcome
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Affiliation(s)
- Hayato Kawachi
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Tadaaki Yamada
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Motohiro Tamiya
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Osaka, Japan
| | - Yoshiki Negi
- Department of Respiratory Medicine and Hematology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Takashi Kijima
- Department of Respiratory Medicine and Hematology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Yasuhiro Goto
- Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Akira Nakao
- Department of Respiratory Medicine, Fukuoka University Hospital, Fukuoka, Fukuoka, Japan
| | - Shinsuke Shiotsu
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Kyoto, Japan
| | - Keiko Tanimura
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Kyoto, Japan
| | - Takayuki Takeda
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Kyoto, Japan
| | - Asuka Okada
- Department of Respiratory Medicine, Saiseikai Suita Hospital, Suita, Osaka, Japan
| | - Taishi Harada
- Department of Medical Oncology, Fukuchiyama City Hospital, Fukuchiyama, Kyoto, Japan
| | - Koji Date
- Department of Pulmonary Medicine, Kyoto Chubu Medical Center, Kyoto, Japan
| | - Yusuke Chihara
- Department of Respiratory Medicine, Uji-Tokushukai Medical Center, Uji, Kyoto, Japan
| | - Isao Hasegawa
- Department of Respiratory Medicine, Saiseikai Shigaken Hospital, Shiga, Japan
| | - Nobuyo Tamiya
- Department of Respiratory Medicine, Rakuwakai Otowa Hospital, Kyoto, Kyoto, Japan
| | - Yuki Katayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Naoya Nishioka
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Kenji Morimoto
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Masahiro Iwasaku
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Shinsaku Tokuda
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Takayuki Shimose
- Department of Statistics and Data Center, Clinical Research Support Center Kyushu, Fukuoka, Japan
| | - Koichi Takayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
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Rocha P, Bach R, Masfarré L, Hernandez S, Navarro-Gorro N, Rossell A, Villanueva X, Giner M, Sanchéz I, Galindo M, Del Rey-Vergara R, Iñañez A, Sanchéz-Espiridion B, Lu W, Acedo-Terrades A, Berenguer-Molins P, Sánchez-Font A, Chalela R, Curull V, Taus Á, Hardy-Werbin M, Sausen M, Georgiadis A, White J, Jackson JB, Moliner L, Clavé S, Bellosillo B, Rovira A, Wistuba I, Soto LMS, Perera-Bel J, Arriola E. Molecular and immunological features associated with long-term benefits in metastatic NSCLC patients undergoing immune checkpoint blockade. Oncoimmunology 2025; 14:2469377. [PMID: 39991958 PMCID: PMC11853546 DOI: 10.1080/2162402x.2025.2469377] [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: 07/03/2024] [Revised: 01/22/2025] [Accepted: 02/14/2025] [Indexed: 02/25/2025] Open
Abstract
INTRODUCTION Immunotherapy is firmly established as a treatment regimen in various solid tumors, driven by its exceptional benefits in a selected group of patients. Despite widespread adoption of immune checkpoint blockade (ICB) across diverse solid tumors, the quest for a clinically informative biomarker for long-term benefit remains unmet. METHODS A total of 49 patients with metastatic NSCLC treated with ICB were included. Long-term (LTR) and short-term responders (STR) were defined as those with a response to ICB lasting more than 24 months or less than 6 months, respectively. Longitudinal blood specimens were collected before ICB treatment initiation and early-on treatment. Plasma ctDNA next-generation sequencing panel (NGS) and serum proteomics were performed. GeoMx DSP on baseline tumor tissue was performed in a subset of patients. RESULTS Our analysis revealed specific characteristics of LTR compared with STR, namely higher PD-L1 in tumor cells (p = 0.005) and higher incidence of irAEs (p = 0.001). Genomic features associated with lack of benefit from ICB included co-occurring mutations in KRAS/STK11 and TP53/KMT2D (p < 0.05). At a baseline, LTR patients exhibited higher serum levels of proteins related with apoptosis (CASP8, PRKRA), chemotaxis, immune proteasome, processing of MHC class I (S100A4, PSMD9, RNF41) and immune homeostasis (HAVCR1, ARG1) (p < 0.05). Protein spatial profiling of tumor samples showed higher levels of proteins linked with the presence of immune cells (CD45), T cells (CD8), antigen presentation (HLA-DR) and immune regulation proteins (PD-L1, IDO1) within the tumor and tumor stroma component (p < 0.05) in LTR patients. Serum longitudinal analysis identified a set of proteins that presented distinct dynamics in LTR compared to STR, making them interesting candidates to evaluate as early predictors of treatment efficacy. CONCLUSIONS Our multimodal analysis of patients with metastatic NSCLC treated with ICB identified clinicopathological and immunological features associated with long-term benefits. The presence of preexisting antitumor immunity emerged as a strong predictor of long-term benefits, providing insights for potential biomarkers and therapeutic strategies for enhancing ICB outcomes in metastatic NSCLC.
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Affiliation(s)
- Pedro Rocha
- Medical Oncology Department, Hospital del Mar, Barcelona, Spain
- Cancer Research Program, Hospital del Mar Research Institute, Barcelona, Spain
| | - Rafael Bach
- Medical Oncology Department, Hospital del Mar, Barcelona, Spain
| | - Laura Masfarré
- Medical Oncology Department, Hospital del Mar, Barcelona, Spain
| | - Sharia Hernandez
- Department of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Adrià Rossell
- Medical Oncology Department, Hospital del Mar, Barcelona, Spain
| | | | - Mario Giner
- Pathology Department, Hospital del Mar, Barcelona, Spain
| | | | - Miguel Galindo
- Cancer Research Program, Hospital del Mar Research Institute, Barcelona, Spain
| | | | - Albert Iñañez
- Cancer Research Program, Hospital del Mar Research Institute, Barcelona, Spain
| | - Beatriz Sanchéz-Espiridion
- Department of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Wei Lu
- Department of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | | | | | | | | | - Victor Curull
- Pulmonology Department, Hospital del Mar, Barcelona, Spain
| | - Álvaro Taus
- Medical Oncology Department, Hospital del Mar, Barcelona, Spain
| | | | | | | | | | | | | | - Sergi Clavé
- Pathology Department, Hospital del Mar, Barcelona, Spain
| | - Beatriz Bellosillo
- Pathology Department, Hospital del Mar, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Ana Rovira
- Medical Oncology Department, Hospital del Mar, Barcelona, Spain
- Cancer Research Program, Hospital del Mar Research Institute, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Ignacio Wistuba
- Department of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Luisa M Solis Soto
- Department of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Edurne Arriola
- Medical Oncology Department, Hospital del Mar, Barcelona, Spain
- Cancer Research Program, Hospital del Mar Research Institute, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
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Zuo CJ, Tian J. Advancing the understanding of the role of apoptosis in lung cancer immunotherapy: Global research trends, key themes, and emerging frontiers. Hum Vaccin Immunother 2025; 21:2488074. [PMID: 40186454 PMCID: PMC11980473 DOI: 10.1080/21645515.2025.2488074] [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: 01/24/2025] [Revised: 03/12/2025] [Accepted: 03/30/2025] [Indexed: 04/07/2025] Open
Abstract
Apoptosis is vital for improving the efficacy of lung cancer (LC) immunotherapy by targeting cancer cell elimination. Despite its importance, there is a lack of comprehensive bibliometric studies analyzing global research on apoptosis in LC immunotherapy. This analysis aims to address this gap by highlighting key trends, contributors, and future directions. A total of 969 publications from 1996 to 2024 were extracted from the Web of Science Core Collection. Analysis was conducted using VOSviewer, CiteSpace, and the R package 'bibliometrix.' The study included contributions from 6,894 researchers across 1,469 institutions in 61 countries, with research published in 356 journals. The volume of publications has steadily increased, led by China and the United States, with Sichuan University as the top contributor. The journal Cancers published the most articles, while Cancer Research had the highest co-citations. Yu-Quan Wei was the leading author, and Jemal, A. was the most frequently co-cited. Key research themes include "cell death mechanisms," "immune regulation," "combination therapies," "gene and nanomedicine applications," and "traditional Chinese medicine (TCM)." Future research is likely to focus on "coordinated regulation of multiple cell death pathways," "modulation of the tumor immune microenvironment," "optimization of combination therapies," "novel strategies in gene regulation," and the "integration of TCM" for personalized treatment. This is the first bibliometric analysis on the role of apoptosis in LC immunotherapy, providing an landscape of global research patterns and emerging therapeutic strategies. The findings offer insights to guide future research and optimize treatment approaches.
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Affiliation(s)
- Chun-Jian Zuo
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jie Tian
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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Chen N, Li Z, Liu H, Jiang A, Zhang L, Yan S, He W, Yang J, Liu T. Enhancing PD-1 blockade in NSCLC: Reprogramming tumor immune microenvironment with albumin-bound statins targeting lipid rafts and mitochondrial respiration. Bioact Mater 2025; 49:140-153. [PMID: 40124597 PMCID: PMC11930202 DOI: 10.1016/j.bioactmat.2025.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 02/09/2025] [Accepted: 03/03/2025] [Indexed: 03/25/2025] Open
Abstract
Non-small cell lung cancer (NSCLC) has shown limited response to immunotherapy, primarily due to an immunosuppressive tumor microenvironment characterized by hypoxia and lipid raft formation, which together inhibit T-cell infiltration and function, impeding effective immune responses. To address these challenges, we developed Abstatin, an albumin-bound fluvastatin formulation that targets lipid raft disruption and mitochondrial respiration inhibition, aiming to reduce hypoxia and destabilize lipid rafts to enhance T-cell activity within the tumor. Using bioinformatics analysis, in vitro assays, and in vivo studies in both murine and humanized PDX models, we demonstrated that Abstatin reprograms the NSCLC microenvironment by concurrently lowering hypoxia levels and lipid raft integrity, thereby restoring T-cell infiltration, enhancing cytotoxic T-cell function, and ultimately improving response to Anti-PD-1 therapy. Results showed that Abstatin significantly amplifies Anti-PD-1 efficacy with minimal toxicity, indicating a favorable safety profile for clinical use. This study highlights Abstatin as a promising immunotherapy adjuvant that addresses critical barriers in NSCLC by modulating metabolic pathways linked to immune resistance. Abstatin's approach, which combines modulation of cellular metabolism with immune sensitization, broadens the potential of immunotherapy and provides a practical, scalable strategy to enhance treatment outcomes in NSCLC and potentially other tumors, offering insights into combinatory cancer therapies.
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Affiliation(s)
- Na Chen
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Zhanfeng Li
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Heyuan Liu
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR China
- Department of Tumor and Immunology in Precision Medical Institute, Western China Science and Technology Innovation Port, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR China
| | - Aimin Jiang
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, PR China
| | - Liqiang Zhang
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR China
| | - Siqi Yan
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR China
| | - Wangxiao He
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR China
| | - Jingyue Yang
- Department of Clinical Oncology, Air Force Medical University, Xi'an, 710032, PR China
| | - Tianya Liu
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR China
- Department of Tumor and Immunology in Precision Medical Institute, Western China Science and Technology Innovation Port, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR China
- Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR China
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Li Y, Yuan X, Yin XF, Zheng D, Shi F, Liu D, Hu L, Shi X, Wen N, He QY, Yang H, Zhang CZ. Proteomics analysis and immune profiling reveal regulators of PD-L1 in oesophageal squamous cell carcinoma. Br J Cancer 2025:10.1038/s41416-025-03068-4. [PMID: 40490504 DOI: 10.1038/s41416-025-03068-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 05/05/2025] [Accepted: 05/16/2025] [Indexed: 06/11/2025] Open
Abstract
BACKGROUND Proteomics studies have advanced our comprehension of cancer biology, accelerated targeted therapy, and improved patient outcomes. METHODS High-resolution mass spectrometry and immune profiling based on immunohistochemistry and multiple immunohistochemistry were employed to investigate proteomic and immune landscapes in oesophageal squamous cell carcinoma (ESCC) and explore the regulators of PD-L1 in ESCC. Molecular validation was performed using qRT-PCR, western blotting, and in vitro functional assays. RESULTS Proteomic profiling of 89 treatment-naive ESCC specimens identified over 9300 proteins, with 6900 proteins detected across most samples. Proteome-based stratification identified three subtypes related to diverse clinical and molecular features. Combined proteomics and immune analyses revealed core proteins associated with the immune landscape in ESCC. Further, integrated proteomics, transcriptomics, and immune profiling nominated COTL1 as a potential regulator of PD-L1 in ESCC. Overexpression of COTL1 upregulated both mRNA and protein levels of PD-L1 and promoted cell proliferation in ESCC. Patients with high COTL1 protein expression were likely to have a poor prognosis, along with increased infiltration of CD4+CD8+ and CD4+GrB+ cells. CONCLUSIONS Collectively, our integrative analysis enables a more comprehensive understanding of the proteomic and immune landscape of ESCC and implicates COTL1 as a potential modulator of PD-L1 and immune cell infiltration.
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Affiliation(s)
- Yuying Li
- MOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Xiaoyi Yuan
- MOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Xing-Feng Yin
- MOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Dandan Zheng
- MOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Fujin Shi
- MOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Danya Liu
- MOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Liling Hu
- MOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Xinyu Shi
- MOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Nengqiao Wen
- Department of Pathology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qing-Yu He
- MOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China.
| | - Hong Yang
- Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Guangdong Esophageal Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou City, China.
| | - Chris Zhiyi Zhang
- MOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China.
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Sugumar K, Alabd A, Alabd A, Hue JJ, Lyons J, Fields S, Wainberg Z, Zheng L, Coogle B, Kasi A, Grewal N, Kindler HL, Starr J, Sama AR, Winter JM. Exceptional responders to immunotherapy in pancreatic cancer: A multi-institutional case series of a rare occurrence. Oncotarget 2025; 16:427-442. [PMID: 40492845 DOI: 10.18632/oncotarget.28739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2025] Open
Abstract
INTRODUCTION Immunotherapy has emerged as a standard treatment option for multiple solid tumors. However, most patients with pancreatic cancer (PC) do not derive a significant benefit. Identification and analyses of exceptional responders could eventually offer hints as to why PC is resistant to immunotherapy. METHODS Oncologists from cancer centers in the United States were contacted to identify patients with PC who responded to immunotherapy. Exceptional responders were defined as those having either partial (PR) or complete response (CR) based on Response Evaluation Criteria in Solid Tumors, or biochemical response (CA 19-9 levels) after starting immunotherapy. Patients receiving concurrent chemotherapy were excluded. RESULTS 14 patients met inclusion criteria. Immunotherapy drugs included checkpoint inhibitors and macrophage inhibitors. Eight patients (42%) were MSI (microsatellite instability)-high. Radiologically, 82% had PR. Four patients (28%) had marked reduction in CA 19-9. The median progression-free survival was 12 months from the start of immunotherapy. Median survival was not reached. The 1- and 2-year survival probabilities were 80%, 70% respectively. CONCLUSION Majority of clinical trials evaluating immunotherapy in PC have yielded disappointing response rates compared to other solid tumors. Our case series adds to published data from early-phase trials supporting the promise of immunotherapy in some patients with PC.
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Affiliation(s)
- Kavin Sugumar
- Department of Surgery, University Hospitals Seidman Cancer Center, Cleveland, OH 44106, USA
| | - Andrew Alabd
- Department of Medicine, Cooper University Healthcare, Camden, NJ 08103, USA
| | - Andre Alabd
- Department of Urology, University of Indiana, Indianapolis, IN 46227, USA
| | - Jonathan J Hue
- Department of Surgery, University Hospitals Seidman Cancer Center, Cleveland, OH 44106, USA
| | - Josh Lyons
- Department of Surgery, University Hospitals Seidman Cancer Center, Cleveland, OH 44106, USA
| | - Sherri Fields
- Department of Medicine, UCLA/Santa Monica Cancer Center, CA 90404, USA
| | - Zev Wainberg
- Department of Medicine, UCLA/Santa Monica Cancer Center, CA 90404, USA
| | - Lei Zheng
- Department of Medicine, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Brianna Coogle
- Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - Anup Kasi
- Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - Nicholas Grewal
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Hedy L Kindler
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Jason Starr
- Department of Medicine, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Ashwin R Sama
- Department of Medicine, Jefferson Medical Oncology Associates, Philadelphia, PA 19107, USA
| | - Jordan M Winter
- Department of Surgery, University Hospitals Seidman Cancer Center, Cleveland, OH 44106, USA
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9
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Tang LB, Peng YL, Chen J, Li JT, Zheng MM, Wu L, Lu C, Wei XW, Cai DX, Guo Z, Ren ZR, Lv SD, Deng Y, Chen ZH, Xu CR, Zhou Q. Rechallenge with immune-checkpoint inhibitors in patients with advanced-stage lung cancer. Nat Rev Clin Oncol 2025:10.1038/s41571-025-01029-7. [PMID: 40490476 DOI: 10.1038/s41571-025-01029-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/05/2025] [Indexed: 06/11/2025]
Abstract
Lung cancer remains the leading cause of cancer-related mortality globally, with many patients diagnosed with advanced-stage disease. Treatment in this setting relies on systemic therapies, including chemotherapy, targeted therapy and immunotherapy. Immune-checkpoint inhibitors (ICIs), which promote or restore antitumour immunity by inhibiting immunosuppressive signalling pathways, are currently the most widely used immunotherapies in these patients. However, immune-related adverse events (irAEs) or disease progression often necessitate discontinuation of these agents, leaving many patients with limited subsequent treatment options. In this scenario, ICI rechallenge has emerged as a potential strategy. Despite this potential, evidence for ICI rechallenge after either disease progression or irAEs in patients with non-small-cell lung cancer is limited and evidence for those with small cell lung cancer seems to be non-existent. In this Review, we provide a comprehensive overview of the available data on ICI rechallenge in the context of both disease progression and irAEs, including a summary of current guidance on clinical management and detailed discussions of safety and efficacy. We also highlight important unanswered questions in an attempt to guide future research in this area.
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Affiliation(s)
- Li-Bo Tang
- School of Medicine, South China University of Technology, Guangzhou, China
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Ying-Long Peng
- School of Medicine, South China University of Technology, Guangzhou, China
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Ji Chen
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Jia-Ting Li
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- Shantou University Medical College, Shantou, China
| | - Mei-Mei Zheng
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Lv Wu
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Chang Lu
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Xue-Wu Wei
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Dong-Xuan Cai
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zhi Guo
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zi-Rui Ren
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Si-Di Lv
- School of Art, Soochow University, Suzhou, China
| | - Yu Deng
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zhi-Hong Chen
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Chong-Rui Xu
- School of Medicine, South China University of Technology, Guangzhou, China
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Qing Zhou
- School of Medicine, South China University of Technology, Guangzhou, China.
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
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10
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Dong H, Li S, Peng Y, Zhang X, Zheng J, Xue C, Zheng Y, Yu Y, Lu X, Hu Z, Cui H. Durvalumab‑induced type 1 diabetes mellitus in lung adenocarcinoma: A case report and literature review. Oncol Lett 2025; 29:277. [PMID: 40247987 PMCID: PMC12005073 DOI: 10.3892/ol.2025.15023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 03/19/2025] [Indexed: 04/19/2025] Open
Abstract
Immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM) is a rare adverse reaction associated with durvalumab. Among the adverse reactions to durvalumab, the incidence of new-onset diabetes is relatively rare, occurring in ~0.2% of cases. The present study reports the case of a 62-year-old woman who developed ICI-T1DM following two cycles of durvalumab, presenting with thirst, polydipsia and polyuria. Laboratory examinations (glycated hemoglobin and glutamic acid decarboxylase antibody), along with consultations from an endocrinologist, led to the patient being diagnosed with ICI-T1DM. Immunotherapy was discontinued, and insulin replacement therapy was initiated. Blood glucose levels were closely monitored using a subcutaneous meter. The onset of diabetic ketoacidosis (DKA) was prevented due to timely treatment. In conclusion, medical oncologists need to be aware that durvalumab, an immunotherapy agent, can induce ICI-T1DM. Therefore, regular monitoring of blood glucose levels and collaborative consultations with endocrinologists are essential for an accurate diagnosis when elevated blood sugar levels are detected. The prompt diagnosis of ICI-T1DM is crucial to prevent the occurrence of DKA.
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Affiliation(s)
- Huijing Dong
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Shengfu Li
- Department of Tuberculosis, Tai Yuan Fourth Peoples (Tuberculosis) Hospital, Taiyuan, Shanxi 030053, P.R. China
| | - Yanmei Peng
- Department of Oncology, Fangshan Hospital Beijing University of Chinese Medicine, Beijing 102400, P.R. China
| | - Xu Zhang
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Jiabin Zheng
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, P.R. China
| | - Chongxiang Xue
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Yumin Zheng
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Yixuan Yu
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Xingyu Lu
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Zixin Hu
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Huijuan Cui
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing 100029, P.R. China
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11
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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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Corre R, Decroisette C, Auliac JB, Falchero L, Curcio H, Amrane K, Perol M, Hominal S, Vieillot S, Huchot E, Desage AL, Bernardi M, Veillon R, Doubre H, Bota S, Legarff G, Justeau G, Bylicki O, Roa M, Descourt R, Chouaïd C, Greillier L. First-Line Pembrolizumab Efficacy in Octogenarians With NSCLCs Expressing ≥ 50% PD-L1 (ESCKEYP GFPC 05-2018). Clin Lung Cancer 2025; 26:331-337. [PMID: 40122771 DOI: 10.1016/j.cllc.2025.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 01/21/2025] [Accepted: 03/01/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND Pembrolizumab alone is a first-line therapeutic option for patients with metastatic non-small cell lung cancer (NSCLC) with ≥ 50% PD-L1 expression, but few data are available for elderly patients, specifically octogenarians. METHODS This retrospective, multicenter study included all consecutive patients with metastatic NSCLC PD-L1 ≥ 50% treated with first-line pembrolizumab monotherapy between May 2017 and November 2019. Information was collected from medical files with local evaluation of therapeutic response and progression-free survival (PFS). RESULTS Among the 844 patients included, 73 (8.4%) were ≥ 80 (median: 82) years old, 74% men, 23.3% with ECOG-PS ≥ 2, 26% had ≥ 5% weight loss, PD-L1 50%-75%/≥ 75%: 45.2%/46.6%, respectively, with significantly more nonsmokers and (17.4% vs. 5.6%, P = .0002) and fewer adenocarcinomas (57.5% vs. 70.8%, P = .0217) than those < 80 years. After median follow-up of 45.7 (95% CI: 43.0-49.1) months, respective median overall survival (OS) for octogenarians versus younger patients lasted 12.0 (95% CI: 7.7-16.2) versus 23.9 (95% CI: 19.5-27.4) months (P = .0002), and median PFS for 5.0 (95% CI: 2.8-9.2) versus 8.3 (95% CI: 7.2-9.8) months (P = .039). Their respective objective response rates did not differ significantly: 42% (95% CI: 24-60) vs. 49% (95% CI: 43-54). CONCLUSIONS Based on the results of this large multicenter population, first-line pembrolizumab efficacy against NSCLCs expressing ≥ 50% PD-L1 in octogenarians seems inferior to that obtained in younger patients. The higher percentage of nonsmokers and fewer adenocarcinomas could partially explain that finding.
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Affiliation(s)
- Romain Corre
- Centre Hospitalier de Cornouaille, Quimper, France
| | | | | | | | | | - Karim Amrane
- Centre Hospitalier des Pays de Morlaix, Morlaix, France
| | | | | | | | | | | | - Marie Bernardi
- Centre Hospitalier du Pays d'Aix, Aix-en-Provence, France
| | | | | | | | | | | | - Oliver Bylicki
- Hôpital d'Instruction des Armées Sainte-Anne, Toulon, France
| | - Magali Roa
- CHI Fréjus-Saint-Raphaël, Fréjus, France
| | - Renaud Descourt
- CHRU Morvan Institut de Cancérologie et d'Hématologie Oncologie Thoracique, Brest, France
| | | | - Laurent Greillier
- Hopital Nord, APHM, Multidisciplinaire et Innovations Thérapeutiques, Marseille, France
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Elkrief A, Routy B, Derosa L, Bolte L, Wargo JA, McQuade JL, Zitvogel L. Gut Microbiota in Immuno-Oncology: A Practical Guide for Medical Oncologists With a Focus on Antibiotics Stewardship. Am Soc Clin Oncol Educ Book 2025; 45:e472902. [PMID: 40262063 DOI: 10.1200/edbk-25-472902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
The gut microbiota has emerged as a critical determinant of immune checkpoint inhibitor (ICI) efficacy, resistance, and toxicity. Retrospective and prospective studies profiling the taxonomic composition of intestinal microbes of patients treated with ICI have revealed specific gut microbial signatures associated with response. By contrast, dysbiosis, which can be caused by chronic inflammatory processes (such as cancer) or comedications, is a risk factor of resistance to ICI. Recent large-scale meta-analyses have confirmed that antibiotic (ATB) use before or during ICI therapy alters the microbiota repertoire and significantly shortens overall survival, even after adjusting for prognostic factors. These results underscore the importance of implementing ATB stewardship recommendations in routine oncology practice. Microbiota-centered interventions are now being explored to treat gut dysbiosis and optimize ICI responses. Early-phase clinical trials evaluating fecal microbiota transplantation (FMT) from ICI responders or healthy donors have shown that this approach is safe and provided preliminary data on potential efficacy to overcome both primary and secondary resistance to ICI in melanoma, non-small cell lung cancer, and renal cell carcinoma. More targeted interventions including live bacterial products including Clostridium butyricum and Akkermansia massiliensis represent novel microbiome-based adjunct therapies. Likewise, dietary interventions, such as high-fiber diets, have shown promise in enhancing ICI activity. In this ASCO Educational Book, we summarize the current state-of-the-evidence of the clinical relevance of the intestinal microbiota in cancer immunotherapy and provide a practical guide for ATB stewardship.
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Affiliation(s)
- Arielle Elkrief
- University of Montreal Hospital Research Centre, Cancer Axis, Montreal, Canada
- University of Montreal Hospital Centre, Department of Hematology-Oncology, Montreal, Canada
| | - Bertrand Routy
- University of Montreal Hospital Research Centre, Cancer Axis, Montreal, Canada
- University of Montreal Hospital Centre, Department of Hematology-Oncology, Montreal, Canada
| | - Lisa Derosa
- INSERM U1015, Equipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
- Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France
- Gustave Roussy, ClinicObiome, Villejuif, France
- Université Paris-Saclay, Faculty of Medicine, Kremlin-Bicêtre, France
| | - Laura Bolte
- Department of Medical Oncology, University Groningen and University Medical Center, Groningen, the Netherlands
- Department of Gastroenterology and Hepatology, University Groningen and University Medical Center, Groningen, the Netherlands
| | | | | | - Laurence Zitvogel
- INSERM U1015, Equipe Labellisée - Ligue Nationale contre le Cancer, Villejuif, France
- Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France
- Gustave Roussy, ClinicObiome, Villejuif, France
- Université Paris-Saclay, Faculty of Medicine, Kremlin-Bicêtre, France
- Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France
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14
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Gaeta B, Eichholz JE, Walch H, Ilica AT, Boe L, Kratochvil L, Yu Y, Gomez DR, Imber BS, Li BT, Murciano-Goroff YR, Arbour KC, Schultz N, Lebow ES, Pike LRG. Intracranial Disease Control and Survival among Patients with KRAS-mutant Lung Adenocarcinoma and Brain Metastases Treated with Stereotactic Radiosurgery. Int J Radiat Oncol Biol Phys 2025; 122:424-434. [PMID: 39929348 DOI: 10.1016/j.ijrobp.2025.01.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 01/14/2025] [Accepted: 01/25/2025] [Indexed: 03/01/2025]
Abstract
PURPOSE Precision medicine according to molecularly defined subgroups offers great potential to improve outcomes for patients with metastatic lung adenocarcinoma. This study describes clinical outcomes and the impact of co-occurring genetic alterations on outcomes following stereotactic radiosurgery (SRS) among patients with Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung adenocarcinoma. METHODS AND MATERIALS A total of 195 patients with KRAS-mutant lung adenocarcinoma were treated with SRS for brain metastases (BMs) between 2014 and 2018 with follow-up until 2022 or death. Coprimary outcomes were median overall survival (OS) and intracranial progression-free survival (iPFS); univariable and multivariable Cox regression models and Kaplan-Meier survival analysis were used. RESULTS Median follow-up from the date of BM diagnosis was 11 months. Median OS and iPFS for the cohort were 27.7 months (95% CI, 19.7-36.8) and 22.1 months (95% CI, 16.8-48.9), respectively. Lesion-level local control at 12 and 24 months was 89.9% and 87.5%, respectively. In a multivariable Cox regression model, inferior OS was associated with coalterations in KEAP1 and STK11 (hazard ratio [HR], 1.94; 95% CI, 1.04-3.62; q = 0.087), progressive (HR, 3.41; 95% CI, 1.38-8.39; q = 0.087), and mixed response (HR, 3.52; 95% CI, 1.2-10.3; q = 0.092) extracranial disease, and 6 or more BMs at time of diagnosis (HR, 2.58; 95% CI, 1.22-6.63; q = 0.087). Positive programmed death ligand 1 status was associated with improved OS (HR, 0.57; 95% CI, 0.37-0.87; P = .01). Inferior iPFS was associated with chemotherapy before SRS (HR, 2.69; 95% CI, 1.42-5.09; q = 0.04) and age >65 years (HR, 2.21; 95% CI, 1.25-3.93; q = 0.055). KRAS G12C was not associated with differences in iPFS, OS, or type of intracranial progression event following SRS. CONCLUSIONS Coalteration of KRAS and KEAP1/STK11 was associated with inferior OS, but not iPFS. Similar outcomes were found in patients harboring KRAS G12C and non-G12C mutant non-small cell lung cancer BMs. Further understanding of molecularly characterized subgroups will be critical in driving personalized radiation therapy for patients with lung cancer BMs.
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Affiliation(s)
- Benjamin Gaeta
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, New York, New York
| | - Jordan E Eichholz
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Henry Walch
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ahmet T Ilica
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Lillian Boe
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Leah Kratochvil
- Memorial Hospital Research Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Yao Yu
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Daniel R Gomez
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York; Global Biomarker Development Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Brandon S Imber
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Bob T Li
- Memorial Hospital Research Program, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Yonina R Murciano-Goroff
- Memorial Hospital Research Program, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Kathryn C Arbour
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nikolaus Schultz
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Emily S Lebow
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York; Global Biomarker Development Program, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Luke R G Pike
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York; Global Biomarker Development Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Baldi S, Alnaggar M, AL-Mogahed M, Khalil KAA, Zhan X. Monoclonal antibody immune therapy response instrument for stratification and cost-effective personalized approaches in 3PM-guided pan cancer management. EPMA J 2025; 16:465-503. [PMID: 40438490 PMCID: PMC12106254 DOI: 10.1007/s13167-025-00403-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 03/06/2025] [Indexed: 06/01/2025]
Abstract
Background Immune checkpoint inhibitors (ICIs), such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 therapies, have revolutionized cancer treatment by harnessing the body's immune system to eliminate cancer cells. Despite their considerable promise, the efficacy of ICIs significantly differs based on tumor types and specific patient conditions, highlighting the necessity for personalized approaches in the framework of predictive preventive personalized medicine (PPPM; 3PM). Main body This review proposes a stratification instrument within the 3PM framework to enhance the therapeutic efficacy of ICIs across Pan-cancer. Predictive approaches need to be utilized to enhance the effectiveness of ICIs. For example, biomarkers such as particular genetic alterations and metabolic pathways provide key information on patient treatment responses. To predict treatment outcomes, uncover resistance mechanisms, and tailor medications, we examine biomarkers including PDL-1 and CTLA4. Focusing on cancers like melanoma, bladder, and renal cell carcinoma, we highlight advances in combination therapies and cellular approaches to overcome resistance. We conducted an analysis of clinical trials and public datasets (TCGA, GEO) to evaluate ICI responses across number of cancer types. Survival analysis employed Kaplan-Meier curves and Cox regression. Pan-cancer analysis shows response rates ranging from 19.8% in bladder cancer to > 39% in melanoma when combination therapy is used, emphasizing the potential of 3PM to improve outcomes. By exploring resistance mechanisms and emerging therapeutic innovations, we propose a cost-effective model for better patient stratification and care. Validation of this model requires standardized biomarkers and prospective trials, promising a shift toward precision oncology. Conclusion Within the 3PM framework, this review addresses the urgent need for cost-effective stratification tools and adaptive combinatorial strategies to optimize outcomes.
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Affiliation(s)
- Salem Baldi
- Department of Medical Laboratory Diagnostics, School of Medical Technology, Shaoyang University, Shaoyang, 422000 China
- Department of Medical Laboratory Diagnostics, Al-Thawra General Hospital, Al Hudaydah, Yemen
| | - Mohammed Alnaggar
- Department of Oncology, South Hubei Cancer Hospital, Chibi, Xianning, 437000 Hubei China
| | - Maged AL-Mogahed
- Department of Urology, The First Bethune Hospital of Jilin University, Changchun, 130012 China
| | - Khalil A. A. Khalil
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, 61922 Bisha, Saudi Arabia
| | - Xianquan Zhan
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong First Medical University & Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, 440 Jiyan Road, Jinan, Shandong 250117 People’s Republic of China
- Shandong Provincial Key Medical and Health Laboratory of Ovarian Cancer Multiomics, & Jinan Key Laboratory of Cancer Multiomics, Shandong First Medical University & Shandong Academy of Medical Sciences, 6699 Qingdao Road, Jinan, Shandong 250117 People’s Republic of China
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16
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Arabi S, Fadaee M, Kazemi T, Rahmani M. Advancements in colorectal cancer immunotherapy: from CAR-T cells to exosome-based therapies. J Drug Target 2025; 33:749-760. [PMID: 39754507 DOI: 10.1080/1061186x.2024.2449482] [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: 09/27/2024] [Revised: 12/03/2024] [Accepted: 12/30/2024] [Indexed: 01/06/2025]
Abstract
Colorectal cancer (CRC) continues to be a major worldwide health issue, with elevated death rates linked to late stages of the illness. Immunotherapy has made significant progress in developing effective techniques to improve the immune system's capacity to identify and eradicate cancerous cells. This study examines the most recent advancements in CAR-T cell treatment and exosome-based immunotherapy for CRC. CAR-T cell therapy, although effective in treating blood cancers, encounters obstacles when used against solid tumours such as CRC. These obstacles include the presence of an immunosuppressive tumour microenvironment and a scarcity of tumour-specific antigens. Nevertheless, novel strategies like dual-receptor CAR-T cells and combination therapy involving cytokines have demonstrated promise in surmounting these obstacles. Exosome-based immunotherapy is a promising approach for targeted delivery of therapeutic drugs to tumour cells, with high specificity and minimal off-target effects. However, there are still obstacles to overcome in the field, such as resistance to treatment, adverse effects associated with the immune system, and the necessity for more individualised methods. The current research is focused on enhancing these therapies, enhancing the results for patients, and ultimately incorporating these innovative immunotherapeutic approaches into the standard treatment protocols for CRC.
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Affiliation(s)
- Sepideh Arabi
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Manouchehr Fadaee
- Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Kazemi
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Mohammadreza Rahmani
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
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Güven DC, Thong MS, Arndt V. Survivorship outcomes in patients treated with immune checkpoint inhibitors: a scoping review. J Cancer Surviv 2025; 19:806-845. [PMID: 38175366 PMCID: PMC12081552 DOI: 10.1007/s11764-023-01507-w] [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: 09/15/2023] [Accepted: 11/26/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have become a central part of cancer care. However, the survivorship outcomes in patients treated with ICIs are understudied. Therefore, we conducted a scoping review to evaluate the current status of the field and to establish research gaps regarding survivorship outcomes with ICIs in real-life cohorts. METHODS We used the Web of Science, PubMed, and Embase databases to systematically filter published studies with real-life cohorts from January 1, 2010, until October 19, 2022. Studies evaluating at least one survivorship outcome in ICI-treated patients were included. RESULTS A total of 39 papers were included. Quality of life (QoL) (n = 23), toxicity burden (n = 16), and psychosocial issues (n = 9) were the most frequently evaluated survivorship outcomes. Anti-PD-1/PD-L1 monotherapy and a response to treatment were associated with better QoL. In addition, the ICIs were associated with grade 3 or higher immune-related adverse events (irAEs) in 10-15% and late/long-term irAEs in 20-30% of the survivors. Regarding psychosocial problems, over 30% of survivors showed evidence of anxiety and depression, and 30-40% of survivors reported neurocognitive impairments. CONCLUSION The survivors treated with ICIs have impairments in most survivorship domains. Further research is needed to gather data on the understudied survivorship outcomes like late and long-term effects, fertility, financial toxicity, and return to work in survivors treated with ICIs. IMPLICATIONS FOR CANCER SURVIVORS Available evidence demonstrates that a significant portion of survivors treated with ICIs have a significant toxicity burden, lower QoL than the general population, and a high rate of psychosocial problems.
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Affiliation(s)
- Deniz Can Güven
- Department of Medical Oncology, Hacettepe University Cancer Institute, 06100 Sihhiye, Ankara, Turkey.
- Health Sciences University, Elazig City Hospital, Elazig, Turkey.
- Unit of Cancer Survivorship, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Melissa Sy Thong
- Unit of Cancer Survivorship, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Volker Arndt
- Unit of Cancer Survivorship, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Ibáñez-Juliá MJ, Bataller L, Cabello-Murgui FJ, Nguyen-Them L, Alentorn A, Torres-Martínez A, Mazón-Momparler M, Gironés-Sarrió R. Clinical and radiological features of pseudoprogression in brain tumors treated with immune checkpoint inhibitors. J Neurooncol 2025:10.1007/s11060-025-05091-0. [PMID: 40426008 DOI: 10.1007/s11060-025-05091-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2025] [Accepted: 05/17/2025] [Indexed: 05/29/2025]
Abstract
PURPOSE Immune checkpoint inhibitors (ICIs) are increasingly used in cancer treatment, resulting in the emergence of various immune-related adverse effects, including pseudoprogression (PsP). We sought to evaluate the characteristics of pseudoprogression in adults treated with ICIs for brain tumors (either primary or secondary), and to compare it with a non- PsP group. METHODS We retrospectively identified adults with brain tumors treated with ICIs at our institution between 2015 and 2023. Eligibility required one brain magnetic resonance imaging scan prior to treatment and another obtained within 6 months after treatment initiation. PsP was defined as radiological worsening within 6 months of ICI initiation, followed by stabilization or improvement without therapy modification. Demographic, clinical, and radiological characteristics were analyzed and compared between the PsP and the non-PsP groups. RESULTS Among 102 eligible patients, 10 (9.8%) developed PsP. Clinical symptoms occurred in 4 (40%) cases, all of which showed favorable outcomes with corticosteroid therapy. The PsP group had higher baseline tumor burden (p = 1.29 × 10⁻¹³) and higher PD-L1 expression (p < 0.001) than the non-PsP group. Median progression-free survival and overall survival were numerically longer in the PsP group with no significant difference. CONCLUSIONS PsP is a frequent complication of ICIs. We describe 4 symptomatic patients with pseudoprogression, challenging the iRANO criteria that recommend excluding this diagnosis in symptomatic cases. Clinical impairment should not automatically rule out pseudoprogression, and each case requires thorough evaluation. High PD-L1 expression and greater tumor burden may be associated with PsP, but further studies are needed to confirm these findings.
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Affiliation(s)
| | - Luis Bataller
- Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain.
- Department of Neurology, Instituto Valenciano de Oncología, Valencia, Spain.
| | | | - Ludovic Nguyen-Them
- Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Agusti Alentorn
- Sorbonne Universités, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, Inserm, Paris, HP, France
- Department of Neurology Mazarin, Hôpitaux universitaires Pitié-Salpêtrière Charles Foix.Assistance Publique Hôpitaux de Paris (APHP), Paris, France
| | - Alba Torres-Martínez
- Medical Oncology Department, Hospital Universitari i Politècnic la Fe, Valencia, Spain
| | | | - Regina Gironés-Sarrió
- Medical Oncology Department, Hospital Universitari i Politècnic la Fe, Valencia, Spain
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Wang C, Wang C, Zhang J, Ding M, Ge Y, He X. Development and validation of a radiogenomics prognostic model integrating PET/CT radiomics and glucose metabolism-related gene signatures for non-small cell lung cancer. Eur J Nucl Med Mol Imaging 2025:10.1007/s00259-025-07354-4. [PMID: 40423774 DOI: 10.1007/s00259-025-07354-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Accepted: 05/13/2025] [Indexed: 05/28/2025]
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) is a highly heterogeneous malignancy characterized by altered glucose metabolism. Integration of PET/CT radiomics with glucose metabolism-related genomic signatures could provide a more comprehensive approach for prognosis and treatment guidance. METHODS Radiomics features were extracted from PET/CT images of 156 NSCLC patients from The Cancer Imaging Archive (TCIA) database, and glucose metabolism-related gene signatures were obtained from TCGA and GEO databases. We developed a multimodal radiogenomics prognostic model (RGC-score) using least absolute shrinkage and selection operator (LASSO) regression, combining PET/CT radiomics, glucose metabolism-related genes (GMR-genes). Functional enrichment analysis, immune infiltration assessment, and drug sensitivity analysis were performed to investigate the biological significance of glucose metabolism-related genes (GMR-genes). RESULTS The RGC-score model effectively stratified NSCLC patients into distinct high- and low-risk groups with significant differences in survival outcomes (P < 0.001), demonstrating excellent predictive performance (1-year AUC = 0.907, 5-year AUC = 0.968).GMR-genes are mainly involved in the process of metabolic remodeling of tumors, which is closely related to the immune microenvironment (especially CD8+ T cell infiltration) and immune checkpoint molecule expression. Additionally, significant differences in drug sensitivity were identified between glucose metabolism subtypes. CONCLUSION The RGC-score robustly predicts NSCLC prognosis and informs metabolic-immune interactions for personalized therapy. Limitations include the retrospective design and modest validation cohort size, necessitating prospective multicenter trials.
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Affiliation(s)
- Chunsheng Wang
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China
- Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211116, Jiangsu, China
| | - Congjie Wang
- Department of Pulmonary and Critical Care Medicine, Yantai Yuhuangding Hospital, Yantai, 264000, Shandong, China
| | - Jianguo Zhang
- Department of Pulmonary Oncology, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China
| | - Mingjun Ding
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China
- Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211116, Jiangsu, China
| | - Yizhi Ge
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China.
- Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211116, Jiangsu, China.
| | - Xia He
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China.
- Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211116, Jiangsu, China.
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20
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Huang L, Zhu H, Dai L, Feng Y, Chen X, Xie Z, Hu X, Liu Y, Hao X, Lin L, Wang H, Zhou S, Yao J, Tang L, Han X, Shi Y. Clinical, immune cell, and genetic features predicting survival and long-term response to first-line chemo-immunotherapy treatment for non-small cell lung cancer. Cancer Immunol Immunother 2025; 74:219. [PMID: 40411563 PMCID: PMC12103420 DOI: 10.1007/s00262-025-04022-2] [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: 12/27/2024] [Accepted: 03/14/2025] [Indexed: 05/26/2025]
Abstract
INTRODUCTION Chemo-immunotherapy has become a standard of care for the first-line treatment of non-small cell lung cancer (NSCLC), but currently still lacks reliable markers to predict therapeutic efficacy and long-term response (LTR). METHODS In this study, we retrospectively summarized the survival outcome of 319 patients with locally advanced or metastatic NSCLC who received anti-programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) based therapy from January 1st, 2018 to February 28th, 2022 at the Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College. Then a comprehensive analysis of the association of LTR or survival outcomes with various characteristics including clinical parameters, peripheral blood lymphocyte subsets and common gene mutations in 167 NSCLC patients who received first-line anti-PD-1 plus chemotherapy treatment was conducted. LTR was defined as progression-free survival (PFS) exceeding 24 months, while non-responders had a PFS of less than 6 months. RESULTS With a median follow-up time of 32.1 months (95% confidence interval [CI] 29.2-38.0), the median overall survival (OS) was 29.9 months (95% CI 23.6-37.5) in locally advanced or metastatic NSCLC receiving anti-PD-1/PD-L1 based treatment. Among 167 patients who received the first-line chemo-immunotherapy, 25.1% (n = 42) achieved LTR. Independent baseline predictors of LTR included age < 65 years (odds ratio [OR] = 3.22, p = 0.024), overweight or obesity (body mass index [BMI] ≥ 24 kg/m2, OR = 3.26, p = 0.020), and a C-reactive protein/albumin ratio (CAR) score < 0.07 (OR = 9.94, p = 0.039). In multivariate cox analysis, both patients with higher CAR scores of ≥ 0.07 (hazard ratio [HR] = 2.83, p = 0.016) and those who were underweight (BMI < 18.5 kg/m2) (HR = 4.52, p = 0.005) were observed with significantly shorter OS. A peripheral B cell percentage ≥ 14.5% was more prevalent among LTR patients (OR = 9.23, p = 0.045) after adjusting for age, BMI and TNM stage. Additionally, the presence of TP53 mutation (16/66) was associated with non-response to first-line chemo-immunotherapy (p = 0.048) and shorter PFS (p = 0.028) and OS (p = 0.023) outcomes in univariate analysis. CONCLUSIONS This study provides some new insights into the features and predictors significantly associated with LTR and survival in NSCLC patient receiving first-line treatment of anti-PD-1 plus chemotherapy. Those whose age < 65 years, overweight or obesity, or has a baseline CAR score < 0.07 are more likely to achieve optimal benefit from the first-line treatment of chemo-immunotherapy.
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Affiliation(s)
- Liling Huang
- Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Haohua Zhu
- Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Liyuan Dai
- Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Yu Feng
- Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Xinrui Chen
- Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Zucheng Xie
- Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Xingsheng Hu
- Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Yutao Liu
- Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Xuezhi Hao
- Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Lin Lin
- Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Hongyu Wang
- Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Shengyu Zhou
- Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Jiarui Yao
- Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Le Tang
- Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Xiaohong Han
- Clinical Pharmacology Research Center, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Yuankai Shi
- Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
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Wekking D, Silva CAC, Viscò R, Denaro N, Lambertini M, Maccioni A, Loddo E, Willard-Gallo K, Scartozzi M, Derosa L, Solinas C. The interplay between gut microbiota, antibiotics, and immune checkpoint inhibitors in patients with cancer: A narrative review with biological and clinical aspects. Crit Rev Oncol Hematol 2025; 212:104767. [PMID: 40414545 DOI: 10.1016/j.critrevonc.2025.104767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2025] [Revised: 05/11/2025] [Accepted: 05/13/2025] [Indexed: 05/27/2025] Open
Abstract
Immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathways have revolutionized cancer therapy. However, primary and secondary resistance to ICI pose significant challenges. Recent studies underscore the critical role of gut microbiota (GM) in modulating ICI efficacy by shaping host immune responses and regulating the tumor microenvironment (TME). The composition of the GM has been linked to ICI treatment outcomes, with certain microbial taxa, such as Faecalibacterium spp., Bifidobacterium spp., Eubacterium spp., Roseburia spp., and Akkermansia muciniphila, associated with favorable responses. Mechanistically, the GM affects immune responses via multiple pathways, including induction of T cell differentiation, promotion of anti- or proinflammatory cytokine environments, and enhancement of T cell priming and effector functions. Moreover, microbial-derived metabolites play a role in shaping tumor immune responses and influencing ICI efficacy. Antibiotic treatment can disrupt GM diversity and composition (gut dysbiosis), potentially diminishing ICI effectiveness. A deeper understanding of the interplay between GM, antibiotic treatment, and ICI efficacy is crucial for developing personalized therapeutic strategies to improve patient outcomes. Herein, we review current evidence on the association between specific microbial taxa and tumor immunosurveillance, the impact of antibiotics on the GM composition and immune modulation, and its implications for ICI therapy efficacy.
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Affiliation(s)
- Demi Wekking
- Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
| | - Carolina Alves Costa Silva
- Gustave Roussy Cancer Campus (GRCC), Clinicobiome, Villejuif, France; Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France
| | - Roberto Viscò
- Ospedale Sant'Antonio Abate, Patologica Clinica, ASP Trapani, Italy
| | - Nerina Denaro
- Medical Oncology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Italy
| | - Matteo Lambertini
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genova, Genova, Italy; Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Antonio Maccioni
- Medical Oncology AOU Cagliari Policlinico Duilio Casula, Monserrato (CA) Italy
| | - Erica Loddo
- Gastroenterology University Hospital, Cagliari, Italy
| | | | - Mario Scartozzi
- Medical Oncology AOU Cagliari Policlinico Duilio Casula, Monserrato (CA) Italy; University Hospital of Cagliari, Italy
| | - Lisa Derosa
- Gustave Roussy Cancer Campus (GRCC), Clinicobiome, Villejuif, France; Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France; Faculté de Médecine, Université Paris-Saclay, Kremlin-Bicêtre, France
| | - Cinzia Solinas
- Medical Oncology AOU Cagliari Policlinico Duilio Casula, Monserrato (CA) Italy
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Zheng Y, Sadée C, Ozawa M, Howitt BE, Gevaert O. Single-cell multimodal analysis reveals tumor microenvironment predictive of treatment response in non-small cell lung cancer. SCIENCE ADVANCES 2025; 11:eadu2151. [PMID: 40408481 PMCID: PMC12101509 DOI: 10.1126/sciadv.adu2151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 04/22/2025] [Indexed: 05/25/2025]
Abstract
Non-small cell lung cancer (NSCLC) constitutes over 80% of lung cancer cases and remains a leading cause of cancer-related mortality worldwide. Despite the advent of immune checkpoint inhibitors, their efficacy is limited to 27 to 45% of patients. Identifying likely treatment responders is essential for optimizing healthcare and improving quality of life. We generated multiplex immunofluorescence (mIF) images, histopathology, and RNA sequencing data from human NSCLC tissues. Through the analysis of mIF images, we characterized the spatial organization of 1.5 million cells based on the expression levels for 33 biomarkers. To enable large-scale characterization of tumor microenvironments, we developed NucSegAI, a deep learning model for automated nuclear segmentation and cellular classification in histology images. With this model, we analyzed the morphological, textural, and topological phenotypes of 45.6 million cells across 119 whole-slide images. Through unsupervised phenotype discovery, we identified specific lymphocyte phenotypes predictive of immunotherapy response. Our findings can improve patient stratification and guide selection of effective therapeutic regimens.
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Affiliation(s)
- Yuanning Zheng
- Stanford Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA 94305, USA
| | - Christoph Sadée
- Stanford Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA 94305, USA
| | - Michael Ozawa
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Brooke E. Howitt
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Olivier Gevaert
- Stanford Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA 94305, USA
- Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA
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Shi Y, Liu X, Liu A, Fang J, Meng Q, Ding C, Ai B, Gu Y, Zhang C, Zhou C, Wang Y, Shui Y, Yu S, Zhang D, Liu J, Zhang H, Zhou Q, Gao X, Chen M, Zhao J, Zhong W, Xu Y, Wang M. Programmed death-ligand 1 tumor proportion score in predicting the safety and efficacy of PD-1/PD-L1 antibody-based therapy in patients with advanced non-small cell lung cancer: A retrospective, multicenter, observational study. Chin Med J (Engl) 2025:00029330-990000000-01563. [PMID: 40413619 DOI: 10.1097/cm9.0000000000003620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Indexed: 05/27/2025] Open
Abstract
BACKGROUND This study aimed to investigate the safety and efficacy of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibody-based therapy in treating patients with advanced non-small cell lung cancer (NSCLC) according to different PD-L1 expression statuses in a real-world setting. METHODS This retrospective, multicenter, observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria: (1) had pathologically confirmed, unresectable stage III-IV NSCLC; (2) had a baseline PD-L1 tumor proportion score (TPS); and (3) had confirmed efficacy evaluation results after PD-1/PD-L1 treatment. Logistic regression, Kaplan-Meier analysis, and Cox regression were used to assess the progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) as appropriate. RESULTS A total of 409 patients, 65.0% (n = 266) with a positive PD-L1 TPS (≥1%) and 32.8% (n = 134) with PD-L1 TPS ≥50%, were included in this study. Cox regression confirmed that patients with a PD-L1 TPS ≥1% had significantly improved PFS (hazard ratio [HR] 0.747, 95% confidence interval [CI] 0.573-0.975, P = 0.032). A total of 160 (39.1%) patients experienced 206 irAEs, and 27 (6.6%) patients experienced 31 grade 3-5 irAEs. The organs most frequently associated with irAEs were the skin (52/409, 12.7%), thyroid (40/409, 9.8%), and lung (34/409, 8.3%). Multivariate logistic regression revealed that a PD-L1 TPS ≥1% (odds ratio [OR] 1.713, 95% CI 1.054-2.784, P = 0.030) was an independent risk factor for irAEs. Other risk factors for irAEs included pretreatment absolute lymphocyte count >2.5 × 109/L (OR 3.772, 95% CI 1.377-10.329, P = 0.010) and pretreatment absolute eosinophil count >0.2 × 109/L (OR 2.006, 95% CI 1.219-3.302, P = 0.006). Moreover, patients who developed irAEs demonstrated improved PFS (13.7 months vs. 8.4 months, P <0.001) and OS (28.0 months vs. 18.0 months, P = 0.007) compared with patients without irAEs. CONCLUSIONS A positive PD-L1 TPS (≥1%) was associated with improved PFS and an increased risk of irAEs in a real-world setting. The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.
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Affiliation(s)
- Yuequan Shi
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
- Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Xiaoyan Liu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Anwen Liu
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Jian Fang
- Department of Thoracic Oncology II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Qingwei Meng
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China
| | - Cuimin Ding
- Department of Respiratory Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050033, China
| | - Bin Ai
- Department of Medical Oncology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Yangchun Gu
- Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital, Beijing 100191, China
| | - Cuiying Zhang
- Department of Medical Oncology, Cancer Center, People's Hospital, Hohhot, Inner Mongolia Autonomous Region 750306, China
| | - Chengzhi Zhou
- Department of Respiratory and Critical Care Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510120, China
| | - Yan Wang
- Department of Medical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China
| | - Yongjie Shui
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
| | - Siyuan Yu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Dongming Zhang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Jia Liu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Haoran Zhang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Qing Zhou
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Xiaoxing Gao
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Minjiang Chen
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Jing Zhao
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Wei Zhong
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Yan Xu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Mengzhao Wang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
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Zheng T, Li X, Zhou L, Jin J. Predictive value of machine learning for PD-L1 expression in NSCLC: a systematic review and meta-analysis. World J Surg Oncol 2025; 23:199. [PMID: 40405177 PMCID: PMC12101016 DOI: 10.1186/s12957-025-03847-6] [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: 02/24/2025] [Accepted: 05/11/2025] [Indexed: 05/24/2025] Open
Abstract
BACKGROUND As machine learning (ML) continuously develops in cancer diagnosis and treatment, some researchers have attempted to predict the expression of programmed death ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) by ML. However, there is a lack of systematic evidence on the effectiveness of ML. METHODS We conducted a thorough search across Embase, PubMed, the Cochrane Library, and Web of Science from inception to December 14th, 2023.A systematic review and meta-analysis was conducted to assess the value of ML for predicting PD-L1 expression in NSCLC. RESULTS Totally 30 studies with 12,898 NSCLC patients were included. The thresholds of PD-L1 expression level were < 1%, 1-49%, and ≥ 50%. In the validation set, in the binary classification for PD-L1 ≥ 1%, the pooled C-index was 0.646 (95%CI: 0.587-0.705), 0.799 (95%CI: 0.782-0.817), 0.806 (95%CI: 0.753-0.858), and 0.800 (95%CI: 0.717-0.883), respectively, for the clinical feature-, radiomics-, radiomics + clinical feature-, and pathomics-based ML models; in the binary classification for PD-L1 ≥ 50%, the pooled C-index was 0.649 (95%CI: 0.553-0.744), 0.771 (95%CI: 0.728-0.814), and 0.826 (95%CI: 0.783-0.869), respectively, for the clinical feature-, radiomics-, and radiomics + clinical feature-based ML models. CONCLUSIONS At present, radiomics- or pathomics-based ML methods are applied for the prediction of PD-L1 expression in NSCLC, which both achieve satisfactory accuracy. In particular, the radiomics-based ML method seems to have wider clinical applicability as a non-invasive diagnostic tool. Both radiomics and pathomics serve as processing methods for medical images. In the future, we expect to develop medical image-based DL methods for intelligently predicting PD-L1 expression.
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Affiliation(s)
- Ting Zheng
- Department of Medical Oncology, The First People's Hospital of Linping District, Hangzhou, 311100, Zhejiang Province, China.
| | - Xingxing Li
- Department of Medical Oncology, The First People's Hospital of Linping District, Hangzhou, 311100, Zhejiang Province, China
| | - Li Zhou
- Department of Medical Oncology, The First People's Hospital of Linping District, Hangzhou, 311100, Zhejiang Province, China
| | - Jianjiang Jin
- Department of Medical Oncology, The First People's Hospital of Linping District, Hangzhou, 311100, Zhejiang Province, China
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25
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Tanaka S, Nozaki K, Watanabe S, Yanagimura N, Arita M, Sato M, Tanaka T, Saida Y, Goto Y, Kushiro K, Fujisaki T, Sato K, Ishikawa D, Miyabayashi T, Ichikawa K, Ota T, Hayashi Y, Koyama K, Ishida A, Kikuchi T. Risk of lung injury with immune checkpoint inhibitors after talc pleurodesis: A retrospective study. Lung Cancer 2025; 204:108590. [PMID: 40412103 DOI: 10.1016/j.lungcan.2025.108590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2025] [Accepted: 05/20/2025] [Indexed: 05/27/2025]
Abstract
INTRODUCTION The safety of administering immune checkpoint inhibitors (ICIs) after talc pleurodesis, particularly the impact of talc on the development of immune-related interstitial lung disease (ILD), remains unclear. METHODS We retrospectively analysed patients with primary lung cancer or malignant pleural mesothelioma who received ICIs within 90 days of talc pleurodesis at facilities participating in the Niigata Lung Cancer Treatment Study Group between November 2016 and June 2023. RESULTS A total of 52 cases were included, with 17 patients (32.7 %) developing ILD following ICI administration. The median time to ILD onset after ICI administration was 62 days. The median overall survival was 6 months in patients who developed ILD and 16.4 months in those who did not (P = 0.081). Among the five patients with pre-existing interstitial changes, four (80.0 %) developed ILD after ICI administration, identifying a high-risk subgroup. CONCLUSION A high incidence of ILD was observed in patients who received ICI therapy after talc pleurodesis. Additionally, overall survival tended to be shorter in patients who developed ILD.
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Affiliation(s)
- Susumu Tanaka
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Koichiro Nozaki
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Satoshi Watanabe
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
| | - Naohiro Yanagimura
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masashi Arita
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Miyuki Sato
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Tomohiro Tanaka
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yu Saida
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yuka Goto
- Department of Respiratory Medicine, Saiseikai Niigata Keno Core Hospital, Niigata, Japan
| | - Kohei Kushiro
- Department of Respiratory Medicine, Kashiwazaki General Medical Center, Niigata, Japan
| | - Toshiya Fujisaki
- Department of Respiratory Medicine, Tachikawa General Hospital, Niigata, Japan
| | - Ko Sato
- Department of Respiratory Medicine, Joetsu General Hospital, Niigata, Japan
| | - Daisuke Ishikawa
- Department of Respiratory Medicine, Niigata Prefectural Central Hospital, Joetsu, Japan
| | - Takao Miyabayashi
- Department of Respiratory Medicine, Niigata City General Hospital, Niigata, Japan
| | - Kosuke Ichikawa
- Department of Respiratory Medicine, Saiseikai Niigata Hospital, Niigata, Japan
| | - Takeshi Ota
- Department of Respiratory Medicine, Niigata Prefectural Shibata Hospital, Niigata, Japan
| | - Yoshiki Hayashi
- Department of Respiratory Medicine, Nagaoka Central General Hospital, Niigata, Japan
| | - Kenichi Koyama
- Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan
| | - Akira Ishida
- Department of Respiratory Medicine, Nagaoka Red Cross Hospital, Nagaoka, Japan
| | - Toshiaki Kikuchi
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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Mizusaki S, Yoneshima Y, Iwama E, Nakashima T, Ibusuki R, Shibahara D, Otsubo K, Tanaka K, Okamoto I. NECTIN4 regulates the cell surface expression of CD155 in non-small cell lung cancer cells and induces tumor resistance to PD-1 inhibitors. Cancer Immunol Immunother 2025; 74:211. [PMID: 40392373 PMCID: PMC12092325 DOI: 10.1007/s00262-025-04079-z] [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: 11/26/2024] [Accepted: 05/03/2025] [Indexed: 05/22/2025]
Abstract
The development of immune checkpoint inhibitors has changed treatment strategies for some patients with non-small cell lung cancer (NSCLC). However, resistance remains a major problem, requiring the elucidation of resistance mechanisms, which might aid the development of novel therapeutic strategies. The upregulation of CD155, a primary ligand of the immune checkpoint receptor TIGIT, has been implicated in a mechanism of resistance to PD-1/PD-L1 inhibitors, and it is therefore important to characterize the mechanisms underlying the regulation of CD155 expression in tumor cells. The aim of this study was to identify a Nectin that might regulate CD155 expression in NSCLC and affect anti-tumor immune activity. In this study, we demonstrated that NECTIN4 regulated the cell surface expression and stabilization of CD155 by interacting and co-localizing with CD155 on the cell surface. In a syngeneic mouse model, NECTIN4-overexpressing cells exhibited increased cell surface CD155 and resistance to anti-PD-1 antibodies. Of note, combination therapy with anti-PD-1 and anti-TIGIT antibodies significantly suppressed tumor growth. These findings provide new insights into the mechanisms of resistance to anti-PD-1 antibodies and suggest that NECTIN4 could serve as a valuable marker in therapeutic strategies targeting TIGIT.
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Affiliation(s)
- Shun Mizusaki
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yasuto Yoneshima
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
| | - Eiji Iwama
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Tadayuki Nakashima
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Ritsu Ibusuki
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Daisuke Shibahara
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kohei Otsubo
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kentaro Tanaka
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Isamu Okamoto
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
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Chen Y, Li Q, Wang Z, Sun LV, Hou SX. A novel NFKB1 agonist remodels tumor microenvironment and activates dendritic cells to promote anti-tumor immunity in colorectal cancer. J Transl Med 2025; 23:561. [PMID: 40394677 PMCID: PMC12090520 DOI: 10.1186/s12967-025-06576-2] [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: 02/13/2025] [Accepted: 05/01/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND The immunosuppressive nature of the tumor microenvironment (TME) and the existence of cancer stem cells (CSCs) present significant hurdles in tumor therapy. The identification of therapeutic agents that can target both CSCs and the TME could be a potential approach to overcome treatment resistance. METHODS We conducted an in vivo chemical screen to identify F1929-1458, which is capable of eliciting an organism-wide response to destroy stem cell tumors in Drosophila. We then performed functional validation using a mouse colorectal cancer graft tumor model established with the CT26 cell line characterized by its high content of CSCs. Single-cell sequencing was employed to analyze alterations in the TME. Small molecule pull-down mass spectrometry, cellular thermal shift assay, drug affinity experiment, and molecular docking were utilized to identify the target of F1929-1458. An in vitro co-culture system was applied to establish that the damage-associated molecular patterns (DAMPs) released by the tumor cells are accountable for the activation of dendritic cells (DCs). RESULTS We demonstrated that F1929-1458 treatment enhanced T cell infiltration and T cell mediated tumor regression, its anti-tumor effect was nullified in nude mice and was abolished after anti-CD3 neutralizing antibody treatment. We found that F1929-1458 binds NFKB1 to activate the NF-κB signaling pathway in tumor cells. The activation further elicits cellular stress, causing tumor cells to release DAMPs (HMGB1-gDNA complex, ATP, and OxLDL). These DAMPs, in turn, stimulate the cGAS-STING and NLRP3 inflammasome pathways in DCs, resulting in the generation of type I IFNs and IL-1β. These cytokines facilitate the maturation of DCs and antigen presentation, ultimately enhancing T cell-mediated anti-tumor immunity. Additionally, we showed that the combination of F1929-1458 and the anti-PD-1 antibody exhibited a synergistic anti-tumor effect. CONCLUSION Our study identified a novel NFKB1 agonist that promotes anti-tumor immunity by remodeling the TME and activating DCs and that may provide a new way to overcome resistance to current anti-tumor immunotherapy in colorectal cancer.
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Affiliation(s)
- Ying Chen
- Department of Cell and Developmental Biology at School of Life Sciences, State Key Laboratory of Genetic Engineering, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Children's Hospital, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Qiaoming Li
- Department of Cell and Developmental Biology at School of Life Sciences, State Key Laboratory of Genetic Engineering, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Children's Hospital, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Zixiang Wang
- Department of Cell and Developmental Biology at School of Life Sciences, State Key Laboratory of Genetic Engineering, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Children's Hospital, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Ling V Sun
- Department of Cell and Developmental Biology at School of Life Sciences, State Key Laboratory of Genetic Engineering, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Children's Hospital, Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
| | - Steven X Hou
- Department of Cell and Developmental Biology at School of Life Sciences, State Key Laboratory of Genetic Engineering, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Children's Hospital, Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
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28
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Park J, Chen YY, Cao JJ, An J, Chiu Yen RW, Outen JD, Baylin SB, Topper MJ. MYC plus class IIa HDAC inhibition drives mitochondrial dysfunction in non-small cell lung cancer. Cell Rep 2025; 44:115722. [PMID: 40392656 DOI: 10.1016/j.celrep.2025.115722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 03/11/2025] [Accepted: 04/29/2025] [Indexed: 05/22/2025] Open
Abstract
Despite much progress in targeting the MYC oncoprotein, combination treatment strategies are needed to exploit this molecular vulnerability. To this end, we interrogated transcriptome data from cancer cell lines treated with MYC inhibitors and identified HDAC5 and HDAC9, both class IIa histone deacetylases (HDACs), as potential therapeutic targets. Notably, these therapeutically actionable HDAC isoforms are known augmenters of several hallmarks of cancer. Dual targeting of MYC and class IIa HDACs induces a significant reduction in viability for non-small cell lung cancer (NSCLC) cell lines with high MYC and mitochondrial activity. Additionally, combination treatment induces a robust MYC suppression with mitochondrial reactive oxygen species (ROS) elevation, which has a causal relationship with therapeutic efficacy. Confirmation of in vivo efficacy was pursued in several animal models, with subsequent molecular-correlate derivation confirming the importance of MYC depletion and mitochondrial dysfunction in drug efficacy. Ultimately, we define a therapeutic approach combining MYC- and class IIa HDAC-inhibition to potentiate anti-tumor efficacy in NSCLC.
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Affiliation(s)
- Jina Park
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ying-Yu Chen
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jennie J Cao
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Julia An
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ray-Whay Chiu Yen
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Stephen B Baylin
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Michael J Topper
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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29
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Boudoussier A, Larrouture I, Henrot P, Veillon R, Bardel C, Chautemps C, Caumont C, Schilfarth P, Duruisseaux M, Zysman M. COPD patients with non-small cell lung cancer respond better to anti-PD-(L)1 immune checkpoint inhibitors. Sci Rep 2025; 15:17145. [PMID: 40382449 PMCID: PMC12085620 DOI: 10.1038/s41598-025-02251-0] [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: 07/17/2024] [Accepted: 05/12/2025] [Indexed: 05/20/2025] Open
Abstract
In studies evaluating the efficacy of anti-programmed cell death 1/ligand 1 immune checkpoint inhibitors (anti-PD-(L)1) among patients with non-small cell lung cancer (NSCLC), smokers tend to have better clinical outcomes than non-smokers. However, it is unclear whether NSCLC patients with co-existing chronic obstructive pulmonary disease (COPD) have better clinical outcomes than patients without COPD, regardless of smoking history. The potential correlation of COPD with an improved response to anti-PD-(L)1 was examined in a large cohort of patients with available pulmonary function test results. Patients with stage IV NSCLC who received a minimum of two doses of anti-PD-(L)1 across various treatment lines from 2015 to 2021 were enrolled. Among the 387 patients, pulmonary function test (PFT) data were available for 234 (61%), 139 (59%) of whom had spirometry diagnosed COPD. A retrospective analysis was conducted to evaluate overall survival (OS) and progression-free survival (PFS) based on the presence or absence of COPD. In the univariate analyses, both PFS and OS significantly improved among patients with COPD, compared with patients who did not have COPD (HR 0.71, 95% CI 0.56-0.89 for PFS; HR 0.69, 95% CI 0.52-0.92 for OS), regardless of smoking status. In the multivariate analyses, PFS and OS remained superior among patients with COPD (HR 0.66, 95% CI 0.51-0.85 for PFS; HR 0.63, 95% CI 0.47-0.85 for OS). Additionally, patients with milder COPD (GOLD 1/2 vs. 3/4) had better clinical outcomes than patients with more severe disease. However, neither lung distension (defined as a total lung capacity > 120%) nor pre-COPD status (defined as a diffusing capacity of lung for carbon monoxide < 70%) had a significant impact on PFS or OS. Our study, conducted in the largest cohort with available PFT data to date, showed that COPD was associated with improved survival outcomes among patients with stage IV NSCLC who received anti-PD-(L)1 treatment, regardless of smoking history. The differences were mainly driven by mild and moderate obstruction (GOLD 1 and 2). The dysregulated PD-1/PD-L1 expression that occurs in COPD may offer insights into the different outcomes and thus warrants further investigation.
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Affiliation(s)
- Augustin Boudoussier
- Service des Maladies Respiratoires et des épreuves fonctionnelles respiratoires, CHU Bordeaux, Pessac, 33604, France
| | | | - Pauline Henrot
- Service des Maladies Respiratoires et des épreuves fonctionnelles respiratoires, CHU Bordeaux, Pessac, 33604, France
- Centre de Recherche cardio-thoracique de Bordeaux, U1045, CIC 1401, Univ-Bordeaux, Pessac, 33604, France
| | - Rémi Veillon
- Service des Maladies Respiratoires et des épreuves fonctionnelles respiratoires, CHU Bordeaux, Pessac, 33604, France
| | - Claire Bardel
- Service des Maladies Respiratoires et des épreuves fonctionnelles respiratoires, CHU Bordeaux, Pessac, 33604, France
| | - Camille Chautemps
- Service des Maladies Respiratoires et des épreuves fonctionnelles respiratoires, CHU Bordeaux, Pessac, 33604, France
| | - Charline Caumont
- Service Biologie des tumeurs, CHU Bordeaux, Pessac, 33604, France
| | - Pierre Schilfarth
- Service des Maladies Respiratoires et des épreuves fonctionnelles respiratoires, CHU Bordeaux, Pessac, 33604, France
| | - Michael Duruisseaux
- Respiratory Department and Early Phase (EPSILYON), Louis Pradel Hospital, Hospices Civils de Lyon Cancer Institute, Lyon, France
- Oncopharmacology Laboratory, Cancer Research Center of Lyon, UMR INSERM 1052 CNRS 5286, Lyon, France
- Université Claude Bernard, Université de Lyon, Lyon, France
| | - Maeva Zysman
- Service des Maladies Respiratoires et des épreuves fonctionnelles respiratoires, CHU Bordeaux, Pessac, 33604, France.
- Centre de Recherche cardio-thoracique de Bordeaux, U1045, CIC 1401, Univ-Bordeaux, Pessac, 33604, France.
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Öksüz NE, Aydemir E, Bir Yucel K. Reevaluating the prognostic impact of spread through air spaces and lymphovascular invasion in resected non-small cell lung cancer: the role of systemic therapy in survival outcomes. Updates Surg 2025:10.1007/s13304-025-02259-1. [PMID: 40382518 DOI: 10.1007/s13304-025-02259-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2025] [Accepted: 05/07/2025] [Indexed: 05/20/2025]
Affiliation(s)
- Nejat Emre Öksüz
- Department of Medical Oncology, Ankara University, Balkiraz Mahallesi, Tıp Fakültesi Caddesi No: 1/4, Mamak, 06620, Ankara, Turkey.
| | - Ergin Aydemir
- Department of Medical Oncology, Medical Oncology, Dr Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey
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31
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Goto N, Agudo J, Yilmaz ÖH. Early immune evasion in colorectal cancer: interplay between stem cells and the tumor microenvironment. Trends Cancer 2025:S2405-8033(25)00112-8. [PMID: 40382216 DOI: 10.1016/j.trecan.2025.04.016] [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: 01/27/2025] [Revised: 04/23/2025] [Accepted: 04/24/2025] [Indexed: 05/20/2025]
Abstract
Most colorectal cancers (CRCs) are characterized by a low mutational burden and an immune-cold microenvironment, limiting the efficacy of immune checkpoint blockade (ICB) therapies. While advanced tumors exhibit diverse immune evasion mechanisms, emerging evidence suggests that aspects of immune escape arise much earlier, within precancerous lesions. In this review, we discuss how early driver mutations and epigenetic alterations contribute to the establishment of an immunosuppressive microenvironment in CRC. We also highlight the dynamic crosstalk between cancer cells, stromal niche cells, and immune cells driving immune evasion and liver metastasis. A deeper understanding of these early events may guide the development of more effective preventive and therapeutic strategies for CRC.
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Affiliation(s)
- Norihiro Goto
- Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology & Hepatology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.
| | - Judith Agudo
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center at Harvard, Boston, MA 02215, USA; Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA 02215, USA; New York Stem Cell Foundation, New York, NY 10019, USA
| | - Ömer H Yilmaz
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Beth Israel Deaconess Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
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Gill GS, Kharb S, Goyal G, Das P, Kurdia KC, Dhar R, Karmakar S. Immune Checkpoint Inhibitors and Immunosuppressive Tumor Microenvironment: Current Challenges and Strategies to Overcome Resistance. Immunopharmacol Immunotoxicol 2025:1-45. [PMID: 40376861 DOI: 10.1080/08923973.2025.2504906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Accepted: 05/06/2025] [Indexed: 05/18/2025]
Abstract
Immune checkpoint inhibitors (ICIs) are shown to improve cancer treatment effectiveness by boosting the immune system of the patient. Nevertheless, the unique and highly suppressive TME poses a significant challenge, causing heterogeneity of response or resistance in a considerable number of patients. This review focuses on the evasive attributes of the TME. Immune evasion mechanism in TME include immunosuppressive cells, cytokine and chemokine signaling, metabolic alterations and overexpression of immune checkpoint molecules such as PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA and their interactions within the TME. In addition, this review focuses on the overcoming resistance by targeting immunosuppressive cells, normalizing tumor blood vessels, blocking two or three checkpoints simultaneously, combining vaccines, oncolytic viruses and metabolic inhibitors with ICIs or other therapies. This review also focuses on the necessity of finding predictive markers for the stratification of patients and to check response of ICIs treatment. It remains to be made certain by new research and intelligent innovations how these discoveries of the TME and its interplay facilitate ICI treatment and change the face of cancer treatment.
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Affiliation(s)
- Gurpreet Singh Gill
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Simmi Kharb
- Department of Biochemistry, Pt. B.D. Sharma Postgraduate Institute of Medical Sciences, Rohtak, India
| | - Gitanjali Goyal
- Department of Biochemistry, All India Institute of Medical Sciences, Bathinda, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Kailash Chand Kurdia
- Department of GI Surgery & Liver Transplantation, All India Institute of Medical Sciences, New Delhi, India
| | - Ruby Dhar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Subhradip Karmakar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
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Gratzke C, Özgüroğlu M, Peer A, Sendur MAN, Retz M, Goh JC, Loidl W, Jayram G, Byun SS, Kwak C, Kwiatkowski M, Kopp RM, Limón JCV, Penagos JFE, De Giorgi U, da Trindade KM, Niu C, Liu Y, Poehlein CH, Piulats JM. Pembrolizumab plus enzalutamide and androgen deprivation therapy versus placebo plus enzalutamide and androgen deprivation therapy for metastatic hormone-sensitive prostate cancer: the randomized, double-blind, phase III KEYNOTE-991 study. Ann Oncol 2025:S0923-7534(25)00200-5. [PMID: 40383194 DOI: 10.1016/j.annonc.2025.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 05/05/2025] [Accepted: 05/06/2025] [Indexed: 05/20/2025] Open
Abstract
BACKGROUND Despite treatment advances, most patients with metastatic hormone-sensitive prostate cancer (mHSPC) experience disease progression to castration-resistant disease within 5 years. The placebo-controlled, double-blind, phase III KEYNOTE-991 study evaluated the efficacy and safety of adding pembrolizumab to enzalutamide and androgen deprivation therapy (ADT) in participants with mHSPC. PATIENTS AND METHODS Eligible participants were aged ≥18 years with next-generation hormonal agent‒naive mHSPC. Participants were randomly assigned (1:1) to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for ≤35 cycles, with oral enzalutamide 160 mg and continuous ADT. Primary end points were radiographic progression-free survival (rPFS) and overall survival. Safety was a secondary end point. RESULTS Between March 2, 2020, and August 9, 2021, 626 participants were randomly assigned to pembrolizumab plus enzalutamide and ADT and 625 participants to placebo plus enzalutamide and ADT. At the first interim analysis, the median follow-up was 21.1 months (range, 14.8-32.0 months). rPFS was not superior with pembrolizumab versus placebo (median not reached in both arms; hazard ratio, 1.20 [95% confidence interval (CI), 0.96 to 1.49]; P = 0.9467). Median overall survival was not reached in either arm (hazard ratio, 1.16 [95% CI, 0.88 to 1.53]; not formally statistically tested per the multiplicity strategy). Grade ≥3 adverse events (AEs) and serious AEs were reported in 61.9% versus 38.1% and 40.3% versus 23.2% of participants in the pembrolizumab versus the placebo arm, respectively. Any-grade rash occurred at a higher frequency with pembrolizumab (25.1%) versus placebo (9.3%). CONCLUSION KEYNOTE-991 did not meet its primary end point and was stopped for futility. The addition of pembrolizumab to enzalutamide and ADT was associated with higher frequencies of grade ≥3 AEs and serious AEs than with placebo. Rash was identified as an additional safety signal with pembrolizumab plus enzalutamide and ADT.
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Affiliation(s)
- C Gratzke
- Department of Urology, University Hospital Freiburg, Freiburg, Germany.
| | - M Özgüroğlu
- Division of Medical Oncology, Department of Internal Medicine, Istanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Istanbul, Türkiye
| | - A Peer
- Department of Oncology, Rambam Medical Center, Haifa, Israel
| | - M A N Sendur
- Department of Medical Oncology, Ankara Yildirim Beyazit University Faculty of Medicine and Ankara Bilkent City Hospital, Ankara, Turkey
| | - M Retz
- Department of Urology, Rechts der Isar Medical Center, Technical University Munich, Munich, Germany
| | - J C Goh
- Gallipoli Medical Research - Greenslopes Private Hospital, Greenslopes, QLD, Australia
| | - W Loidl
- Department of Urology and Andrology, Ordensklinikum Linz GmbH Elisabethinen, Linz, Austria
| | - G Jayram
- Urology Associates P.C., Nashville, TN, USA
| | - S-S Byun
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - C Kwak
- Department of Urology, Seoul National University Hospital, Seoul, Republic of Korea
| | - M Kwiatkowski
- Oddział Dzienny Chemioterapii, Szpital Wojewódzki im. Mikołaja Kopernika, Koszalin, Poland
| | - R M Kopp
- Sociedad de Oncología y Hematología del Cesar S.A.S., Valledupar, Colombia
| | - J C V Limón
- Hospital Civil de Guadalajara "Fray Antonio Alcalde", Guadalajara, México; Universidad de Guadalajara, Guadalajara, México
| | - J F E Penagos
- Hospital San Lucas Cardiología del Sureste, Tuxtla Gutiérrez, México
| | - U De Giorgi
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori, Meldola, Italy
| | | | - C Niu
- MSD China, Beijing, China
| | - Y Liu
- Merck & Co., Inc., Rahway, NJ, USA
| | | | - J M Piulats
- Instituto Catalan de Oncologia - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
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Kilickap S, Özgüroğlu M, Sezer A, Gümüş M, Bondarenko I, Gogishvili M, Turk HM, Cicin I, Bentsion D, Gladkov O, Sriuranpong V, Quek RGW, McIntyre DAG, He X, McGinniss J, Seebach F, Gullo G, Rietschel P, Pouliot J. Cemiplimab monotherapy as first-line treatment of patients with brain metastases from advanced non-small cell lung cancer with programmed cell death-ligand 1 ≥50. Cancer 2025; 131:e35864. [PMID: 40323717 PMCID: PMC12051739 DOI: 10.1002/cncr.35864] [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: 08/16/2024] [Revised: 02/13/2025] [Accepted: 02/20/2025] [Indexed: 05/07/2025]
Abstract
BACKGROUND In the phase 3 EMPOWER-Lung 1 study, first-line cemiplimab monotherapy provided significant survival benefit versus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50%. This exploratory subgroup analysis investigated the clinical outcomes of cemiplimab treatment in patients with advanced NSCLC with brain metastases. METHODS Patients with advanced NSCLC were randomized (1:1) to cemiplimab 350 mg every 3 weeks or four cycles of platinum doublet chemotherapy (NCT03088540). Patients with symptomatic radiotherapy-treated brain metastases were eligible to enroll. Of the 565 patients with confirmed PD-L1 expression ≥50%, 69 (12%) had brain metastases at baseline. RESULTS Patients with brain metastases who received cemiplimab had a median overall survival (OS) of 52.4 months compared with 20.7 months for those who received chemotherapy (hazard ratio [HR], 0.40; p = .0031) and a median progression-free survival (PFS) of 12.5 versus 5.3 months (HR, 0.33; p = .0002), respectively. Patients without brain metastases had a median OS of 24.3 months with cemiplimab versus 12.5 months with chemotherapy (HR, 0.63; p < .0001); their median PFS was 6.5 months versus 5.2 months (HR, 0.55; p < .0001), respectively. Cemiplimab was associated with a significant improvement in global health status/quality of life in all patients, including those with brain metastases. The cemiplimab safety profile was generally similar in all patients. CONCLUSIONS In patients with advanced NSCLC with PD-L1 ≥50%, first-line cemiplimab monotherapy improved survival and patient-reported outcomes over chemotherapy for those who received prior radiotherapy for symptomatic brain metastases.
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MESH Headings
- Humans
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/pathology
- Brain Neoplasms/secondary
- Brain Neoplasms/drug therapy
- Brain Neoplasms/mortality
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Female
- Lung Neoplasms/pathology
- Lung Neoplasms/drug therapy
- Lung Neoplasms/mortality
- Male
- Middle Aged
- B7-H1 Antigen/metabolism
- Aged
- Adult
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Aged, 80 and over
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Agents, Immunological/adverse effects
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Affiliation(s)
- Saadettin Kilickap
- Department of Medical OncologyIstinye University Faculty of MedicineIstanbulTurkey
| | - Mustafa Özgüroğlu
- Cerrahpaşa Medical FacultyIstanbul University‐CerrahpaşaIstanbulTurkey
| | - Ahmet Sezer
- Department of Medical OncologyBaşkent UniversityAdanaTurkey
| | - Mahmut Gümüş
- Department of Medical OncologySchool of MedicineIstanbul Medeniyet UniversityIstanbulTurkey
| | - Igor Bondarenko
- Department of Oncology and Medical RadiologyDnipropetrovsk Medical AcademyDniproUkraine
| | | | - Haci M. Turk
- Department of Medical OncologyBezmialem Vakif University, Medical FacultyIstanbulTurkey
| | - Irfan Cicin
- Istinya University Faculty of Medicine, Florya Medical Park HospitalIstanbulTurkey
| | - Dmitry Bentsion
- Radiotherapy DepartmentSverdlovsk Regional Oncology CentreSverdlovskRussia
| | | | - Virote Sriuranpong
- Division of Medical OncologyDepartment of MedicineFaculty of MedicineChulalongkorn University and the King Chulalongkorn Memorial HospitalBangkokThailand
| | | | | | - Xuanyao He
- Regeneron Pharmaceuticals, IncTarrytownNew YorkUSA
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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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Biney F, Giroux-Leprieur É, Daniel C, Du Rusquec P, Auliac JB, Assié JB, Anane-Abrous S, Chouaid C. [Influence of smoking on the efficacy of immunotherapy in advanced lung cancers]. Rev Mal Respir 2025:S0761-8425(25)00182-2. [PMID: 40374498 DOI: 10.1016/j.rmr.2025.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 04/21/2025] [Indexed: 05/17/2025]
Abstract
INTRODUCTION Lung cancer is the leading cause of death worldwide. It occurs mainly in smokers, but also in 25% of cases in non-smokers. As regards metastatic stages, while immunotherapy has led to improved overall survival, smoking status may potentially influence its effectiveness. The objective of this study was to analyze its effectiveness as first-line treatment for advanced non-small cell lung cancers (NSCLC) according to patient smoking status. METHOD This retrospective study covers all patients with stage IV NSCLC treated with first- line immunotherapy, alone or in combination, between January 2018 and 2019, in three Ile de France centers. The primary and secondary endpoints were, respectively, overall survival and progression-free survival, according to smoking status. RESULTS The analysis included 105 patients (66.7% men) of whom 38% were active smokers and 9.5% non-smokers, with adenocarcinoma in 65.7% of cases. Median OS and PFS were 17, 23.2, and 24.9 months and 4.9, 7.6, and 4 months for smokers, ex-smokers, and non-smokers respectively, without significant differences. CONCLUSION In this study, smoking status did not seem to modify the effectiveness of immunotherapy. Studies on a larger population are called for.
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Affiliation(s)
- F Biney
- Service de pneumologie, CHSF, Corbeil Essonne, France.
| | - É Giroux-Leprieur
- Service de pneumologie et oncologie thoracique, université Paris-Saclay, UVSQ, EA 4340 BECCOH, AP-HP-hôpital Ambroise-Paré, Boulogne-Billancourt, France
| | | | | | - J B Auliac
- Service de pneumologie, hôpital Intercommunal, Créteil, France
| | - J B Assié
- Service de pneumologie, hôpital Intercommunal, Créteil, France; Centre de recherche des Cordeliers, Inserm, Sorbonne université, université Paris Cité, Functional Genomics of Solid Tumors Laboratory, Paris, France
| | - S Anane-Abrous
- Service de radiothérapie, hôpital Intercommunal, Créteil, France
| | - C Chouaid
- Service de pneumologie, hôpital Intercommunal, Créteil, France
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Wheatley-Price P, Navani V, Pabani A, Routy B, Snow S, Denault MH, Kim Y, Syed I, Devost N, Hui D, Qadeer RA, Arora P, Velummailum R, Springford A, McKibbon C, Ho C. Real-world survival outcomes, treatment patterns, and impact of PD-L1 expression among patients with unresectable, stage III NSCLC treated with CRT → durvalumab in Canada: The RELEVANCE study. Lung Cancer 2025; 204:108583. [PMID: 40393235 DOI: 10.1016/j.lungcan.2025.108583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 04/28/2025] [Accepted: 05/13/2025] [Indexed: 05/22/2025]
Abstract
BACKGROUND Chemoradiotherapy (CRT) followed by durvalumab (CRT → durvalumab) is standard of care to treat patients with unresectable, stage III non-small cell lung cancer (NSCLC). The RELEVANCE study was designed to provide real-world effectiveness and safety data for CRT → durvalumab in Canadian settings. PATIENTS AND METHODS RELEVANCE was a retrospective, observational, multicenter chart review that included adult patients with unresectable, stage III NSCLC treated with CRT alone or CRT → durvalumab at 5 Canadian cancer centers. Key outcomes included treatment patterns, adverse events of special interest (AESI), and overall survival (OS). RESULTS 487 patients were included (144 CRT alone; 343 CRT → durvalumab). Median follow-up was 43.1 and 35.8 months for the CRT alone and CRT → durvalumab groups, respectively. The most frequently observed regimen included radiotherapy dose 54-66 Gy and radiosensitizing carboplatin. Median treatment duration was 1.5 months (CRT alone) and 13.4 months (CRT → durvalumab), and 47 % of patients completed a full course of durvalumab. Median OS and 3-year OS rate were 21.3 months and 32 % for CRT alone and 44.6 months and 56 % for CRT → durvalumab. Exploratory analysis by programmed cell death-ligand 1 (PD-L1) expression status of the CRT → durvalumab group noted 3-year OS rates of 69 %, 44 %, and 39 % in the PD-L1 ≥ 50 % (high), 1 %-49 % (intermediate), and < 1 % (negative) populations, respectively (32 %, 38 %, and 24 % for CRT alone, respectively). PD-L1 high expression was associated with lower risk of death vs. PD-L1 negative expression (P < 0.05). The most common AESI with CRT → durvalumab was pneumonitis. Median OS for patients who completed durvalumab was not reached and was 41.3 months among patients who discontinued durvalumab due to AEs. CONCLUSION Results validate the treatment benefit and safety of the PACIFIC regimen in real-world Canadian settings. Among patients who received CRT → durvalumab, there was a correlation between increasing PD-L1 status and improved OS; however, shorter OS was observed in patients discontinuing durvalumab early due to AEs. TWITTER ABSTRACT Real-world Canadian RELEVANCE study validates effectiveness and safety of durvalumab in patients with unresectable, stage III NSCLC.
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Affiliation(s)
| | - Vishal Navani
- Division of Medical Oncology, University of Calgary, Calgary, AB, Canada
| | - Aliyah Pabani
- Division of Medical Oncology, University of Calgary, Calgary, AB, Canada; Johns Hopkins Hospital and Johns Hopkins University, Baltimore, MD, USA
| | - Bertrand Routy
- Centre de recherche CHUM (CRCHUM), Université de Montréal, Montréal, QC, Canada
| | - Stephanie Snow
- QEII Health Sciences Centre, Dalhousie University, Halifax, NS, Canada
| | - Marie-Hélène Denault
- Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, QC, Canada
| | | | - Iqra Syed
- AstraZeneca Canada, Mississauga, ON, Canada
| | | | - Daphne Hui
- AstraZeneca Canada, Mississauga, ON, Canada
| | | | - Paul Arora
- Cytel, Toronto, ON, Canada; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
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Kaleem M, Azmi L, Shahzad N, Taha M, Kumar S, Mujtaba MA, Hazazi AAH, Kayali A. Epigenetic dynamics and molecular mechanisms in oncogenesis, tumor progression, and therapy resistance. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04217-5. [PMID: 40358685 DOI: 10.1007/s00210-025-04217-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Accepted: 04/22/2025] [Indexed: 05/15/2025]
Abstract
Cancer progression is governed by a dynamic interplay of genetic, epigenetic, and molecular mechanisms that regulate tumor initiation, growth, metastasis, and therapy resistance. This review highlights key molecular pathways involved in oncogenesis, focusing on genetic alterations (mutations, amplifications, and translocations) in oncogenes (RAS and MYC) and tumor suppressor genes (TP53 and PTEN). Additionally, genomic instability, resulting from defective DNA repair mechanisms like mismatch repair and homologous recombination (HR), is identified as a critical factor contributing to tumor heterogeneity and clonal evolution. Epigenetic modifications, including DNA methylation, histone acetylation, and non-coding RNA regulation, further remodel chromatin structure and modulate gene expression, influencing tumor initiation, growth, metastasis, and response to treatment. Post-translational modifications, such as the attachment of a Small Ubiquitin-like Modifier (SUMO) to a target protein and ubiquitination, further influence autophagy, apoptosis, and cellular plasticity, enabling cancer cells to survive therapeutic stress. Cutting-edge technologies such as CRISPR-Cas9-mediated epigenome editing and single-cell RNA sequencing have opened new doors to understanding cellular diversity and regulatory networks in cancer. The review further examines the tumor microenvironment, including stromal remodeling, immune evasion, and hypoxia-driven signaling pathways, which are critical modulators of tumor progression and drug resistance to treatment. By integrating molecular, genetic, and epigenetic perspectives, this study underscores the crucial need for innovative, targeted therapeutic approaches to address the complexity and adaptability of cancer, thereby paving the way for more effective treatments.
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Affiliation(s)
- Mohammed Kaleem
- Department of Pharmacology, Dadasaheb Balpande College of Pharmacy, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra, India
| | - Lubna Azmi
- Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Science, University of Lucknow, Uttar Pradesh, Lucknow, India
| | - Naiyer Shahzad
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Murtada Taha
- Department of Clinical Laboratory Science, Prince Sultan Military College of Health Sciences, Dhahran, Saudi Arabia
| | - Shiv Kumar
- School of Biomedical Engineering, Indian Institute of Technology (BHU) Varanasi, Uttar Pradesh, Varanasi, India
| | - Md Ali Mujtaba
- Department of Pharmaceutics, Faculty of Pharmacy, Northern Border University, Arar, Saudi Arabia.
- Center for Health Research, Northern Border University, Arar, Saudi Arabia.
| | | | - Asaad Kayali
- Department of Health Sciences, Higher Colleges of Technology, Al Ain, United Arab Emirates
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Zolezzi A, Gualano G, Mastrobattista A, Vittozzi P, Di Bari V, Cerva C, Mosti S, Lugini A, Albarello F, Di Stefano F, Valli MB, Palmieri F. A Case of Pulmonary Fibrosis and COVID-19-Related Pneumonia in a Pembrolizumab-Treated Patient. Infect Dis Rep 2025; 17:53. [PMID: 40407655 PMCID: PMC12101223 DOI: 10.3390/idr17030053] [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: 03/24/2025] [Revised: 05/05/2025] [Accepted: 05/09/2025] [Indexed: 05/26/2025] Open
Abstract
Pembrolizumab is used as a first-line treatment of non-small cell lung cancer. Pneumonitis and interstitial lung disease are among the most common immune-related adverse events. The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections on patients with cancer treated with chemotherapy or immune checkpoint inhibitors (ICIs) is not fully known. Blocking immune checkpoints may conversely augment dysfunctional T-cell responses in severe patients and, in turn, mediate immunopathology. Here, we present a case of SARS-CoV-2 infection complicated by acute respiratory distress syndrome (ARDS) and a fibrotic-like pattern in a patient treated with pembrolizumab for lung cancer. The patient showed a dramatic clinical and radiological response after steroid therapy. Further research is needed to better understand the long-term implications of pembrolizumab therapy in patients recovering from coronavirus disease 2019 (COVID-19) and to develop evidence-based guidelines for managing these complex cases. Patients undergoing oncologic immunotherapy might benefit from early high-dose steroid treatment in cases of viral infections, such as SARS-CoV-2.
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Affiliation(s)
- Alberto Zolezzi
- Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (A.Z.); (A.M.); (P.V.); (V.D.B.); (C.C.); (S.M.); (F.P.)
| | - Gina Gualano
- Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (A.Z.); (A.M.); (P.V.); (V.D.B.); (C.C.); (S.M.); (F.P.)
| | - Annelisa Mastrobattista
- Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (A.Z.); (A.M.); (P.V.); (V.D.B.); (C.C.); (S.M.); (F.P.)
| | - Pietro Vittozzi
- Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (A.Z.); (A.M.); (P.V.); (V.D.B.); (C.C.); (S.M.); (F.P.)
| | - Virginia Di Bari
- Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (A.Z.); (A.M.); (P.V.); (V.D.B.); (C.C.); (S.M.); (F.P.)
| | - Carlotta Cerva
- Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (A.Z.); (A.M.); (P.V.); (V.D.B.); (C.C.); (S.M.); (F.P.)
| | - Silvia Mosti
- Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (A.Z.); (A.M.); (P.V.); (V.D.B.); (C.C.); (S.M.); (F.P.)
| | - Antonio Lugini
- Medical Oncology, Azienda Ospedaliera San Giovanni Addolorata, 00184 Rome, Italy;
| | - Fabrizio Albarello
- Diagnostic Imaging Unit for Infectious Diseases, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (F.A.); (F.D.S.)
| | - Federica Di Stefano
- Diagnostic Imaging Unit for Infectious Diseases, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (F.A.); (F.D.S.)
| | - Maria Beatrice Valli
- Laboratory of Virology and Biosafety Laboratories, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy;
| | - Fabrizio Palmieri
- Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy; (A.Z.); (A.M.); (P.V.); (V.D.B.); (C.C.); (S.M.); (F.P.)
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Marković F, Stjepanović M, Rančić M, Cekić M, Kontić M. Real-World Outcomes of First-Line Pembrolizumab Monotherapy in Metastatic NSCLC with High PD-L1 Expression (TPS ≥ 50%): A Multicenter Study from Serbia. Biomedicines 2025; 13:1175. [PMID: 40427002 PMCID: PMC12108898 DOI: 10.3390/biomedicines13051175] [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: 04/11/2025] [Revised: 05/08/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Pembrolizumab monotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC) patients whose tumors express a PD-L1 tumor proportion score (TPS) of ≥50%. However, real-world data regarding its effectiveness outside of clinical trials, particularly in Eastern European populations, are limited. Methods: We conducted a retrospective, multicenter study including 225 patients with metastatic NSCLC and PD-L1 TPS ≥ 50% who received first-line pembrolizumab monotherapy in Serbia between 2019 and 2022. Patient demographics, clinical characteristics, and treatment outcomes were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards regression was performed to identify predictors of outcomes. Results: The median PFS was 9.7 months (95% CI: 7.979-11.421), and the median OS was 17.0 months (95% CI: 12.813-20.187) at a median follow-up of 18.1 months. The overall response rate (ORR) was 36.4%, and the disease control rate (DCR) was 73.4%. Multivariable analysis identified good performance status (ECOG PS 0-1), PD-L1 TPS ≥ 90%, and the occurrence of immune-related adverse events (irAEs) as independent predictors of improved PFS and OS. Conclusions: Our study highlights the efficacy and safety of first-line pembrolizumab monotherapy in a real-world Serbian population with metastatic NSCLC and high PD-L1 expression. Furthermore, it confirms the prognostic value of ECOG PS, high PD-L1 expression, and the development of irAEs in predicting favorable clinical outcomes.
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Affiliation(s)
- Filip Marković
- Clinic for Pulmonology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia; (M.S.); (M.K.)
| | - Mihailo Stjepanović
- Clinic for Pulmonology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia; (M.S.); (M.K.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Milan Rančić
- Pulmonary Diseases Clinic, University Clinical Center Nis, 18000 Nis, Serbia; (M.R.); (M.C.)
- Faculty of Medicine, University of Nis, 18000 Nis, Serbia
| | - Marina Cekić
- Pulmonary Diseases Clinic, University Clinical Center Nis, 18000 Nis, Serbia; (M.R.); (M.C.)
- Faculty of Medicine, University of Nis, 18000 Nis, Serbia
| | - Milica Kontić
- Clinic for Pulmonology, University Clinical Centre of Serbia, 11000 Belgrade, Serbia; (M.S.); (M.K.)
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
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Sun Y, Liu JQ, Chen WJ, Tang WF, Zhou YL, Liu BJ, Wei Y, Dong JC. Astragaloside III inhibits MAPK-mediated M2 tumor-associated macrophages to suppress the progression of lung Cancer cells via Akt/mTOR signaling pathway. Int Immunopharmacol 2025; 154:114546. [PMID: 40184811 DOI: 10.1016/j.intimp.2025.114546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 02/25/2025] [Accepted: 03/21/2025] [Indexed: 04/07/2025]
Abstract
Tumor-associated macrophages (TAMs) play a key role in facilitating a range of cancerous processes by modulating the tumor microenvironment thus being a target for cancer treatment. Astragaloside III (AS-III), a compound derived from Astragalus triterpenoid saponins, has demonstrated immunomodulatory and anticancer properties, but the underlying mechanism remains unclear. Here, we demonstrated that AS-III suppressed metastasis, angiogenesis and induced apoptosis of lung cancer in vitro and in vivo by inhibiting macrophage M2 polarization and inducing M1 phenotype transformation. This was achieved through the inhibition of the MAPK signaling pathway. Furthermore, the tumor inhibitory effects of AS-III were found to be mediated by the Akt/mTOR pathway. Overall, these results highlight the role of AS-III in modifying the TAMs in TME, offering fresh perspectives on tumor immunotherapy by means of targeting macrophage.
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Affiliation(s)
- Yan Sun
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China; Institute of Integrative Medicine, Fudan University, Shanghai, China
| | - Jia-Qi Liu
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China; Institute of Integrative Medicine, Fudan University, Shanghai, China
| | - Wen-Jing Chen
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China; Institute of Integrative Medicine, Fudan University, Shanghai, China
| | - Wei-Feng Tang
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China; Institute of Integrative Medicine, Fudan University, Shanghai, China
| | - Yao-Long Zhou
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China; Institute of Integrative Medicine, Fudan University, Shanghai, China
| | - Bao-Jun Liu
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China; Institute of Integrative Medicine, Fudan University, Shanghai, China
| | - Ying Wei
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China; Institute of Integrative Medicine, Fudan University, Shanghai, China.
| | - Jing-Cheng Dong
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai, China; Institute of Integrative Medicine, Fudan University, Shanghai, China.
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Canali B, Apolone G, Ascierto PA, De Braud F, Grossi F, Perrone F, Fiorentino F, Di Costanzo A, Candelora L, Patanè G, Zapparelli G, Mezzanotte C, Didoni G, Riccaboni M. Effect of immuno-oncology on clinical and economic outcomes for a selection of cancers in Italy. Expert Rev Pharmacoecon Outcomes Res 2025:1-11. [PMID: 40329477 DOI: 10.1080/14737167.2025.2493130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 04/03/2025] [Accepted: 04/08/2025] [Indexed: 05/08/2025]
Abstract
OBJECTIVES This study assesses the impact of immune-oncology (IO) drugs' availability on cancer incidence-adjusted mortality rates from melanoma, lung, and renal cancers at population level in Italy between 2008 and 2019. METHODS We conducted a retrospective study on cross-sectional time-series aggregated data collected from publicly available sources and IQVIA proprietary databases. Three fixed-effects regression models were used to estimate how IO availability affects incidence-adjusted mortality for each cancer type. Estimated deaths were compared with deaths in a scenario with no IO drugs availability. Finally, the number of averted deaths was valued using the human capital approach. RESULTS A 1% increase in IO availability reduces incidence-adjusted mortality rates for melanoma, lung, and renal cancers by 0.125% (95% CI: 0.138-0.112; p < 0.01), 0.011% (95% CI: 0.013-0.009; p < 0.01) and 0.005% (95% CI: 0.006-0.003; p < 0.01) between the introduction of the drug in the therapeutic area and 2019. This reduction resulted in total savings of € 49.0 million, € 61.3 million, and € 10.9 million in indirect costs due to premature mortality, respectively. CONCLUSIONS IO drugs introduction in Italy between 2008 and 2019 was associated with a significant decrease in deaths from each cancer and, consequently, in savings in indirect costs related to premature mortality.
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Affiliation(s)
- Beatrice Canali
- Real World Solutions, IQVIA Solutions Italy S.r.l, Milan, Italy
| | - Giovanni Apolone
- Scientific Directorate, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Paolo A Ascierto
- Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples, Italy
| | - Filippo De Braud
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesco Grossi
- Department of Medicine and Technological Innovation, Università degli Studi dell'Insubria, Varese, Italy
- Medical Oncology Division, ASST Sette Laghi, Varese, Italy
| | - Francesco Perrone
- Clinical Trial Unit, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples, Italy
| | | | | | - Laura Candelora
- Real World Solutions, IQVIA Solutions Italy S.r.l, Milan, Italy
| | | | | | - Claudia Mezzanotte
- Pricing, Access Strategy & Health Economics, Bristol Myers Squibb, Rome, Italy
| | - Guido Didoni
- Pricing, Access Strategy & Health Economics, Bristol Myers Squibb, Rome, Italy
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Hu X, Melson JW, Pan SS, Salei YV, Pai L, Parsons SK, Cao Y. Palliative and end-of-life care in Asian and White patients with metastatic lung cancer. Oncologist 2025; 30:oyaf065. [PMID: 40349132 PMCID: PMC12065943 DOI: 10.1093/oncolo/oyaf065] [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: 06/19/2024] [Accepted: 02/24/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Data on palliative and end-of-life care for Asian patients with metastatic lung cancer in the United States are limited, though this is the leading cause of cancer death in this group. Early palliative care improved quality of life and survival in patients with metastatic lung cancer treated with chemotherapy. We examined palliative and end-of-life care patterns in Asian and White patients with metastatic lung cancer in the era of novel therapy. METHODS Patients newly diagnosed with metastatic lung cancer from 2014 to 2019 were identified at our institution. Patient and disease characteristics and treatment information were compared between Asian and White patients by Mann-Whitney U test and Chi-square tests. Time-to-palliative care involvement was compared via log-rank test. RESULTS Both Asian (N = 89) and White (N = 197) patients had low rates of palliative care involvement (38.2% vs 37.6%), with median time from diagnosis to first encounter exceeding a year. The most given frontline systemic therapy was targeted therapy and chemotherapy in Asian and White patients, respectively. Of 22 Asian (24.7%) and 74 White (37.6%) patients who died, Asian patients more often died in-hospital (68.2% vs 32.4%, P = .004), and did not have documented code status discussions with their outpatient oncologists (0% vs 24.3%, P = .010) within 6 months preceding death. CONCLUSION Early palliative care appears challenging to implement for Asian and White patients newly diagnosed with metastatic lung cancer in a real-world setting. A more patient-centered approach to integrating palliative and end-of-life care communications and interventions alongside precision oncology warrants further study.
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Affiliation(s)
- Xiao Hu
- Division of Hematology-Oncology, Department of Medicine, Tufts Medical Center, Boston, MA, United States
| | - John W Melson
- Division of Hematology, Oncology and Palliative Care, Department of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Stacey S Pan
- Division of Hematology-Oncology, Department of Medicine, Tufts Medical Center, Boston, MA, United States
| | - Yana V Salei
- Department of Medicine, Tufts Medical Center, Boston, MA, United States
| | - Lori Pai
- Division of Hematology-Oncology, Department of Medicine, Tufts Medical Center, Boston, MA, United States
| | - Susan K Parsons
- Division of Hematology-Oncology, Department of Medicine, Tufts Medical Center, Boston, MA, United States
- Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, United States
| | - Yu Cao
- Division of Hematology-Oncology, Department of Medicine, Tufts Medical Center, Boston, MA, United States
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Zhang J, Song Z, Zhang Y, Zhang C, Xue Q, Zhang G, Tan F. Recent advances in biomarkers for predicting the efficacy of immunotherapy in non-small cell lung cancer. Front Immunol 2025; 16:1554871. [PMID: 40406096 PMCID: PMC12095235 DOI: 10.3389/fimmu.2025.1554871] [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: 01/03/2025] [Accepted: 04/18/2025] [Indexed: 05/26/2025] Open
Abstract
Lung cancer continues to be the primary cause of cancer-related deaths globally, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all instances. Recently, immune checkpoint inhibitors (ICIs) have transformed the treatment approach for NSCLC, however, only a subset of patients experiences significant benefits. Therefore, identifying reliable biomarkers to forecast the efficacy of ICIs is crucial for ensuring the safety and effectiveness of treatments, becoming a major focus of current research efforts. This review highlights the recent advances in predictive biomarkers for the efficacy of ICIs in the treatment of NSCLC, including PD-L1 expression, tertiary lymphoid structures (TLS), tumor-infiltrating lymphocytes (TILs), tumor genomic alterations, transcriptional signatures, circulating biomarkers, and the microbiome. Furthermore, it underscores the pivotal roles of liquid biopsy, sequencing technologies, and digital pathology in biomarker discovery. Special attention is given to the predictive value of TLS, circulating biomarkers, and transcriptional signatures. The review concludes that the integration of multiple biomarkers holds promise for achieving more accurate efficacy predictions and optimizing personalized immunotherapy strategies. By providing a comprehensive overview of the current progress, this review offers valuable insights into biomarker-based precision medicine for NSCLC and outlines future research directions.
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Affiliation(s)
- Jiacheng Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zehao Song
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuanjie Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Thoracic Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chentong Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qi Xue
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guochao Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fengwei Tan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Thoracic Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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Heyward J, Lesko CR, Murray JC, Mehta HB, Segal JB. Harm-Benefit Balance of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer. JAMA Oncol 2025:2833552. [PMID: 40338588 PMCID: PMC12062994 DOI: 10.1001/jamaoncol.2025.0985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 02/28/2025] [Indexed: 05/09/2025]
Abstract
Importance The benefits and harms of immune checkpoint inhibitor (ICI) therapy for lung cancer vary across groups, including those typically underrepresented in randomized clinical trials. Objective To quantify the harms and benefits of ICI-containing regimens in individuals with non-small cell lung cancer and assess heterogeneity across priority subgroups. Design, Setting, and Participants This retrospective cohort study conducted in 2024 used 2013 to 2019 Surveillance, Epidemiology, and End Results (SEER) Medicare data of individuals 66 years or older with non-small cell lung cancer who were exposed to any ICI. Exposures ICI + chemotherapy, single ICI (reference group). Main Outcomes Severe immune-related adverse events (irAE; harm) and mortality (when delayed mortality was the benefit). Severe irAEs were defined using validated diagnosis and medication codes. Mortality was ascertained from Medicare data. Hazard ratios (HRs) were estimated and 95% CIs were stratified by whether an ICI was used as the first or second or later systemic anticancer treatment (SACT) and in subgroups defined by preexisting autoimmune disease, sex, and age. The harm-benefit tradeoff was described as excess severe irAEs per year of life gained in which the gain in survival time was assessed using restricted mean survival time. Results Of 17 681 Medicare beneficiaries, 8797 (49.5%) were female, and the mean (SD) age was 74 (6.0) years. Compared with a single ICI (14 249 [80.6%]), individuals treated with ICI + chemotherapy (3432 [19.4%]) had an elevated risk of severe irAE in the first SACT setting (hazard ratio [HR], 1.18; 95% CI, 1.06-1.30) but not in the second or later SACT setting (HR, 1.04; 95% CI, 0.92-1.19); there was a decreased risk of mortality in the first SACT setting (HR, 0.66; 95% CI, 0.62-0.72) but not in the second or later SACT setting (HR, 0.94; 95% CI, 0.68-1.03). In the first SACT setting, ICI + chemotherapy delayed mortality more among patients with (vs without) autoimmune disease at baseline. For each 1 year of life gained, the risk of severe irAEs was 0.31 (95% CI, 0.09-0.53) and the tradeoff was also statistically significant in men and patients without autoimmune disease. Conclusions The results of this cohort study suggest that given both treatment-related harms and benefits, ICI + chemotherapy use in the first SACT setting requires informed decision-making; the potential benefits of ICI + chemotherapy vs single ICI in high-risk subgroups is encouraging.
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Affiliation(s)
- James Heyward
- Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Catherine R. Lesko
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Joseph C. Murray
- Division of Oncology, Johns Hopkins Medicine, Baltimore, Maryland
| | - Hemalkumar B. Mehta
- Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Jodi B. Segal
- Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Division of General Internal Medicine, Johns Hopkins Medicine, Baltimore, Maryland
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von Bubnoff D, Schmitt C, Goldinger SM, Schadendorf D, Kähler KC, Hafner C, Kramer N, Fröhlich W, Dummer R, Berking C, Schliep S, Kirchberger MC, Heinzerling L. Prognostic and predictive value of IDO expression in metastatic melanoma treated with Ipilimumab. PLoS One 2025; 20:e0321937. [PMID: 40334245 PMCID: PMC12058187 DOI: 10.1371/journal.pone.0321937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 03/11/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND The tumor microenvironment is crucial for prognosis and response to immunotherapy in several tumor entities. METHODS In a multicenter retrospective study, a total of 86 tumor samples from patients with metastatic melanoma were evaluated for baseline expression of indoleamine 2,3-dioxygenase (IDO) and programmed death ligand 1 (PD-L1). Expression patterns of IDO and PD-L1 on tumor cells and antigen-presenting cells (APCs) as determined by immunohistochemical (IHC) staining of paraffin-embedded tissue sections were correlated with response to ipilimumab and overall survival (OS). Statistical analysis was performed using the Spearman correlation, the Mann-Whitney test and Kaplan-Meier estimator. RESULTS IDO expression in tumor cells or APCs was not predictive for treatment response. The median OS was 26 months in IDO-positive and IDO-negative patients, regardless of IDO expression in tumor cells or APCs. A correlation of IHC expression scores of IDO and PD-L1 could not be documented. CONCLUSION The exact role of IDO in creating an immunosuppressive tumor environment and its reversal needs to be further elucidated.
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Affiliation(s)
| | - Christina Schmitt
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
| | - Simone M. Goldinger
- Department of Dermatology, University Hospital of Zurich, Zürich, Switzerland
| | - Dirk Schadendorf
- Department of Dermatology, University Hospital Essen, Essen, Germany
| | - Katharina C. Kähler
- Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Christian Hafner
- Department of Dermatology, University Hospital Regensburg, Regensburg, Germany
| | - Nora Kramer
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
| | - Waltraud Fröhlich
- Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Reinhard Dummer
- Department of Dermatology, University Hospital of Zurich, Zürich, Switzerland
| | - Carola Berking
- Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Stefan Schliep
- Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Michael C. Kirchberger
- Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Lucie Heinzerling
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
- Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
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Han L, Huang B, Li L, Xu B, Yang Y, Zhao L, Wang Z, Zhang C, Gao Q. Utility of the neutrophil-to-lymphocyte ratio and the ratio of neutrophil-to-lymphocyte ratio after and before adverse events for differential diagnosis of immune-related adverse events and bacterial infections in cancer patients treated with PD-(L)1 inhibitors. J Leukoc Biol 2025; 117:qiaf029. [PMID: 40083232 DOI: 10.1093/jleuko/qiaf029] [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: 08/12/2024] [Revised: 12/25/2024] [Accepted: 03/13/2025] [Indexed: 03/16/2025] Open
Abstract
Differential diagnosis of immune-related adverse events (irAEs) or bacterial infections is sometimes very difficult in cancer patients undergoing treatment with PD-(L)1 inhibitors. This study aimed to assess the effectiveness of the neutrophil-to-lymphocyte ratio (NLR) in distinguishing between irAEs and bacterial infections in cancer patients receiving PD-(L)1 inhibitors. We conducted a retrospective analysis of cancer patients who received at least 1 dose of PD-(L)1 inhibitors at Affiliated Cancer Hospital of Zhengzhou University from 2018 to 2023. We compared the changes in peripheral blood cell counts before and after the occurrence of adverse events, as well as the ratios of the NLR that were closest after the occurrence of adverse events (post-NLR) to the NLR that were closest before the occurrence of adverse events (pre-NLR). Among the 4173 patients who were administered PD-(L)1 inhibitors, 217 individuals experienced a total of 249 irAEs, while 256 patients were diagnosed with 257 bacterial infections. The post-NLR increased significantly compared with pre-NLR in patients with bacterial infection (P < 0.001), while the post-NLR had smaller increase compared with pre-NLR in patients sufffering irAEs (P < 0.001). Notably, the NLR was significantly higher in patients with bacterial infection compared with those with irAEs (P < 0.001). Furthermore, the post-NLR/pre-NLR ratio was higher in the bacterial infection group than in the irAEs group (P < 0.001). The NLR along with the post-NLR/pre-NLR ratio could serve as valuable diagnostic indicators for irAEs and bacterial infections in cancer patients undergoing treatment with PD-(L)1 inhibitors.
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Affiliation(s)
- Lu Han
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Beibei Huang
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Linlin Li
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Benling Xu
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Yonghao Yang
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Lingdi Zhao
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Zibing Wang
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Chaoji Zhang
- Department of Cardiac Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Quanli Gao
- Department of Immunology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
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Wang Q, Yuan F, Zuo X, Li M. Breakthroughs and challenges of organoid models for assessing cancer immunotherapy: a cutting-edge tool for advancing personalised treatments. Cell Death Discov 2025; 11:222. [PMID: 40335487 PMCID: PMC12059183 DOI: 10.1038/s41420-025-02505-w] [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: 11/08/2024] [Revised: 04/16/2025] [Accepted: 04/23/2025] [Indexed: 05/09/2025] Open
Abstract
Organoid models are powerful tools for evaluating cancer immunotherapy that provide a more accurate representation of the tumour microenvironment (TME) and immune responses than traditional models. This review focuses on the latest advancements in organoid technologies, including immune cell co-culture, 3D bioprinting, and microfluidic systems, which enhance the modelling of TME and facilitate the assessment of immune therapies such as immune checkpoint inhibitors (ICIs), CAR-T therapies, and oncolytic viruses. Although these models have great potential in personalised cancer treatment, challenges persist in immune cell diversity, long-term culture stability, and reproducibility. Future developments integrating artificial intelligence (AI), multi-omics, and high-throughput platforms are expected to improve the predictive power of organoid models and accelerate the clinical translation of immunotherapy.
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Affiliation(s)
- Qian Wang
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, 210009, Jiangsu, PR China
- The Fourth Clinical College of Nanjing Medical University, Nanjing, 210009, Jiangsu, PR China
| | - Fangwei Yuan
- Department of Thoracic Surgery, Lian Shui County People's Hospital, Huaian, 223400, Jiangsu, PR China
| | - Xianglin Zuo
- Biobank of Jiangsu Cancer Hospital (Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University), Nanjing, 210000, Jiangsu, PR China.
| | - Ming Li
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, 210009, Jiangsu, PR China.
- The Fourth Clinical College of Nanjing Medical University, Nanjing, 210009, Jiangsu, PR China.
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Nagano Y, Takahashi M, Sumi T, Yokoo K, Ishikawa T, Honjo O, Kudo S, Kondo S, Tanaka Y, Shioya M, Hashimoto M, Otsuka M, Sudo Y, Yanagi M, Yabe H, Nishikiori H, Yamazoe M, Asai Y, Fukataki Y, Hinotsu S, Chiba H. Efficacy of nivolumab + ipilimumab ± chemotherapy versus pembrolizumab + chemotherapy in patients with PD-L1-negative non-small cell lung cancer (START001 PART-B): a multicenter retrospective observational study. Jpn J Clin Oncol 2025:hyaf073. [PMID: 40333938 DOI: 10.1093/jjco/hyaf073] [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: 01/24/2025] [Accepted: 04/17/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND Programmed death ligand 1 (PD-L1) serves as a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer (NSCLC). This study aimed to identify the most suitable first-line treatment regimen for patients with PD-L1 expression <1% (PD-L1-negative) NSCLC by comparing nivolumab plus ipilimumab (NI), NI combined with chemotherapy (NICT), and pembrolizumab and chemotherapy (PCT). METHODS We analyzed data from 141 patients with PD-L1-negative NSCLC treated with NI, NICT, or PCT at 14 Japanese institutions between December 2020 and November 2022. Propensity score analysis was employed to minimize selection bias, and Kaplan-Meier analysis and Cox proportional hazards regression were used to evaluate progression-free survival (PFS) and overall survival (OS). RESULTS Neither NI nor NICT demonstrated superior PFS or OS than PCT. Subgroup analyses revealed no significant differences between treatment groups across age, histological subtypes, or clinical features. Results from propensity score matching and inverse probability of treatment weighting were consistent with those observed in the overall cohort. Moreover, safety profiles showed that PCT was associated with the lowest rates of treatment discontinuation and immune-related adverse events requiring systemic corticosteroid therapy. CONCLUSIONS In patients with PD-L1-negative NSCLC, the efficacy of NI and NICT was not superior to that of PCT. Thus, we concluded that PCT could be a favorable treatment option for this patient population.
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Affiliation(s)
- Yutaro Nagano
- Department of Respiratory Medicine, Otaru General Hospital, 1-1-1 Wakamatsu, Otaru, Hokkaido 047-0017, Japan
- Department of Respiratory Medicine, Hakodate Municipal Hospital, 1-10-1 Minato-cho, Hakodate, Hokkaido 041-0821, Japan
| | - Mamoru Takahashi
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 291 Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Toshiyuki Sumi
- Department of Respiratory Medicine, Hakodate Goryoukaku Hospital, 38-3 Goryokaku-cho, Hakodate, Hokkaido 041-8611, Japan
| | - Keiki Yokoo
- Department of Respiratory Medicine, Teine Keijinkai Hospital, 1-40 Maeda 1-jo 12-chome, Teine-ku, Sapporo, Hokkaido 006-0811, Japan
| | - Tatsuru Ishikawa
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 291 Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Osamu Honjo
- Department of Respiratory Medicine, Sapporo Minami-Sanjo Hospital, 4-2 Minami 3-jo Nishi 6-chome, Chuo-ku, Sapporo, Hokkaido 060-0063, Japan
| | - Sayaka Kudo
- Department of Respiratory Medicine, Kushiro City General Hospital, 1-12 Shunkodai, Kushiro, Hokkaido 085-0822, Japan
| | - Shun Kondo
- Department of Respiratory Medicine, Steel Memorial Muroran Hospital, 45 Chiribetsu-cho 1-chome, Muroran, Hokkaido 050-0076, Japan
| | - Yusuke Tanaka
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 291 Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
- Department of Respiratory Medicine, 3-8 Kita 4-jo Nishi 7-chome, Chuo-ku, Tonan Hospital, Sapporo, Hokkaido 060-0004, Japan
| | - Makoto Shioya
- Department of Respiratory Medicine, Otaru General Hospital, 1-1-1 Wakamatsu, Otaru, Hokkaido 047-0017, Japan
| | - Midori Hashimoto
- Department of Respiratory Medicine, NTT-East Corporation Sapporo Medical Center, Minami 1-jo Nishi 15-chome, Chuo-ku, Sapporo, Hokkaido 060-0062, Japan
| | - Mitsuo Otsuka
- Department of Respiratory Medicine, Hokkaido P.W.F.A.C Sapporo-Kosei Hospital, 5 Kita 3-jo Higashi 8-chome, Chuo-ku, Sapporo, Hokkaido 060-0033, Japan
| | - Yuta Sudo
- Department of Respiratory Medicine, Japanese Red Cross Asahikawa Hospital, 1-1 Akebono 1-jo 1-chome, Asahikawa, Hokkaido 070-0061, Japan
| | - Masahiro Yanagi
- Department of Respiratory Medicine, Muroran City General Hospital, 8-1 Yamate-cho 3-chome, Muroran, Hokkaido 051-0012, Japan
| | - Hayato Yabe
- Department of Respiratory Medicine, Japan Community Healthcare Organization Sapporo Hokushin Hospital, 2-1 Atsubetsu Chuo 2-jo 6-chome, Atsubetsu-ku, Sapporo, Hokkaido 004-8618, Japan
| | - Hirotaka Nishikiori
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 291 Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Masami Yamazoe
- Department of Respiratory Medicine, Hakodate Municipal Hospital, 1-10-1 Minato-cho, Hakodate, Hokkaido 041-0821, Japan
| | - Yuichiro Asai
- Department of Respiratory Medicine, 3-8 Kita 4-jo Nishi 7-chome, Chuo-ku, Tonan Hospital, Sapporo, Hokkaido 060-0004, Japan
| | - Yasuko Fukataki
- Department of Biostatics and Data Management, Sapporo Medical University School of Medicine, 291 Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkadio 060-8543, Japan
| | - Shiro Hinotsu
- Department of Biostatics and Data Management, Sapporo Medical University School of Medicine, 291 Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkadio 060-8543, Japan
| | - Hirofumi Chiba
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 291 Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
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Chen Y, Wang P, Lian R, Yuan M, Yu P, He H, Chen P, Zhou H, Chen W, Zhang D, Lin H, Liu S, Wang F. Comprehensive characterization of PD-L1 expression and immunotherapy-related genomic biomarkers in early- versus advanced-stage non-small cell lung cancer. BMC Pulm Med 2025; 25:219. [PMID: 40336032 PMCID: PMC12056983 DOI: 10.1186/s12890-025-03687-w] [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: 11/30/2023] [Accepted: 04/28/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND Programmed death-ligand 1 (PD-L1) expression is a key biomarker for predicting the efficacy of immune checkpoint inhibitors (ICIs). With the successful application of perioperative immunotherapy, understanding PD-L1-associated clinical and molecular characteristics in early-stage non-small cell lung cancer (NSCLC) patients is essential. METHODS We analyzed 3185 NSCLC patients undergoing targeted next-generation sequencing (NGS) and PD-L1 immunohistochemistry (IHC). Associations between PD-L1 expression and molecular profiles were compared across early- (I-III) and advanced-stage (IV) cohorts. RESULTS In early-stage NSCLC (n = 974), high PD-L1 expression was less common than in advanced-stage patients (lung adenocarcinoma [LUAD]: 7.52% vs. 15.98%, p < 0.001; lung squamous cell carcinoma [LUSC]: 18.33% vs. 20.84%, p = 0.058). For LUAD, high PD-L1 expression was more frequent in older patients, males and smokers. Additionally, LUSC overall showed a higher rate of high PD-L1 expression than LUAD. In LUAD, early-stage patients had a lower proportion of tumor mutation burden-high (TMB-H) compared to advanced-stage patients (p < 0.001), but no significant difference was observed in LUSC (p = 0.597). Early-stage patients also had a lower proportion of immunotherapy resistance genes than advanced-stage (LUAD: 31.15% vs. 48.50%, p = 0.014; LUSC: 13.64% vs. 45.24%, p = 0.0067). Moreover, among LUAD patients with high PD-L1 expression and all LUSC patients, early-stage patients exhibited more significantly different genetic features compared to advanced-stage patients. CONCLUSIONS This study provides a comprehensive analysis of immunotherapy-related biomarker rates in early-stage NSCLC patients, offering insights for perioperative immunotherapy research and biomarker analysis. TRIAL REGISTRATION Not applicable.
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Affiliation(s)
- Yujie Chen
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Fuma Road, Jin'an District, Fuzhou, 350011, Fujian Province, China
| | - Peiyuan Wang
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Fuma Road, Jin'an District, Fuzhou, 350011, Fujian Province, China
- Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, 350011, China
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fuzhou, 350011, China
| | - Rong Lian
- Beijing GenePlus Technology Co., Ltd., Beijing, China
| | - Mingming Yuan
- Beijing GenePlus Technology Co., Ltd., Beijing, China
| | - Pengli Yu
- Beijing GenePlus Technology Co., Ltd., Beijing, China
| | - Hao He
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Fuma Road, Jin'an District, Fuzhou, 350011, Fujian Province, China
| | - Peng Chen
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Fuma Road, Jin'an District, Fuzhou, 350011, Fujian Province, China
| | - Hang Zhou
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Fuma Road, Jin'an District, Fuzhou, 350011, Fujian Province, China
| | - Weijie Chen
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Fuma Road, Jin'an District, Fuzhou, 350011, Fujian Province, China
| | - Derong Zhang
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Fuma Road, Jin'an District, Fuzhou, 350011, Fujian Province, China
| | - Hui Lin
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Fuma Road, Jin'an District, Fuzhou, 350011, Fujian Province, China
| | - Shuoyan Liu
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Fuma Road, Jin'an District, Fuzhou, 350011, Fujian Province, China.
- Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, 350011, China.
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fuzhou, 350011, China.
| | - Feng Wang
- Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Fuma Road, Jin'an District, Fuzhou, 350011, Fujian Province, China.
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