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Cao Z, Wang Z, Yang L, Li T, Tao X, Niu X. Reshaping the immune microenvironment and reversing immunosenescence by natural products: Prospects for immunotherapy in gastric cancer. Semin Cancer Biol 2025; 110:1-16. [PMID: 39923925 DOI: 10.1016/j.semcancer.2025.02.002] [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: 12/10/2024] [Revised: 01/25/2025] [Accepted: 02/03/2025] [Indexed: 02/11/2025]
Abstract
Gastric cancer (GC) represents a global health-care challenge. Recent progress in immunotherapy has elicited attracted considerable attention as a viable treatment option through modulating the host immune system and unleashing pre-existing immunity, which has profoundly revolutionized oncology, especially GC. Nonetheless, low clinical response and intrinsic and acquired resistance remain persistently challenging. The microenvironment of GC comprising multifarious stromal cell types has remarkable immunosuppressive elements that may impact the efficacy of immunotherapy. Immunosenescence is increasingly regarded as a factor that contributes to cancer development, remodels the tumor microenvironment and affects the efficacy of immunotherapy. Natural products are at the forefront of traditional medicine. Senotherapeutics is a class of drugs and natural products capable of delaying, preventing, or reversing the senescence process (i.e., senolytics) or suppressing senescence-associated secretory phenotype (i.e., senomorphics). Emerging evidence supports that natural products can improve the efficacy of existing immunotherapy and expand their indications in GC mainly based upon remodeling the immunosuppressive microenvironment and reversing immunosenescence. The review provides an integrated review of previously reported and ongoing clinical trials with immunotherapeutic regimens in GC and discusses current challenges. Next, we focus on natural compounds that exert anti-GC functions and possess immunomodulatory properties. More attention is paid to the potential of these natural compounds in modulating the immune microenvironment and immunosenescence. Lastly, we discuss the nanomedicine that can overcome the deficiencies of natural products. Altogether, our review suggests the enormous potential of natural compounds in GC immunotherapy, and provides an important direction for future research.
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Affiliation(s)
- Zhipeng Cao
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning 110122, China
| | - Zhilin Wang
- Department of Pain Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Li Yang
- Department of Anesthesiology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, China
| | - Tian Li
- Tianjin Key Laboratory of Acute Abdomen Disease-Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China.
| | - Xueshu Tao
- Department of Pain Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Xing Niu
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning 110122, China.
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Li Z, Li Z, Sun C, Zhang X, Fei H, Xing C, Zhao D. Association between adjuvant radiotherapy in adults with gastric cancer and risk of second primary malignancy: a retrospective cohort study using the Surveillance, Epidemiology and End Results database. BMJ Open 2025; 15:e086349. [PMID: 39938963 PMCID: PMC11822440 DOI: 10.1136/bmjopen-2024-086349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 01/27/2025] [Indexed: 02/14/2025] Open
Abstract
OBJECTIVES This study aims to assess the association between adjuvant radiotherapy and the development of second primary malignancies (SPMs) and identify its determinants in patients who have undergone surgical treatment for gastric cancer. DESIGN Retrospective cohort study using the Surveillance, Epidemiology and End Results (SEER) database. SETTING Cohorts (18 registries, 2000-2018, from SEER) were screened for any malignancy that developed after sufficient latency from diagnosis of surgically treated non-metastatic gastric cancer. PARTICIPANTS 24 777 surgically treated gastric cancer cases were included in the cohort. Among them, 6128 patients underwent adjuvant radiotherapy. OUTCOME MEASURES The cumulative incidence of SPMs was estimated using Fine and Gray's competing risk model and the radiotherapy-correlated risks were calculated using Poisson regression analysis. RESULTS Among patients with sufficient latency, there was no significant association between radiotherapy and the risk of developing second primary solid malignancies (relative risk=1.05, 95% CI 0.83 to 1.33) or haematological malignancies (relative risk=1.17, 95% CI 0.62 to 2.11). Interestingly, radiotherapy was associated with a reduced cumulative incidence of second lung and bronchus cancer compared with no radiotherapy, with a 15-year incidence of 1.4%-3.17% (p<0.05). Radiotherapy was not associated with a significant increase in standardised incidence ratios of SPMs. CONCLUSIONS Adjuvant radiotherapy was not associated with an increased risk of developing SPMs in surgically treated patients with gastric cancer. Clinical trials are warranted to further verify the findings.
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Affiliation(s)
- Zheng Li
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zefeng Li
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chongyuan Sun
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaojie Zhang
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - He Fei
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Cheng Xing
- Department of General Surgery, Beijing Hospital, Beijing, China
| | - Dongbing Zhao
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Ku G, Haag GM, Park H, Lam VK, George TJ, Kim SS, Gutierrez M, Shankaran V, Stein S, Denlinger CS, Elimova E, Nagrial A, He AR, Sawyer MB, Yoon HH, Geva R, Starr J, Curigliano G, Golan T, von Moos R, Fritsch R, Lim D, Wang Q, Patel A, Aoyama T, Lei M, Greenawalt D, Di Bartolomeo M. Nivolumab combination therapies in patients with advanced gastric and gastroesophageal junction cancer: the phase II FRACTION gastric cancer study. ESMO Open 2025; 10:104107. [PMID: 39798422 PMCID: PMC11772135 DOI: 10.1016/j.esmoop.2024.104107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 12/03/2024] [Accepted: 12/09/2024] [Indexed: 01/15/2025] Open
Abstract
BACKGROUND Nivolumab-based therapies are efficacious with acceptable safety in patients with gastric cancer (GC) and gastroesophageal junction cancer (GEJC). Novel nivolumab-based combination immunotherapies may offer enhanced efficacy in these indications. FRACTION-GC was a signal-seeking, randomized, open-label, phase II adaptive-design trial assessing efficacy and safety of nivolumab in combination with ipilimumab [cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody], relatlimab (lymphocyte-activation gene 3 antibody), or IDO1i (BMS986205, an indoleamine-2,3-dioxygenase-1 inhibitor) in patients with unresectable, advanced/metastatic GC/GEJC. PATIENTS AND METHODS Previously treated patients with GC/GEJC were randomized to receive nivolumab + ipilimumab, nivolumab + relatlimab, or nivolumab + IDO1i across two tracks: anti-programmed death-(ligand) 1/anti-CTLA-4-naïve (track 1) and -experienced (track 2). Primary endpoints were objective response rate (ORR) by investigator per RECIST v1.1, duration of response, and progression-free survival (PFS) rate at 24 weeks. Secondary endpoint was safety. RESULTS Eighty-one patients in track 1 and 81 in track 2 received one combination therapy. With a median follow-up of 50.2 months, ORR [95% confidence interval (CI)] by investigator for nivolumab + ipilimumab, nivolumab + relatlimab, and nivolumab + IDO1i in track 1 was 4% (0.1% to 21.9%), 5% (0.1% to 24.9%), and 13% (4.4% to 28.1%), and for track 2 was 9% (1.1% to 28.0%), 6% (0.7% to 18.7%), and 0% (0% to 15.4%), respectively. PFS rate at 24 weeks (95% CI) was 24% (11% to 39%) for nivolumab + IDO1i track 1, 17% (16% to 32%) for nivolumab + relatlimab track 2, and not estimable for other treatment arms. Grade 3/4 treatment-related adverse events were reported in 22%, 5%, and 18% of patients receiving nivolumab + ipilimumab, nivolumab + relatlimab, and nivolumab + IDO1i in track 1 and in 35%, 11%, and 18% of patients in track 2, respectively. No treatment-related deaths were reported. CONCLUSIONS While ORR did not meet prespecified expansion criteria in any treatment arm, the safety profile of the combinations was manageable. FRACTION-GC represents a novel adaptive protocol for testing multiple combination immunotherapies.
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Affiliation(s)
- G Ku
- Memorial Sloan Kettering Cancer Center, New York, USA.
| | - G M Haag
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital and Clinical Cooperation Unit Applied Tumor-Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - H Park
- Washington University School of Medicine, St Louis, USA
| | - V K Lam
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - T J George
- University of Florida Health Cancer Center, Gainesville, USA
| | - S S Kim
- Division of Medical Oncology, University of Colorado Cancer Center, Aurora, USA
| | - M Gutierrez
- John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, USA
| | - V Shankaran
- University of Washington School of Medicine, Seattle, USA
| | - S Stein
- Yale University School of Medicine, New Haven, USA
| | | | - E Elimova
- Princess Margaret Cancer Centre, Toronto, Canada
| | - A Nagrial
- Department of Medical Oncology, Westmead Hospital, University of Sydney, Sydney, Australia
| | - A R He
- Georgetown University Medical Center, Washington, USA
| | - M B Sawyer
- Cross Cancer Institute, University of Alberta, Edmonton, Canada
| | | | - R Geva
- Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - J Starr
- Mayo Clinic, Jacksonville, USA
| | - G Curigliano
- Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy; European Institute of Oncology, IRCCS, Milan, Italy
| | - T Golan
- Sheba Medical Center, Tel-Aviv University, Tel Aviv, Israel
| | - R von Moos
- Cancer Center, Kantonsspital Graubünden, Chur, Switzerland
| | - R Fritsch
- Department of Medical Oncology and Hematology, Universitätsspital Zürich, Zurich, Switzerland
| | - D Lim
- City of Hope National Medical Center, Duarte, USA
| | - Q Wang
- Bristol Myers Squibb, Princeton, USA
| | - A Patel
- Bristol Myers Squibb, Princeton, USA
| | - T Aoyama
- Bristol Myers Squibb, Princeton, USA
| | - M Lei
- Bristol Myers Squibb, Princeton, USA
| | | | - M Di Bartolomeo
- Fondazione IRCCS Istituto Nazionale Tumori Milano, Milan, Italy
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Naleid N, Mahipal A, Chakrabarti S. Toxicity Associated with Pembrolizumab Monotherapy in Patients with Gastrointestinal Cancers: A Systematic Review of Clinical Trials. Biomedicines 2025; 13:229. [PMID: 39857812 PMCID: PMC11762711 DOI: 10.3390/biomedicines13010229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 01/10/2025] [Accepted: 01/17/2025] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Pembrolizumab, an immune checkpoint inhibitor targeting programmed death 1 (PD-1), is a widely employed therapy for various gastrointestinal (GI) cancers. We conducted a systematic review of clinical trials investigating pembrolizumab monotherapy in GI cancer patients to assess the spectrum and incidence of immune-related adverse events (irAEs) associated with pembrolizumab. Methods: A comprehensive search of PubMed/MEDLINE was performed to identify clinical trials investigating pembrolizumab monotherapy in GI cancer patients. Primary endpoints included the incidence of grade 3 or higher irAEs and the rate of treatment discontinuation due to irAEs. Secondary endpoints encompassed the incidence of any-grade irAEs, as well as specific irAEs. Results: Data extraction and analysis were performed on 25 articles. The analysis included 3101 patients with a median age of 62 years (range 53-68), with 30.2% being female. Tumor types encompassed were colorectal (12%), esophagogastric (46%), hepatocellular carcinoma (24%), and other GI tumor types (18%). The rate of treatment discontinuation due to irAEs was 6.8%. The most prevalent grade 3 or higher irAEs were hepatitis (3.6%), pneumonitis (0.8%), and colitis (0.7%). Death attributed to irAEs was infrequent (0.9%). Conclusions: In patients with GI cancers treated with pembrolizumab monotherapy, severe toxicities are infrequent, and irAEs leading to treatment discontinuation or death are uncommon.
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Affiliation(s)
- Nikolas Naleid
- Department of Medicine, University Hospitals of Cleveland, Lakeside Building, 11100 Euclid Avenue, Cleveland, OH 44016, USA
| | - Amit Mahipal
- University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Sakti Chakrabarti
- University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
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Xin L, Liu J, Lai JY, Xu HS, Fan LJ, Zou YH, Zhou Q, Yue ZQ, Gan JH. Methionine restriction promotes the polarization of macrophages towards M1 and the immunotherapy effect of PD-L1/PD-1 blockades by inhibiting the secretion of MIF by gastric carcinoma cells. Transl Oncol 2025; 51:102181. [PMID: 39541710 PMCID: PMC11600783 DOI: 10.1016/j.tranon.2024.102181] [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: 04/16/2024] [Revised: 09/13/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND The limited curative effect of PD-L1/PD-1 blockades presents challenges to immunotherapy for advanced gastric cancer. We have found that methionine restriction (MR) enhances the drug resistance of gastric carcinoma cells. We aimed to explore whether MR can enhance the efficacy of PD-L1/PD-1 blockades in gastric cancer. METHODS To conduct MR, gastric carcinoma cells were transfected with LV-METase in vitro, and 615 mice were injected with MFC cells with stable METase expression in vivo. Flow cytometry was conducted to measure the proportions of M1/M2 macrophages and CD8+ GZMB+/IFN-γ+ T cells. Additionally, the levels of M1/M2 macrophage markers and MIF were also detected. RESULTS MR increased M1 and down-regulated M2 macrophages. MR suppressed MIF levels in gastric carcinoma cells, while the addition of anti-MIF neutralizing antibody inhibited the effect of MR on macrophage M1/M2 polarization. MR enhanced the increase of the proportion of CD8+ GZMB+ T cells and CD8+ IFN-γ+ T cells induced by PD-L1/PD-1 blockades. In vivo detection verified the efficacy of the combination of MR and PD-L1/PD-1 blockades on gastric cancer. CONCLUSIONS MR inhibits the secretion of MIF by gastric carcinoma cells, promotes macrophage M1 polarization, and enhances the therapeutic effect of PD-L1/PD-1 blockades in gastric cancer.
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Affiliation(s)
- Lin Xin
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China; Intelligent Medical Imaging of Jiangxi Key Laboratory, Nanchang 330006, China.
| | - Jiang Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Jun-Yan Lai
- Class 2210, The Second clinical medical college, Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - He-Song Xu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Luo-Jun Fan
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Yong-Hui Zou
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Qi Zhou
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Zhen-Qi Yue
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Jin-Heng Gan
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
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Zhu M, Zhang LT, Lai W, Yang F, Zhou D, Xu R, Tong G. Prognostic value of inflammatory and nutritional indexes among patients with unresectable advanced gastric cancer receiving immune checkpoint inhibitors combined with chemotherapy-a retrospective study. PeerJ 2024; 12:e18659. [PMID: 39713151 PMCID: PMC11660861 DOI: 10.7717/peerj.18659] [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: 11/17/2024] [Indexed: 12/24/2024] Open
Abstract
Background Recent studies have revealed that inflammatory factors and nutritional status of patients with advanced gastric cancer (AGC) are related to the efficacy of drug therapy and patient prognosis. This study seeks to evaluate the correlation between inflammatory markers, nutritional status, and clinical outcomes of immune checkpoint inhibitor (ICI)-based therapies among inoperable AGC patients. Method This retrospective study included 88 AGC patients who received ICIs combined with chemotherapy. Inflammatory and nutritional indicators from patients before and after two cycles of treatment were collected. Finally, the correlations between these indicators and the clinical response and survival of AGC patients with ICI treatment were examined. Results The results revealed that an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0, neutrophil count to lymphocyte count ratio (NLR) < 2.84, platelet count to lymphocyte count ratio (PLR) < 82.23, lymphocyte count to monocyte count ratio ≥ 2.35, the hemoglobin, albumin, lymphocyte and platelet score (HALP) ≥ 31.17, prognostic nutritional index (PNI) ≥ 46.53, albumin ≥ 41.65, the decreased HALP group and the decreased PNI group were significantly correlated with improved objective response rate. Additionally, an ECOG PS score of 0, NLR < 2.84 and the decreased HALP group was associated with a superior disease control rate. Meanwhile, an ECOG PS score of 0 (progression-free survival (PFS): P = 0.003; overall survival (OS): P = 0.001) and decreased PLR following treatment (PFS: P = 0.011; OS: P = 0.008) were significant independent predictors of PFS and OS. Lastly, a systemic immune inflammation index ≥ 814.8 was also a positive independent predictor of OS among AGC patients. Conclusion Our study supports the potential of inflammatory and nutritional factors to serve as predictors of the efficacy and prognosis in patients undergoing ICI-based therapies for AGC. However, further investigations are necessary to validate these findings.
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Affiliation(s)
- Meiqin Zhu
- Department of Medical Oncology, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Lin-Ting Zhang
- Department of Oncology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
- Shantou University Medical College, Shantou, Guangdong, China
| | - Wenjuan Lai
- Nursing Department, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Fang Yang
- Department of Oncology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Danyang Zhou
- Department of Oncology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Ruilian Xu
- Department of Medical Oncology, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, China
| | - Gangling Tong
- Department of Oncology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
- Shantou University Medical College, Shantou, Guangdong, China
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Zhang J, Zhao P, Xu R, Han L, Chen W, Zhang Y. Comparison of the efficacy and safety of perioperative immunochemotherapeutic strategies for locally advanced esophageal cancer: a systematic review and network meta-analysis. Front Immunol 2024; 15:1478377. [PMID: 39712027 PMCID: PMC11659204 DOI: 10.3389/fimmu.2024.1478377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 11/20/2024] [Indexed: 12/24/2024] Open
Abstract
Background The aim of this network meta-analysis was to clarify the efficacy and safety of different immune checkpoint inhibitors (ICIs) in combination with chemotherapy in the neoadjuvant phase for the treatment of locally advanced esophageal cancer. Methods We searched PubMed, EMBASE, Web of Science, Cochrane Library, CNKI and WanFang databases from January 2000 until May 2024. The primary endpoints were pathological complete response (pCR), major pathological response (MPR), R0 resection rate, objective response rate (ORR), disease control rate (DCR), treatment-related adverse events(TRAEs) of any grade and TRAEs of grade 3 or higher. The Newcastle-Ottawa Scale (NOS) and the Cochrane Risk of Bias tool were used to evaluate risk of bias. To analyze the data, Review Manager 5.3 and Stata16.0 were applied. Results Fourteen eligible studies (six randomized controlled trials) and 8 retrospective cohort studies) enrolling 1139 patients were included for this network meta-analysis. All studies originated from China. For patients with locally advanced esophageal cancer, neoadjuvant immunochemotherapeutic strategies showed significant advantages over traditional neoadjuvant therapy in terms of pCR, MPR, ORR and DCR. Among the analyzed regimens, camrelizumab plus chemotherapy demonstrated the most pronounced improvements in pCR and MPR, while pembrolizumab plus chemotherapy achieved the best outcomes in terms of ORR and DCR. There were no significant differences observed among the various neoadjuvant treatment strategies regarding R0 resection rate, any grade TRAEs, or grade≥3 TRAEs. The most common TRAEs in the neoadjuvant chemotherapy plus immunotherapy group were myelosuppression and gastrointestinal damage, with most grade 3 or higher TRAEs being hematologic adverse events. The most frequent immune-related adverse events(irAEs) included rash (4.2-21.7%), thyroid dysfunction (hypothyroidism or hyperthyroidism, 6.3-17.4%), and pneumonia (4.2-6.3%), with the majority being mild to moderate (grade 1 or 2). Conclusions Neoadjuvant immunotherapy combined with chemotherapy regimens demonstrate relatively high efficacy and tolerable safety profiles. Among the evaluated regimens, the combination chemotherapy with camrelizumab had relatively high pCR and MPR, whereas the combination chemotherapy with pembrolizumab had relatively high ORR and DCR. There were no significant differences in safety among the various regimens. Our study suggests that evaluating the efficacy and safety of different ICIs may be helpful in clinical decision-making. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42024583548.
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Affiliation(s)
- Jiao Zhang
- Department of Pharmacy, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Peixi Zhao
- Department of Pharmacy, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
- Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China
| | - Rui Xu
- Department of Oncology, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Le Han
- Department of Chest Surgery, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Wenjuan Chen
- Department of Chest Surgery, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yili Zhang
- Department of Oncology, Shaanxi Province Tumor Hospital of Xi’an Jiaotong University, Xi’an, China
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Wan L, Tian F, Wang L, Hou Y, Liu W, Liu Q, Chen D, Li X, Xiang J, Qin ZY, Wang T, Mao B, Wu L, Hu L. Toxicity profiles of immunochemotherapy for gastric or gastroesophageal junction adenocarcinoma: a systematic review and meta-analysis. Cell Oncol (Dordr) 2024; 47:2335-2347. [PMID: 39636470 DOI: 10.1007/s13402-024-01021-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/24/2024] [Indexed: 12/07/2024] Open
Abstract
PURPOSE Neoadjuvant immunochemotherapy is emerging as a promising regimen for patients with locally advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. However, it remains unclear whether immunochemotherapy will bring more adverse events (AEs) leading to a delay or even cancellation of surgeries. We aimed to provide a comprehensive analysis of the toxicity profiles for immune checkpoint inhibitors (ICIs) combined with chemotherapy among patients with G/GEJ adenocarcinoma. METHODS Published trials up to January 2024 were identified on Web of Science, Cochrane Library, Embase, and PubMed. Single-group and controlled clinical trials with ICIs in combination with chemotherapy in patients with G/GEJ adenocarcinoma were included. Two reviewers independently extracted data including incidence rate of AEs. The primary outcomes included the proportion of patients with adverse events leading to treatment discontinuation, grade 3 or higher adverse events, and serious adverse events. This study is registered with PROSPERO (CRD42023492676). RESULTS Twenty studies were included for a total of 6692 patients. In patients receiving immunochemotherapy, 17% (95% confidence interval (CI), 11-23%) had adverse events leading to treatment discontinuation, 23% (95% CI, 19-27%) had serious adverse events, and 64% (95% CI, 58-70%) had grade 3 or higher adverse events. Compared with patients receiving chemotherapy alone, patients with immunochemotherapy were associated with higher rates of adverse events leading to discontinuation (RR, 1.45; 95% CI, 1.32-1.60), serious adverse events (RR, 1.27; 95% CI, 1.04-1.57), and grade 3 or higher adverse events (RR, 1.15; 95% CI, 1.07-1.23). CONCLUSIONS In conclusion, the incidence of adverse events leading to discontinuation, serious adverse events, and grade 3 or higher adverse events were higher in patients receiving immunochemotherapy compared to those with chemotherapy.
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Affiliation(s)
- Linghong Wan
- Department of Gastroenterology and Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
| | - Fanxuan Tian
- Department of Gastroenterology and Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
| | - Lei Wang
- Department of Gastroenterology and Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
| | - Yongying Hou
- Department of Gastroenterology and Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
- Department of Pathology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P. R. China
| | - Wenkang Liu
- Department of Gastroenterology and Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
| | - Qin Liu
- Department of Gastroenterology and Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
| | - Dongfeng Chen
- Department of Gastroenterology and Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
| | - Xianfeng Li
- Department of Gastroenterology and Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
| | - Junyv Xiang
- Department of Gastroenterology and Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
| | - Zhong-Yi Qin
- Department of Gastroenterology and Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
| | - Tao Wang
- Department of Gastroenterology and Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China
| | - Bijng Mao
- Department of Oncology, The Third Affiliated Hospital of Chongqing Medical University, 1 Shuanghu Branch Road, Yubei District, Chongqing, 401120, P. R. China.
| | - Linyu Wu
- Department of Gastroenterology and Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China.
| | - Lu Hu
- Department of Gastroenterology and Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, P. R. China.
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9
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Cen S, Yuan M, Sun Q, Hou G, Ying J, Xu Q, Zheng Y, Dong Y, Pan H, Han W. Efficacy and safety of dual blockade of HER2 and PD-1 in patients with HER2-positive gastric cancer: a retrospective, multicentre study. Sci Rep 2024; 14:25030. [PMID: 39443515 PMCID: PMC11500361 DOI: 10.1038/s41598-024-76296-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 10/11/2024] [Indexed: 10/25/2024] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) expression is one of the most important pathological characteristics of gastric cancer. The positive rate of HER2 expression in patients with gastric cancer is approximately 20%. The phase III Keynote-811 study revealed that anti-HER2 and anti-PD-1 therapy combined with chemotherapy could significantly improve the objective response rate as first-line treatment in patients with HER2-positive advanced gastric cancer. In the present study, we aimed to evaluate the efficacy of combination therapy with trastuzumab and PD-1 inhibitors in patients with advanced HER2-positive gastric cancer in a real-world setting. Seventy-two HER2-positive gastric cancer patients from three hospitals in China were retrospectively reviewed. These patients were treated with trastuzumab plus one anti-PD-1 agent with or without chemotherapy. The overall response rate, progression-free survival and overall survival were assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). From January 2018 to October 2021, 72 patients with HER2-positive gastric cancer received trastuzumab and a PD-1 inhibitor with or without chemotherapy as neoadjuvant chemotherapy, first-line therapy, second-line therapy or salvage therapy. The ORR was 54.2% for all patients and 79.4% for previously untreated patients. The median PFS and median OS were 10 months (95% CI: 8-13 months) and 26.1 months (95% CI: 18.5-NA months), respectively, for all patients. Grade 3 adverse effects occurred in approximately 25% of patients. Immune-related adverse effects occurred in approximately 12.5% of patients. Trastuzumab and PD-1 inhibitor combination therapy with or without chemotherapy achieved satisfactory survival outcomes in patients with HER2-positive gastric cancer with acceptable safety.
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Affiliation(s)
- Shuyi Cen
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine(HIM), Chinese Academy of Sciences, 38# Guangji Road, Hangzhou, 310022, Zhejiang, PRC, China
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, 3# East Qinchun Road, Hangzhou, 310016, Zhejiang, PRC, China
| | - Meiqin Yuan
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine(HIM), Chinese Academy of Sciences, 38# Guangji Road, Hangzhou, 310022, Zhejiang, PRC, China
| | - Qunan Sun
- Department of Medical Oncology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, 88# Jiefang Road, Hangzhou, 310009, Zhejiang, PRC, China
| | - Guilan Hou
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine(HIM), Chinese Academy of Sciences, 38# Guangji Road, Hangzhou, 310022, Zhejiang, PRC, China
| | - Jieer Ying
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine(HIM), Chinese Academy of Sciences, 38# Guangji Road, Hangzhou, 310022, Zhejiang, PRC, China
| | - Qi Xu
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine(HIM), Chinese Academy of Sciences, 38# Guangji Road, Hangzhou, 310022, Zhejiang, PRC, China
| | - Yu Zheng
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, 3# East Qinchun Road, Hangzhou, 310016, Zhejiang, PRC, China
| | - Ying Dong
- Department of Medical Oncology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, 88# Jiefang Road, Hangzhou, 310009, Zhejiang, PRC, China
| | - Hongming Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, 3# East Qinchun Road, Hangzhou, 310016, Zhejiang, PRC, China.
| | - Weidong Han
- Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine(HIM), Chinese Academy of Sciences, 38# Guangji Road, Hangzhou, 310022, Zhejiang, PRC, China.
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, 3# East Qinchun Road, Hangzhou, 310016, Zhejiang, PRC, China.
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10
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Shaibu Z, Yang F, Ting L, Dzidula L, Yusuf AE, Chen ZH, Zhu W. Comparative efficacy of programmed death ligand 1 inhibition and chemotherapy in advanced gastric or gastroesophageal junction cancer with combined positive score - a meta-analysis. Contemp Oncol (Pozn) 2024; 28:183-190. [PMID: 39512538 PMCID: PMC11538983 DOI: 10.5114/wo.2024.144107] [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: 08/17/2024] [Accepted: 09/24/2024] [Indexed: 11/15/2024] Open
Abstract
Advanced gastric and gastroesophageal junction cancer (G/GEJC) poses significant therapeutic challenges. Immune checkpoint inhibitors, particularly targeting programmed cell death ligand-1 (PD-L1), have emerged as promising agents to enhance patient outcomes. This meta-analysis evaluates the efficacy of PD-L1 inhibitors compared to chemotherapy in patients with advanced G/GEJC characterised by varying combined positive scores (CPS). We systematically searched PubMed, Google Scholar, and Web of science for clinical trial studies comparing PD-L1 inhibitors and chemotherapy in CPS-positive patients, focusing on studies published up to 10 April 2023. Studies were evaluated with risk of bias tools. The primary clinical endpoint analysed in this study was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). This study is registered with Prospero (CRD42023495607). A total of 10 studies comprising 4522 participants were included. Our analysis revealed no statistically significant difference in CPS values between PD-L1 inhibitors and chemotherapy groups (≥ 1 : 1.03 [95% CI: 0.86-1.24], ≤ 1 : 0.92 [95% CI: 0.77-1.11]). However, the pooled hazard ratio for OS favoured PD-L1 inhibitors (hazard ratios - HR, 0.83, [95% CI: 0.78-0.88] and p < 0.00001), while PFS was better after chemotherapy (HR 1.28, [95% CI: 1.04-1.58], p = 0.02). Program death ligand-1 inhibitors improve OS, while chemotherapy enhances PFS in advanced G/GEJC, warranting further investigation into the impact of CPS on treatment outcomes.
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Affiliation(s)
- Zakari Shaibu
- Department of Gastrointestinal Surgery, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, 212002 Jiangsu, People’s Republic of China
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Fumeng Yang
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Liu Ting
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Lily Dzidula
- Claremont Graduate University, School of Community and Global Health, Claremont, USA
| | - Amina Elmi Yusuf
- Department of Emergency Medicine, Second Affiliated Hospital of Nanjing Medical University, China
| | - Zhi-hong Chen
- Department of Gastrointestinal Surgery, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, 212002 Jiangsu, People’s Republic of China
| | - Wei Zhu
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
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11
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Zhu C, Da M, Li Y, Peng L. Case report: pathological complete response after S-1/oxaliplatin regimen combined with trastuzumab and tislelizumab in patients with locally advanced gastric cancer. Front Oncol 2024; 14:1425572. [PMID: 39301541 PMCID: PMC11410570 DOI: 10.3389/fonc.2024.1425572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 08/21/2024] [Indexed: 09/22/2024] Open
Abstract
Background The efficacy of a regimen combining Tegafur, Gimeracil and Oteracil Potassium Capsules (S-1), oxaliplatin (SOX) with trastuzumab and tislelizumab chemotherapy for advanced gastric cancer (GC) has not been reported. Case summary A 56-year-old male was diagnosed with GC combined with peripheral lymph node metastasis. The patient received neoadjuvant chemotherapy, including SOX, tislelizumab and trastuzumab. After 4 cycles of chemotherapy, the tumor shrank significantly, and radical surgery was performed with good clinical results. To date, the patient has been followed up for 6 months with no significant side effects. Conclusion In this study, the patient received combination chemotherapy with SOX trastuzumab and tislelizumab and successfully underwent radical surgery with good clinical outcomes. Combined SOX with trastuzumab and tislelizumab may be an effective neoadjuvant chemotherapy regimen.
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Affiliation(s)
- Chenglou Zhu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Mingxu Da
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou, China
| | - Yaoqi Li
- Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou, China
| | - Lingzhi Peng
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou, China
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12
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Li J, Hu X, Zhang S. Efficacy and side effects of pembrolizumab plus chemotherapy vs. chemotherapy alone in patients with advanced gastric or gastroesophageal junction adenocarcinoma: A meta‑analysis. Oncol Lett 2024; 28:371. [PMID: 38910906 PMCID: PMC11190732 DOI: 10.3892/ol.2024.14504] [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: 03/13/2024] [Accepted: 05/24/2024] [Indexed: 06/25/2024] Open
Abstract
Recently, the treatment plan of pembrolizumab plus chemotherapy was regarded as a promising treatment for patients with advanced gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJC). However, the efficacy and side effects of pembrolizumab plus chemotherapy still lack evidence-based medical evidence to support. Therefore, a meta-analysis was conducted to evaluate the hot issue. By searching PubMed, EMBASE, Cochrane Library, Web of Science, any randomized clinical studies of pembrolizumab plus chemotherapy versus chemotherapy in patients with advanced GC/GEJC met the inclusion criteria were included. The quality of the literature was evaluated and the data was extracted. A correlative software was also used to analyze the data and to draw a conclusion. After screening 14,015 studies, four studies were eligible for the meta-analysis. Compared with chemotherapy alone group, the overall survival (OS) rate was significantly longer. In programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥1 subgroup and PD-L1 CPS ≥10 subgroup analyses, the results showed that the response rate (RR) and complete response rate (CR) were both higher in pembrolizumab plus chemotherapy group compared with chemotherapy alone group. There were not significant differences in the CR, the treatment-related adverse events, succumbed to drug-related events and succumbed to immune-mediated events between the two groups. However, the effect events such as the treatment-related adverse events led to discontinuation, the 3-5 treatment-related adverse events and the immune-mediated adverse events and infusion reactions were more common in pembrolizumab plus chemotherapy group. In conclusion, the current meta-analysis revealed that, in treating advanced GC/GEJC, pembrolizumab plus chemotherapy had improved therapeutic efficacies than chemotherapy alone, as evidenced by the significantly longer OS. Furthermore, the patients in PD-L1 CPS ≥1 subgroup and PD-L1 CPS ≥10 subgroup appeared to benefit from pembrolizumab plus chemotherapy treatment because of higher RR and CR. However, side effects such as the treatment-related adverse events leading to discontinuation, the 3-5 treatment-related adverse events, and immune-mediated adverse events and infusion reactions deserved more attention.
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Affiliation(s)
- Jinquan Li
- Department of Gastrointestinal Surgery, The First People's Hospital of Jingdezhen, Jingdezhen, Jiangxi 33300, P.R. China
| | - Xiaosheng Hu
- Department of Gastrointestinal Surgery, The First People's Hospital of Jingdezhen, Jingdezhen, Jiangxi 33300, P.R. China
| | - Shanzhong Zhang
- Department of Gastrointestinal Surgery, The First People's Hospital of Jingdezhen, Jingdezhen, Jiangxi 33300, P.R. China
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13
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Gao Z, Xu G, Wang S, Guo N, Yu Y, Wang X. Unusual presentation of PD-1 inhibitors in people living with HIV with advanced gastric cancer: Case report. Int J STD AIDS 2024; 35:733-738. [PMID: 38644514 DOI: 10.1177/09564624241248676] [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: 04/23/2024]
Abstract
This paper seeks to determine the effect of combination anti-PD-1 and antiretroviral therapy (ART) on people living with HIV (PLWH) with advanced gastric cancer. In our case, a PLWH with recurrent locally advanced gastric cancer was treated with anti-PD-1 inhibitor and ART. A significant reduction in tumor lesions (as demonstrated by contrast-enhanced CT imaging) and a better quality of life were achieved following treatment. There have been limited studies on the treatment of PLWH with advanced gastric cancer. Chemotherapy is most often used, however, with unsatisfactory outcomes. to date, there have been no published reports on the use of PD-1 inhibitors in PLWH with advanced gastric cancer. Our report provides a valuable reference for future management of such patients.
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Affiliation(s)
- Zhidi Gao
- Department of Oncology, Qingdao Branch of Shandong Public Health Clinical Center, Qingdao, People's Republic of China
| | - Guangyong Xu
- Department of Infectious Diseases, Qingdao Branch of Shandong Public Health Clinical Center, Qingdao, People's Republic of China
| | - Su Wang
- Department of Oncology, Hiser Hospital Affiliated to Qingdao University, Shandong, People's Republic of China
| | - Na Guo
- Department of Oncology, Qingdao Branch of Shandong Public Health Clinical Center, Qingdao, People's Republic of China
| | - Yang Yu
- Department of Oncology, Qingdao Branch of Shandong Public Health Clinical Center, Qingdao, People's Republic of China
| | - Xiaoni Wang
- Imaging Department, Qingdao Branch of Shandong Public Health Clinical Center, Qingdao, People's Republic of China
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14
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Younis A, Gribben J. Immune Checkpoint Inhibitors: Fundamental Mechanisms, Current Status and Future Directions. IMMUNO 2024; 4:186-210. [DOI: 10.3390/immuno4030013] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Immune checkpoint inhibitors (ICI) are a promising form of immunotherapy that have significantly changed the therapeutic landscape for many advanced cancers. They have shown unique clinical benefit against a broad range of tumour types and a strong overall impact on survival in studied patient populations. However, there are still many limitations holding back this immunotherapy from reaching its full potential as a possible curative option for advanced cancer patients. A great deal of research is being undertaken in the hope of driving advancements in this area, building a better understanding of the mechanisms behind immune checkpoint inhibition and ultimately developing more effective, safer, and wider-reaching agents. Taking into account the current literature on this topic, this review aims to explore in depth the basis of the use of ICIs in the treatment of advanced cancers, evaluate its efficacy and safety, consider its current limitations, and finally reflect on what the future holds for this very promising form of cancer immunotherapy.
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Affiliation(s)
- Abdullah Younis
- Barts and the London School of Medicine and Dentistry, London E1 2AD, UK
| | - John Gribben
- Barts Cancer Institute, Queen Mary University of London, London EC1M 6AU, UK
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15
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Liu P, Wu J, Chen L, Wu Z, Wu Y, Zhang G, Yu B, Zhang B, Wei N, Shi J, Zhang C, Lei L, Yu S, Lai J, Guo Z, Zheng Y, Jing Z, Jiang H, Wang T, Zhou J, Wu Y, Sun C, Shen J, Zhang J, Wu Z. Water-filtered infrared A radiation hyperthermia combined with immunotherapy for advanced gastrointestinal tumours. Cancer Med 2024; 13:e70024. [PMID: 39049187 PMCID: PMC11269209 DOI: 10.1002/cam4.70024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 06/18/2024] [Accepted: 07/05/2024] [Indexed: 07/27/2024] Open
Abstract
This study pioneered the use of WIRA whole-body infrared hyperthermia combined with ICI therapy to treat GIT and verified the feasibility and safety of HIT. The final results showed a DCR of 55.6%, with a median PFS of 53.5 days, median OS of 134 days, and an irAE incidence of 22.2%. Therefore, we believe that HIT can exert multiple synergistic sensitisation effects, thereby providing clinical benefits to patients with advanced GITs, increasing overall safety, and improving patients' QOL.
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Affiliation(s)
- Pengyuan Liu
- Department of Oncology, Zhejiang HospitalHangzhouChina
| | - Jing Wu
- Department of Oncology, Zhejiang HospitalHangzhouChina
| | - Liting Chen
- Department of Oncology, Zhejiang HospitalHangzhouChina
| | - Zhenhai Wu
- Department of Oncology, Zhejiang HospitalHangzhouChina
| | - Yufei Wu
- ACS (International) School of SingaporeSingapore
| | - Ganlu Zhang
- Department of Oncology, Zhejiang HospitalHangzhouChina
| | - Bingqi Yu
- Department of Oncology, Zhejiang HospitalHangzhouChina
| | - Beibei Zhang
- Department of Oncology, Zhejiang HospitalHangzhouChina
| | - Nan Wei
- Department of Oncology, Zhejiang HospitalHangzhouChina
| | - Jinan Shi
- Department of Oncology, Zhejiang HospitalHangzhouChina
| | | | - Lan Lei
- Department of Oncology, Zhejiang HospitalHangzhouChina
| | - Shuhuan Yu
- Department of Oncology, Zhejiang HospitalHangzhouChina
| | - Jianjun Lai
- Department of Oncology, Zhejiang HospitalHangzhouChina
| | - Zhen Guo
- Department of Oncology, Zhejiang HospitalHangzhouChina
| | - Yuli Zheng
- Department of Oncology, Zhejiang HospitalHangzhouChina
| | - Zhao Jing
- Department of Oncology, Zhejiang HospitalHangzhouChina
| | - Hao Jiang
- Department of Oncology, Zhejiang HospitalHangzhouChina
| | | | - Jueyi Zhou
- Department of OncologyLishui People's HospitalLishuiChina
| | - Yajun Wu
- TCM Dispensary, Zhejiang HospitalHangzhouChina
| | - Chuan Sun
- Geriatrics Institute of Zhejiang ProvinceDepartment of Geriatrics, Zhejiang HospitalHangzhouChina
| | - Jie Shen
- Department of Medical Oncology, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jian Zhang
- Department of Gastrointestinal Surgery, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Zhibing Wu
- Department of Oncology, Zhejiang HospitalHangzhouChina
- Department of Radiation Oncology, Affiliated Zhejiang HospitalZhejiang University School of MedicineHangzhouChina
- Cancer CenterZhejiang UniversityHangzhouChina
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16
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Yao J, Tan X, Sha Y, Chen Y, Chen R, Shi D. An updated review of immunotherapy in esophageal cancer: PD-L1 footprint. Cent Eur J Immunol 2024; 49:77-90. [PMID: 38812606 PMCID: PMC11130989 DOI: 10.5114/ceji.2024.139269] [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: 05/11/2023] [Accepted: 12/15/2023] [Indexed: 05/31/2024] Open
Abstract
Esophageal cancer is considered one of the most significant challenges to public health worldwide. While various therapeutic options exist for esophageal cancer, including chemotherapy, radiotherapy, and surgery, several adverse effects of these medications have been reported. Therefore, a new generation of therapeutic lines should be applied to minimize complications. In this regard, immunotherapy is a novel approach that aims to kill tumor cells directly by targeting them. Specifically, monoclonal antibodies can target specific markers of esophageal cancer tumor cells, keeping other normal cells safe. Multiple monoclonal antibodies optimized for esophageal cancer, such as pembrolizumab, ramucirumab, trastuzumab, nivolumab, and ipilimumab, are available. On the other hand, esophageal cancer tumor cells express a specific inhibitory ligand and its receptor called programmed cell death, which can suppress T cell immune responses. This receptor provides an inhibitory signal, causing the highest expression of the PD-L1 ligand on tumor cells. The outcomes of this interaction lead to the suppression of the activation and function of T lymphocytes. Therefore, immunotherapy for esophageal cancer targeting the PD-1/PD-L1 pathway has shown a remarkable correlation with cancer care. This study presents a comprehensive review of the latest findings related to immunotherapy in esophageal cancer.
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Affiliation(s)
- Juan Yao
- Department of Radiation Oncology, Huaian Hospital of Huaian City (Huai’a Cancer Hospital), Huaian, Jiangsu 223200, P.R. of China
| | - Xiaoyan Tan
- Department of Obstetrics and Gynecology, Huaian Hospital of Huaian City (Huai’an Cancer Hospital), Huaian, Jiangsu 223200, P.R. of China
| | - Yanping Sha
- Department of Radiation Oncology, Huaian Hospital of Huaian City (Huai’a Cancer Hospital), Huaian, Jiangsu 223200, P.R. of China
| | - Yurao Chen
- Department of Radiation Oncology, Huaian Hospital of Huaian City (Huai’a Cancer Hospital), Huaian, Jiangsu 223200, P.R. of China
| | - Ronghuai Chen
- Department of Radiation Oncology, Huaian Hospital of Huaian City (Huai’a Cancer Hospital), Huaian, Jiangsu 223200, P.R. of China
| | - Dongping Shi
- Department of Infection, Huaian Hospital of Huaian City (Huai’a Cancer Hospital), Huaian, Jiangsu 223200, P.R. of China
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17
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Che G, Yin J, Wang W, Luo Y, Chen Y, Yu X, Wang H, Liu X, Chen Z, Wang X, Chen Y, Wang X, Tang K, Tang J, Shao W, Wu C, Sheng J, Li Q, Liu J. Circumventing drug resistance in gastric cancer: A spatial multi-omics exploration of chemo and immuno-therapeutic response dynamics. Drug Resist Updat 2024; 74:101080. [PMID: 38579635 DOI: 10.1016/j.drup.2024.101080] [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: 12/07/2023] [Revised: 03/17/2024] [Accepted: 03/17/2024] [Indexed: 04/07/2024]
Abstract
BACKGROUND Gastric Cancer (GC) characteristically exhibits heterogeneous responses to treatment, particularly in relation to immuno plus chemo therapy, necessitating a precision medicine approach. This study is centered around delineating the cellular and molecular underpinnings of drug resistance in this context. METHODS We undertook a comprehensive multi-omics exploration of postoperative tissues from GC patients undergoing the chemo and immuno-treatment regimen. Concurrently, an image deep learning model was developed to predict treatment responsiveness. RESULTS Our initial findings associate apical membrane cells with resistance to fluorouracil and oxaliplatin, critical constituents of the therapy. Further investigation into this cell population shed light on substantial interactions with resident macrophages, underscoring the role of intercellular communication in shaping treatment resistance. Subsequent ligand-receptor analysis unveiled specific molecular dialogues, most notably TGFB1-HSPB1 and LTF-S100A14, offering insights into potential signaling pathways implicated in resistance. Our SVM model, incorporating these multi-omics and spatial data, demonstrated significant predictive power, with AUC values of 0.93 and 0.84 in the exploration and validation cohorts respectively. Hence, our results underscore the utility of multi-omics and spatial data in modeling treatment response. CONCLUSION Our integrative approach, amalgamating mIHC assays, feature extraction, and machine learning, successfully unraveled the complex cellular interplay underlying drug resistance. This robust predictive model may serve as a valuable tool for personalizing therapeutic strategies and enhancing treatment outcomes in gastric cancer.
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Affiliation(s)
- Gang Che
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China
| | - Jie Yin
- Department of Colorectal Medicine, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Wankun Wang
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China
| | - Yandong Luo
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Yiran Chen
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China
| | - Xiongfei Yu
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China
| | - Haiyong Wang
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China
| | - Xiaosun Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China
| | - Zhendong Chen
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China
| | - Xing Wang
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China
| | - Yu Chen
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China
| | - Xujin Wang
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China
| | - Kaicheng Tang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Jiao Tang
- College of Computer Science and Technology, Nanjing University of Aeronautics and Astronautics of (NUAA), Nanjing 211106, China
| | - Wei Shao
- College of Computer Science and Technology, Nanjing University of Aeronautics and Astronautics of (NUAA), Nanjing 211106, China
| | - Chao Wu
- Department of Medical Oncology, Senior Department of Oncology, Chinese PLA General Hospital, The Fifth Medical Center, Beijing 100853, China.
| | - Jianpeng Sheng
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; Center for Intelligent Oncology Designated by State Ministry of Education, Chongqing University, Chongqing 400030, China; Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing 400030, China.
| | - Qing Li
- College of Bioengineering, Chongqing University, Chongqing 400030, China.
| | - Jian Liu
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China.
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Yee EJ, Gilbert D, Kaplan J, Wani S, Kim SS, McCarter MD, Stewart CL. Effect of Neoadjuvant Chemotherapy on Tumor-Infiltrating Lymphocytes in Resectable Gastric Cancer: Analysis from a Western Academic Center. Cancers (Basel) 2024; 16:1428. [PMID: 38611107 PMCID: PMC11010931 DOI: 10.3390/cancers16071428] [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: 02/24/2024] [Revised: 03/29/2024] [Accepted: 04/06/2024] [Indexed: 04/14/2024] Open
Abstract
Tumor-infiltrating lymphocytes (TILs) are an emerging biomarker predictive of response to immunotherapy across a spectrum of solid organ malignancies. The characterization of TILs in gastric cancer (GC) treated with contemporary, multiagent neoadjuvant chemotherapy (NAC) is understudied. In this retrospective investigation, we analyzed the degree of infiltration, phenotype, and spatial distribution of TILs via immunohistochemistry within resected GC specimens treated with or without NAC at a Western center. We hypothesized that NAC executes immunostimulatory roles, as evidenced by an increased number of anti-tumor TILs in the tumor microenvironment. We found significantly elevated levels of conventional and memory CD8+ T cells, as well as total TILs (CD4+, CD8+, Treg, B cells), within chemotherapy-treated tumors compared with chemotherapy-naïve specimens. We also revealed important associations between survival and pathologic responses with enhanced TIL infiltration. Taken together, our findings advocate for an immunostimulatory role of chemotherapy and underscore the potential synergistic effect of combining chemotherapy with immunotherapy in resectable gastric cancer.
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Affiliation(s)
- Elliott J. Yee
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; (D.G.); (M.D.M.); (C.L.S.)
| | - Danielle Gilbert
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; (D.G.); (M.D.M.); (C.L.S.)
| | - Jeffrey Kaplan
- Department of Pathology, University of Colorado, Aurora, CO 80045, USA;
| | - Sachin Wani
- Division of Gastroenterology, Department of Medicine, University of Colorado, Aurora, CO 80045, USA;
| | - Sunnie S. Kim
- Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO 80045, USA;
| | - Martin D. McCarter
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; (D.G.); (M.D.M.); (C.L.S.)
| | - Camille L. Stewart
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; (D.G.); (M.D.M.); (C.L.S.)
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Fu M, Zhang X, Shen F, Ma J, Li Z. Prognostic value of peripheral blood neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, pan-immune-inflammation value and systemic immune-inflammation index for the efficacy of immunotherapy in patients with advanced gastric cancer. Immunotherapy 2024. [PMID: 38578121 DOI: 10.2217/imt-2024-0031] [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] [Indexed: 04/06/2024] Open
Abstract
Aim: The study aimed to assess the value of pretreatment peripheral blood neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), pan-immune-inflammation value (PIV) and systemic immune-inflammation index (SII) for predicting immunotherapy prognosis and efficacy in advanced gastric cancer (GC). Methods: A total of 84 advanced GC patients received immunotherapy were retrospectively collected. The optimal cut-off values were determined by receiver operating characteristic curves. The univariate and multivariate analysis investigated the effects of NLR, PLR, PIV and SII on patients prognosis. Results: NLR, PLR, PIV and SII had predictive value of efficacy. NLR ≥3.65 was an independent risk factor for worse outcomes. Conclusion: NLR, PLR, PIV and SII have predictive value of efficacy and NLR ≥3.65 suggests a poor prognosis following immunotherapy in advanced GC.
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Affiliation(s)
- Maodong Fu
- Department of Integrated Traditional Chinese & Western Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, Fujian, 361015, People's Republic of China
- Xiamen Clinical Research Center for Cancer Therapy, Xiamen, Fujian, 361015, People's Republic of China
| | - Xiuping Zhang
- Department of Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, Fujian, 361015, People's Republic of China
- Xiamen Clinical Research Center for Cancer Therapy, Xiamen, Fujian, 361015, People's Republic of China
| | - Feng Shen
- Department of Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, Fujian, 361015, People's Republic of China
- Xiamen Clinical Research Center for Cancer Therapy, Xiamen, Fujian, 361015, People's Republic of China
| | - Jun Ma
- Department of Integrated Traditional Chinese & Western Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, Fujian, 361015, People's Republic of China
- Xiamen Clinical Research Center for Cancer Therapy, Xiamen, Fujian, 361015, People's Republic of China
| | - Zhiyong Li
- Department of Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, Fujian, 361015, People's Republic of China
- Xiamen Clinical Research Center for Cancer Therapy, Xiamen, Fujian, 361015, People's Republic of China
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20
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Verschoor YL, van de Haar J, van den Berg JG, van Sandick JW, Kodach LL, van Dieren JM, Balduzzi S, Grootscholten C, IJsselsteijn ME, Veenhof AAFA, Hartemink KJ, Vollebergh MA, Jurdi A, Sharma S, Spickard E, Owers EC, Bartels-Rutten A, den Hartog P, de Miranda NFCC, van Leerdam ME, Haanen JBAG, Schumacher TN, Voest EE, Chalabi M. Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial. Nat Med 2024; 30:519-530. [PMID: 38191613 PMCID: PMC10878980 DOI: 10.1038/s41591-023-02758-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 12/07/2023] [Indexed: 01/10/2024]
Abstract
Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements, most patients die of their disease. Although immune checkpoint blockade became part of the standard-of-care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment (TME) in early disease remain largely unknown. We hypothesized higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with nonmetastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors (n = 21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by four cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well tolerated. There were grade 3 immune-related adverse events in two of 20 patients (10%) but no grade 4 or 5 immune-related adverse events, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent anti-programmed cell death ligand 1 (PD-L1) and the subsequent combination with chemotherapy on the TME. Twenty of 21 patients underwent surgery and were evaluable for secondary pathologic response and survival endpoints, and 19 were evaluable for exploratory translational analyses. A major pathologic response (≤10% residual viable tumor) was observed in 14 of 20 (70%, 95% confidence interval 46-88%) patients, including 9 (45%, 95% confidence interval 23-68%) pathologic complete responses. At a median follow-up of 47 months, 13 of 14 responders were alive and disease-free, and five of six nonresponders had died as a result of recurrence. Notably, baseline anti-programmed cell death protein 1 (PD-1)+CD8+ T cell infiltration was significantly higher in responders versus nonresponders, and comparison of TME alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy showed an increased immune activation on single-agent PD-1/L1 axis blockade. On the basis of these data, monotherapy anti-PD-L1 before its combination with chemotherapy warrants further exploration and validation in a larger cohort of patients with nonmetastatic G/GEJ cancer. ClinicalTrials.gov registration: NCT03448835 .
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Affiliation(s)
- Yara L Verschoor
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Joris van de Haar
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
- Oncode Institute, Amsterdam, the Netherlands
| | - José G van den Berg
- Department of Pathology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Johanna W van Sandick
- Department of Surgery, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Liudmila L Kodach
- Department of Pathology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Jolanda M van Dieren
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Sara Balduzzi
- Biometrics department, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Cecile Grootscholten
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | | | - Alexander A F A Veenhof
- Department of Surgery, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Koen J Hartemink
- Department of Surgery, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Marieke A Vollebergh
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
- Department of Medical Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | | | | | | | - Emilia C Owers
- Department of Nuclear Medicine, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Annemarieke Bartels-Rutten
- Department of Radiology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Peggy den Hartog
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | | | - Monique E van Leerdam
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - John B A G Haanen
- Department of Medical Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
- Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands
- Oncology Service, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Ton N Schumacher
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
- Oncode Institute, Amsterdam, the Netherlands
- Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands
| | - Emile E Voest
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
- Oncode Institute, Amsterdam, the Netherlands
| | - Myriam Chalabi
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
- Department of Medical Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
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21
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Wang H, Zhou Z, Zhang J, Hao T, Wang P, Wu P, Su R, Yang H, Deng G, Chen S, Gu L, He Y, Zeng L, Zhang C, Yin S. Pumilio1 regulates NPM3/NPM1 axis to promote PD-L1-mediated immune escape in gastric cancer. Cancer Lett 2024; 581:216498. [PMID: 38029539 DOI: 10.1016/j.canlet.2023.216498] [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: 09/25/2023] [Revised: 11/08/2023] [Accepted: 11/16/2023] [Indexed: 12/01/2023]
Abstract
Abnormal regulation of RNA binding proteins (RBPs) plays an essential role in tumorigenesis and progression, but their functions and mechanisms remain largely elusive. Previously, we reported that Pumilio 1 (PUM1), a RBP, could regulate glycolysis metabolism and promote the progression of gastric cancer (GC). However, the role of PUM1 in tumor immune regulation remains largely elusive. In this study, we report that PUM1 induces immune escape through posttranscriptional regulation of PD-L1 in GC. We used multiplexed immunohistochemistry to analyze the correlation between PUM1 expression and immune microenvironment in GC. The effect of PUM1 deficiency on tumor killing of T cells was examined in vitro and in vivo. The molecular mechanism of PUM1 was evaluated via RNA immunoprecipitation, chromatin immunoprecipitation, Western blot, co-immunoprecipitation, and RNA stability assays. Clinically, elevated PUM1 expression is associated with high-expression of PD-L1, lack of CD8+ T cell infiltration and poor prognosis in GC patients. PUM1 positively regulates PD-L1 expression and PUM1 reduction enhances T cell killing of tumors. Mechanistically, PUM1 directly binds to nucleophosmin/nucleoplasmin 3 (NPM3) mRNA and stabilizes NPM3. NPM3 interacts with NPM1 to promote NPM1 translocation into the nucleus and increase the transcription of PD-L1. PUM1 inhibits the anti-tumor activity of T cells through the PUM1/NPM3/PD-L1 axis. In summary, this study reveals the critical post-transcriptional effect of PUM1 in the modulation of PD-L1-dependent GC immune escape, thus provides a novel indicator and potential therapeutic target for cancer immunotherapy.
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Affiliation(s)
- Han Wang
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China; Department of Gastrointestinal Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Zhijun Zhou
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Junchang Zhang
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China; Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Tengfei Hao
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Pengliang Wang
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Pei Wu
- Department of Gastrointestinal Surgery, Yongchuan Hospital of Chongqing Medical university, Chongqing, China
| | - Rishun Su
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Huan Yang
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Guofei Deng
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Songyao Chen
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Liang Gu
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yulong He
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China; Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Leli Zeng
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
| | - Changhua Zhang
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
| | - Songcheng Yin
- Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
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22
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Yu X, Zhai X, Wu J, Feng Q, Hu C, Zhu L, Zhou Q. Evolving perspectives regarding the role of the PD-1/PD-L1 pathway in gastric cancer immunotherapy. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166881. [PMID: 37696462 DOI: 10.1016/j.bbadis.2023.166881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 08/08/2023] [Accepted: 09/04/2023] [Indexed: 09/13/2023]
Abstract
Gastric cancer (GC) is an increasing global health problem and is one of the leading cancers worldwide. Traditional therapies, such as radiation and chemotherapy, have made limited progress in enhancing their efficacy for advanced GC. The development of immunotherapy for advanced GC has considerably improved with a deeper understanding of the tumor microenvironment. Immunotherapy using checkpoint inhibitors is a new therapeutic option that has made substantial advances in the treatment of other malignancies and is increasingly used in other clinical oncology treatments. Particularly, therapeutic antibodies targeting the programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway have been effectively used in the clinical treatment of cancer. Monoclonal antibodies blocking the PD-1/PD-L1 pathway have been developed for cancer immunotherapy to enhance T cell function to restore the immune response and represent a breakthrough in the treatment of GC. This review provides an outline of the progress of PD-1/PD-L1 blockade therapy and its expression characteristics and clinical application in advanced GC.
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Affiliation(s)
- Xianzhe Yu
- Department of Medical Oncology, Cancer Center & Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People's Republic of China; Department of Gastrointestinal Surgery, Chengdu Second People's Hospital, No. 10 Qinyun Nan Street, Chengdu, Sichuan Province, People's Republic of China
| | - Xiaoqian Zhai
- Department of Medical Oncology, Cancer Center & Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People's Republic of China
| | - Juan Wu
- Out-patient Department, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People's Republic of China
| | - Qingbo Feng
- Department of General Surgery, Affiliated Hospital of Zunyi Medical University, Affiliated Digestive Hospital of Zunyi Medical University, Zunyi, Guizhou Province, People's Republic of China
| | - Chenggong Hu
- Department of Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
| | - Lingling Zhu
- Department of Medical Oncology, Cancer Center & Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People's Republic of China.
| | - Qinghua Zhou
- Department of Medical Oncology, Cancer Center & Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People's Republic of China.
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23
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Li D, Loriot Y, Burgoyne AM, Cleary JM, Santoro A, Lin D, Aix SP, Garrido-Laguna I, Sudhagoni R, Guo X, Andrianova S, Paulson S. Cabozantinib plus atezolizumab in previously untreated advanced hepatocellular carcinoma and previously treated gastric cancer and gastroesophageal junction adenocarcinoma: results from two expansion cohorts of a multicentre, open-label, phase 1b trial (COSMIC-021). EClinicalMedicine 2024; 67:102376. [PMID: 38204489 PMCID: PMC10776423 DOI: 10.1016/j.eclinm.2023.102376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/22/2023] [Accepted: 11/28/2023] [Indexed: 01/12/2024] Open
Abstract
Background Cabozantinib is approved for previously treated advanced hepatocellular carcinoma (aHCC) and has been investigated in gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJ). Atezolizumab plus bevacizumab is approved for unresectable or metastatic HCC untreated with prior systemic therapy. We evaluated efficacy and safety of cabozantinib plus atezolizumab in aHCC previously untreated with systemic anticancer therapy or previously treated GC/GEJ. Methods COSMIC-021 (ClinicalTrials.gov, NCT03170960) is an open-label, phase 1b study in solid tumours with a dose-escalation stage followed by tumour-specific expansion cohorts, including aHCC (cohort 14) and GC/GEJ (cohort 15). Eligible patients were aged ≥18 years with measurable locally advanced, metastatic, or recurrent disease per RECIST version 1.1. Patients received oral cabozantinib 40 mg daily and intravenous atezolizumab 1200 mg once every 3 weeks until progressive disease or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1. Findings Patients were screened between February 14, 2019, and May 7, 2020, and 61 (30 aHCC, 31 GC/GEJ) were enrolled and received at least one dose of study treatment. Median duration of follow-up was 31.2 months (IQR 28.5-32.7) for aHCC and 30.4 months (28.7-31.9) for GC/GEJ. Objective response rate was 13% (4/30, 95% CI 4-31) for aHCC and 0% (95% CI 0-11) for GC/GEJ. Six (20%) aHCC patients and three (10%) GC/GEJ patients had treatment-related adverse events resulting in discontinuation of either study drug. Interpretation Cabozantinib plus atezolizumab had clinical activity with a manageable safety profile in aHCC previously untreated with systemic anticancer therapy. Clinical activity of cabozantinib plus atezolizumab was minimal in previously treated GC/GEJ. Funding Exelixis, Inc., Alameda, CA, USA.
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Affiliation(s)
- Daneng Li
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Yohann Loriot
- Department of Cancer Medicine, Gustave Roussy Institute, INSERM 981, University Paris-Saclay, Villejuif, France
| | | | - James M. Cleary
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Armando Santoro
- IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Rozzano, Italy
- Humanitas University, Pieve Emanuele, Italy
| | - Daniel Lin
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Santiago Ponce Aix
- Hospital Universitario 12 de Octubre, H12O-CNIO Lung Cancer Clinical Research Unit, Universidad Complutense and Ciberonc, Madrid, Spain
| | | | | | | | | | - Scott Paulson
- Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX, USA
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24
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Li L, Chen G, Chen EY, Strickland MR, Zhao W, Zhang J, Li Z. Development and validation of a nomogram to predict pathological complete response in patients with locally advanced gastric adenocarcinoma treated with neoadjuvant chemotherapy in combination with PD-1 antibodies. J Gastrointest Oncol 2023; 14:2373-2383. [PMID: 38196541 PMCID: PMC10772673 DOI: 10.21037/jgo-23-751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 11/20/2023] [Indexed: 01/11/2024] Open
Abstract
Background Currently, the survival benefits of combining neoadjuvant chemotherapy with programmed death 1 (PD-1) antibody immunotherapy in advanced gastric adenocarcinoma remain controversial. Emerging evidence suggests that the survival benefits of neoadjuvant therapy in advanced gastric adenocarcinoma hinge upon the attainment of pathological complete response (pCR). Therefore, the prediction of pCR in patients undergoing neoadjuvant chemotherapy combined with PD-1 antibody immunotherapy holds significant importance and is beneficial for the individualized treatment of gastric cancer (GC) patients. Methods Clinical and pathological characteristics of patients with GC who received neoadjuvant chemotherapy combined with PD-1 inhibitor (camrelizumab) therapy and radical gastrectomy between January 2019 and December 2020 at the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital were retrospectively analyzed. A total of 52 patients were enrolled in the study, with all subjects assigned to the training set. The neoadjuvant regimen consisted of a combination of PD-1 inhibitor and fluorouracil analogues plus oxaliplatin, comprising two drugs. The patients were divided into a pCR group and a non-pCR group according to pCR occurrence. Multifactor logistic regression analysis was applied to determine the correlation between each factor and pCR. A prediction model was developed based on the results of the logistic regression analysis. The predictive performance of the model was evaluated using the receiver operating characteristic curves. Internal verification was completed via the bootstrapping method. Results The pCR was observed in 10 out of 52 patients (19.2%). The results of binary logistic regression multivariate analysis showed that cN stage [odds ratio (OR): 0.215; P=0.03], combined positive score (CPS) (OR: 6.364; P=0.026), and tumor diameter (OR: 0.112; P=0.026) were independent predictors of pCR. The nomogram prediction model for the pCR was plotted with a concordance index of 0.923 [95% confidence interval (CI): 0.8441-1]. Conclusions Neoadjuvant chemotherapy combined with PD-1 antibodies may be the preferred option for patients with advanced gastric adenocarcinoma who have a small tumor diameter, no or few lymph node metastases, and high CPS. The presented nomogram model exhibits the potential to predict pCR in advanced gastric adenocarcinoma patients, showcasing satisfactory predictive performance and potentially facilitating the implementation of personalized treatment strategies.
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Affiliation(s)
- Liang Li
- Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Guanglong Chen
- Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Emerson Y. Chen
- Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Matthew R. Strickland
- Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA
| | - Weijie Zhao
- Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Jialin Zhang
- Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Zhi Li
- Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
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25
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Yerolatsite M, Torounidou N, Gogadis A, Kapoulitsa F, Ntellas P, Lampri E, Tolia M, Batistatou A, Katsanos K, Mauri D. TAMs and PD-1 Networking in Gastric Cancer: A Review of the Literature. Cancers (Basel) 2023; 16:196. [PMID: 38201623 PMCID: PMC10778110 DOI: 10.3390/cancers16010196] [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: 10/20/2023] [Revised: 12/11/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common and aggressive types of cancer. Immune checkpoint inhibitors (ICIs) have proven effective in treating various types of cancer. The use of ICIs in GC patients is currently an area of ongoing research. The tumor microenvironment (TME) also seems to play a crucial role in cancer progression. Tumor-associated macrophages (TAMs) are the most abundant population in the TME. TAMs are capable of displaying programmed cell death protein 1 (PD-1) on their surface and can form a ligand with programmed death ligand 1 (PD-L1), which is found on the surface of cancer cells. Therefore, it is expected that TAMs may significantly influence the immune response related to immune checkpoint inhibitors (ICIs). AIM OF THE STUDY Understanding the role of TAMs and PD-1/PD-L1 networking in GC. METHODS A systematic review of published data was performed using MEDLINE (PubMed), Embase, and Cochrane databases. We retrieved articles investigating the co-existence of TAMs and PD-1 in GC and the prognosis of patients expressing high levels of PD-1+ TAMs. RESULTS Ten articles with a total of 2277 patients were included in the systematic review. The examined data suggest that the expression of PD-L1 has a positive correlation with the infiltration of TAMs and that patients who express high levels of PD-1+ TAMs may have a worse prognosis than those who express low levels of PD-1+ TAMs. CONCLUSIONS TAMs play a pivotal role in the regulation of PD-1/PD-L1 networking and the progression of GC cells. Nevertheless, additional studies are needed to better define the role of TAMs and PD-1/PD-L1 networking in GC.
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Affiliation(s)
- Melina Yerolatsite
- Department of Medical Oncology, University of Ioannina, 45500 Ioannina, Greece; (N.T.); (A.G.); (F.K.); (P.N.); (D.M.)
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45445 Ioannina, Greece
| | - Nanteznta Torounidou
- Department of Medical Oncology, University of Ioannina, 45500 Ioannina, Greece; (N.T.); (A.G.); (F.K.); (P.N.); (D.M.)
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45445 Ioannina, Greece
| | - Aristeidis Gogadis
- Department of Medical Oncology, University of Ioannina, 45500 Ioannina, Greece; (N.T.); (A.G.); (F.K.); (P.N.); (D.M.)
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45445 Ioannina, Greece
| | - Fani Kapoulitsa
- Department of Medical Oncology, University of Ioannina, 45500 Ioannina, Greece; (N.T.); (A.G.); (F.K.); (P.N.); (D.M.)
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45445 Ioannina, Greece
| | - Panagiotis Ntellas
- Department of Medical Oncology, University of Ioannina, 45500 Ioannina, Greece; (N.T.); (A.G.); (F.K.); (P.N.); (D.M.)
| | - Evangeli Lampri
- Department of Pathology, University of Ioannina, 45500 Ioannina, Greece; (E.L.); (A.B.)
| | - Maria Tolia
- Department of Radiotherapy, University of Crete, 71003 Heraklion, Greece;
| | - Anna Batistatou
- Department of Pathology, University of Ioannina, 45500 Ioannina, Greece; (E.L.); (A.B.)
| | | | - Davide Mauri
- Department of Medical Oncology, University of Ioannina, 45500 Ioannina, Greece; (N.T.); (A.G.); (F.K.); (P.N.); (D.M.)
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45445 Ioannina, Greece
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Liu DHW, Grabsch HI, Gloor B, Langer R, Dislich B. Programmed death-ligand 1 (PD-L1) expression in primary gastric adenocarcinoma and matched metastases. J Cancer Res Clin Oncol 2023; 149:13345-13352. [PMID: 37491637 PMCID: PMC10587283 DOI: 10.1007/s00432-023-05142-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 07/06/2023] [Indexed: 07/27/2023]
Abstract
BACKGROUND Combination of immunotherapy and chemotherapy is recommended for first line treatment of gastric adenocarcinoma (GC) patients with locally advanced unresectable disease or metastatic disease. However, data regarding the concordance rate between PD-L1 combined positive score (CPS) in primary GC and matched regional lymph node metastasis (LNmet) or matched distant metastasis (Dmet) is limited. METHODS Tissue microarray sections from primary resected GC, LNmet and Dmet were immunohistochemically stained with anti-PD-L1 (clone SP263). PD-L1 expression was scored separately in tumour cells and immune cells and compared between matched primary GC, LNmet and/or Dmet. CPS was calculated and results for CPS cut-offs 1 and 5 were compared between matched samples. RESULTS 275 PD-L1 stained GC were analysed. 189 primary GC had matched LNmet. CPS cut-off 1 concordance rate between primary GC and LNmet was 77%. 23 primary GC had matched Dmet but no matched LNmet, CPS cut-off 1 concordance rate was 70%. 63 primary GC had both matched LNmet and matched Dmet, CPS cut-off 1 concordance rate of 67%. CPS cut-off 5 results were similar. The proportion of PD-L1 positive tumour cells increased from primary GC (26%) to LNmet (42%) and was highest in Dmet (75%). CONCLUSION Our study showed up to 33% discordance of PD-L1 CPS between primary GC and LNmet and/or Dmet suggesting that multiple biopsies of primary GC and metastatic sites might need to be tested before considering treatment options. Moreover, this is the first study that seems to suggest that tumour cells acquire PD-L1 expression during disease progression.
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Affiliation(s)
- Drolaiz H W Liu
- Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
- Institute of Clinical Pathology and Molecular Pathology, Kepler University Hospital and Johannes Kepler University, Krankenhausstraße 9, 4021, Linz, Austria
| | - Heike I Grabsch
- Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
- Pathology and Data Analytics, Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - Beat Gloor
- Department of Visceral Surgery and Medicine, Inselspital Bern, University of Bern, Bern, Switzerland
| | - Rupert Langer
- Institute of Clinical Pathology and Molecular Pathology, Kepler University Hospital and Johannes Kepler University, Krankenhausstraße 9, 4021, Linz, Austria.
| | - Bastian Dislich
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
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Negura I, Pavel-Tanasa M, Danciu M. Regulatory T cells in gastric cancer: Key controllers from pathogenesis to therapy. Cancer Treat Rev 2023; 120:102629. [PMID: 37769435 DOI: 10.1016/j.ctrv.2023.102629] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/20/2023] [Accepted: 09/22/2023] [Indexed: 09/30/2023]
Abstract
Gastric cancer (GC) is a highly aggressive malignancy that remains a significant contributor to cancer-related mortality worldwide, despite a decline in incidence in recent years. Early-stage GC poses a diagnostic challenge due to its asymptomatic nature, leading to poor prognoses for most patients. Conventional treatment approaches, including chemotherapy and surgery, have shown limited efficacy in improving outcomes for GC patients. The advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer therapy, yielding durable responses across various malignancies. However, the clinical benefits of ICIs in GC have been modest, underscoring the need for a comprehensive understanding of immune cell functions within the GC tumor microenvironment (TME). Regulatory T cells (Tregs), a subset of T lymphocytes, play a pivotal role in GC development and progression and serve as prognostic biomarkers for GC patients. This review aims to elucidate the multifaceted roles of Tregs in the pathogenesis, progression, and prognosis of gastric cancer, and establish their actual and future potential as therapeutic targets. By providing insights into the intricate interplay between Tregs and the TME, this review strives to stimulate further investigation and facilitate the development of targeted Treg-based therapeutic strategies for GC.
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Affiliation(s)
- Ion Negura
- Department of Pathology, Grigore T. Popa University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania
| | - Mariana Pavel-Tanasa
- Department of Immunology, Grigore T. Popa University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania.
| | - Mihai Danciu
- Department of Pathology, Grigore T. Popa University of Medicine and Pharmacy Iasi, 700115 Iasi, Romania
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28
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Cheng R, Li B, Wang H, Zeng Y. Immune checkpoint inhibitors and cellular immunotherapy for advanced gastric, gastroesophageal cancer: a long pathway. Clin Transl Oncol 2023; 25:3122-3138. [PMID: 37036597 DOI: 10.1007/s12094-023-03181-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 03/28/2023] [Indexed: 04/11/2023]
Abstract
Although the incidence rate and mortality of gastric/gastroesophageal cancer (G/GEJC) are declining globally, G/GEJC remains a health issue in East Asia. When diagnosed as advanced stage, treatment after serial lines of chemotherapy is limited, with a median overall survival of less than 1 year. Immunotherapy, including immune checkpoint inhibitors (ICIs) and cellular immunotherapy, has changed the prospects of cancer therapy by reversing immune suppression in the tumor microenvironment. As part of this review, we enumerated the clinical uses of ICIs related to the immunosuppressive signaling axis PD-1/PD-L1 and CTLA-4/B7. ICIs were initially approved as a secondary treatment option for patients with severe pretreating advanced gastric and gastroesophageal cancer (AG/GEJC). Till now, it has become the mainstream therapy in combination with chemotherapy and targeted therapy for patients identified by biomarkers. Numerous evidence showed microsatellite instability (MSI), programmed cell death ligand 1 (PD-L1) expression, tumor mutation burden (TMB) and Epstein-Barr virus (EBV) status might be indicative to the use of ICIs. In addition, we discussed the current limitations and prospects of ICIs in AG/GGEJC, as well as the first clinical application of novel CAR-T cell therapies.
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Affiliation(s)
- Runzi Cheng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, People's Republic of China
- Shantou University Medical College, Shantou, People's Republic of China
| | - Baizhi Li
- Shantou University Medical College, Shantou, People's Republic of China
| | - Huaiming Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, People's Republic of China
| | - Yongming Zeng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, People's Republic of China.
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29
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Baccili Cury Megid T, Farooq AR, Wang X, Elimova E. Gastric Cancer: Molecular Mechanisms, Novel Targets, and Immunotherapies: From Bench to Clinical Therapeutics. Cancers (Basel) 2023; 15:5075. [PMID: 37894443 PMCID: PMC10605200 DOI: 10.3390/cancers15205075] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/16/2023] [Accepted: 10/17/2023] [Indexed: 10/29/2023] Open
Abstract
Gastric cancer is a global health concern, ranking fifth in cancer diagnoses and fourth in cancer-related deaths worldwide. Despite recent advancements in diagnosis, most cases are detected at advanced stages, resulting in poor outcomes. However, recent breakthroughs in genome analysis have identified biomarkers that hold positive clinical significance for GC treatment. These biomarkers and classifications offer the potential for more precise diagnostic and therapeutic approaches for GC patients. In this review, we explore the classification and molecular pathways in this disease, highlighting potential biomarkers that have emerged in recent studies including targeted therapies and immunotherapies. These advancements provide a promising direction for improving the management of GC.
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Affiliation(s)
| | | | | | - Elena Elimova
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; (T.B.C.M.); (A.R.F.); (X.W.)
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30
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Liu L, Niu L, Zheng X, Xiao F, Sun H, Deng W, Cai J. PD-L1 expression-related PI3K pathway correlates with immunotherapy efficacy in gastric cancer. Ther Adv Med Oncol 2023; 15:17588359231205853. [PMID: 37868079 PMCID: PMC10586003 DOI: 10.1177/17588359231205853] [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: 04/13/2023] [Accepted: 09/18/2023] [Indexed: 10/24/2023] Open
Abstract
Background The programed death ligand-1 combined positive score (PD-L1 CPS), the only FDA-approved biomarker for immune checkpoint inhibitor therapy in gastric cancer (GC) patients, is an important but imperfect predictive biomarker. The molecular characteristics of tumors that influence the PD-L1 CPS are largely unknown and would be helpful for screening patients who would benefit from immunotherapy. Methods PD-L1 immunohistochemistry (IHC) and targeted next-generation sequencing techniques were used to compare genomic alterations in 492 GC patients in two groups (PD-L1 CPS ⩾ 1, positive; CPS < 1, negative). Screened PD-L1 expression-related factors were analyzed for immunotherapy efficacy in three distinct GC cohorts from public databases. Results Positive PD-L1 expression occurred in 40% of GC patients and was associated with a higher proportion of phosphatidylinositol 3-kinase (PI3K), SWItch/Sucrose NonFermentable (SWI/SNF), lysine demethylase (KDM), and DNA (cytosine-5)-methyltransferase (DNMT) (all p < 0.01), pathway alterations. Compared to wild-type GC patients, those with PI3K pathway alterations had a higher response rate (p = 0.002) and durable clinical benefit rate with immunotherapy (p = 0.023, p = 0.038) as well as longer progression-free survival (p = 0.084, p = 0.0076) and overall survival (p = 0.2, p = 0.037) with immunotherapy. Conclusion This study revealed PD-L1 expression-related factors in the tumor genome in a GC cohort. Alterations in the PI3K pathway associated with PD-L1 positivity were shown to be associated with better immunotherapy efficacy in three distinct GC cohorts from public databases. Our results provide a potential avenue for patient selection and rational immune combination development for GC patients.
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Affiliation(s)
- Langbiao Liu
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lei Niu
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xue Zheng
- Genecast Biotechnology Co., Ltd, Wuxi City, Jiangsu, China
| | - Fei Xiao
- Genecast Biotechnology Co., Ltd, Wuxi City, Jiangsu, China
| | - Huaibo Sun
- Genecast Biotechnology Co., Ltd, Wuxi City, Jiangsu, China
| | - Wei Deng
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, No. 95, Yong’an Road, Xicheng District, Beijing 100050,China
| | - Jun Cai
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, No. 95, Yong’an Road, Xicheng District, Beijing, 100050, China
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31
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Cheng Y, Bu D, Zhang Q, Sun R, Lyle S, Zhao G, Dong L, Li H, Zhao Y, Yu J, Hao X. Genomic and transcriptomic profiling indicates the prognosis significance of mutational signature for TMB-high subtype in Chinese patients with gastric cancer. J Adv Res 2023; 51:121-134. [PMID: 36351537 PMCID: PMC10491970 DOI: 10.1016/j.jare.2022.10.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 10/11/2022] [Accepted: 10/31/2022] [Indexed: 11/07/2022] Open
Abstract
INTRODUCTION Gastric cancer (GC)is the third leading cause of cancer-related deaths in China and immunotherapy emerging as a revolutionary treatment for GC recently. Tumor mutational burden (TMB) is a predictive biomarker of immunotherapy in multiple cancers. However, the prognostic significance and subtype of TMB in GC is not fully understood. OBJECTIVES This study aims to evaluate the prognostic value of TMB in Chinese GC and further classify TMB-high GC (GCTMB-H) patients combing with mutational signatures. METHODS Genomic profiling of 435 cancer-gene panel was performed using 206 GC samples from Chinese people. Actionable genetic alterations were compared across all the samples to generate actionable subtyping. The prognostic value of TMB in Chinese GC was evaluated. Mutational signatures were analyzed on TMB-H subtype to stratify the prognosis of TMB. Transcriptomic analysis was applied to compare the distributed immunocytes among different subtypes. RESULTS 88.3% (182/206) of GC samples had at least one mutation, while 45.1% (93/206) had at least one somatic copy number alteration (SCNA). 29.6% (61/206) of GC samples were TMB-H, including 13 MSI-H and 48 MSS tumors. According to distinct genetic alteration profiles of 69 actionable genes, we classified GC samples into eight molecular subtypes, including TMB-H, ERBB2 amplified, ATM mutated, BRCA2 mutated, CDKN2A/B deleted, PI3KCA mutated, KRAS mutated, and less-mutated subtype. TMB-H subtype presented a remarkable immune-activated phenotype as determined by transcriptomic analysis that was further validated in the TCGA GC cohort. GCTMB-H patients exhibited significantly better survival (P = 0.047). But Signature 1-high GCTMB-H patients had relatively worse prognosis (P = 0.0209, HR = 2.571) than Signature 1-low GCTMB-H patients from Chinese GC cohort, also validated in TCGA GC cohort, presenting highly activated carbohydrate, fatty acid or lipid metabolism. CONCLUSION The Signature 1-high GCTMB-H could be a marker of poor prognosis and is associated with metabolism disorder.
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Affiliation(s)
- Yanan Cheng
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Dechao Bu
- Research Center for Ubiquitous Computing Systems, Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| | - Qiaoling Zhang
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Rebecca Sun
- KEW, Inc., 303 Wyman Street, Waltham, MA, USA
| | | | - Gang Zhao
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Li Dong
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Hui Li
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Yi Zhao
- Research Center for Ubiquitous Computing Systems, Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China.
| | - Jinpu Yu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
| | - Xishan Hao
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China; National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
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Nie Y, Zhao W, Lu L, Zhou F. Predictive biomarkers and new developments of immunotherapy in gastric cancer: a 2023 update. Am J Cancer Res 2023; 13:3169-3184. [PMID: 37559976 PMCID: PMC10408463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 06/29/2023] [Indexed: 08/11/2023] Open
Abstract
Gastric cancer is an extremely common digestive tract tumor. The promotion and application of standardized therapy, treatment scheme optimization, and development of new targeted drugs and immunotherapies have improved gastric cancer survival somewhat. However, gastric cancer prognosis generally remains non-optimistic. Immune checkpoint inhibitors (ICI) have gradually become a new choice for gastric cancer treatment and can prolong the survival of some patients. Among them, high-microsatellite instability, Epstein-Barr virus-positive status, or high-tumor mutational burden patients with gastric cancer may be the potential population to benefit from immunotherapy. Nevertheless, there remains a lack of unified and effective predictive markers. Accordingly, this review mainly focused on the possible predictive biomarkers of anti-PD-1/PD-L1 in gastric cancer treatment. Furthermore, the application of anti-PD-1/PD-L1 therapy-related clinical trials on gastric cancer is discussed. The current findings suggest that immunotherapy is a promising application in gastric cancer treatment. Therefore, combining immunotherapy and other therapies may be the trend in the future. Nevertheless, exploring biomarkers to predict ICI response remains a major challenge.
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Affiliation(s)
- Yanli Nie
- Department of Gastrointestinal Medical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430079, Hubei, China
| | - Wei Zhao
- PLA Rocket Force Characteristic Medical CenterBeijing 100088, China
| | - Li Lu
- Department of Gastrointestinal Surgical Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan 430079, Hubei, China
| | - Fuxiang Zhou
- Department of Radiation Oncology and Medical Oncology, Zhongnan Hospital of Wuhan UniversityWuhan 430071, Hubei, China
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Shao XX, Xu Q, Wang BZ, Tian YT. Modified stomach-partitioning gastrojejunostomy for initially unresectable advanced gastric cancer with outlet obstruction: A case report. World J Gastrointest Surg 2023; 15:1247-1255. [PMID: 37405097 PMCID: PMC10315123 DOI: 10.4240/wjgs.v15.i6.1247] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/03/2023] [Accepted: 04/17/2023] [Indexed: 06/15/2023] Open
Abstract
BACKGROUND Chemotherapy followed by gastrojejunostomy remains the main treatment for unresectable gastric cancer (GC) in the middle- or lower-third regions with gastric outlet obstruction (GOO). Radical surgery is performed as part of a multimodal treatment strategy for selected patients who respond well to chemotherapy. This study describes a case of successful radical resection with completely laparoscopic subtotal gastrectomy after a modified stomach-partitioning gastrojejunostomy (SPGJ) for obstruction relief, in a patient with GOO.
CASE SUMMARY During the initial esophagogastroduodenoscopy, an advanced growth was detected in the lower part of the stomach, which caused an obstruction in the pyloric ring. Following this, a computed tomography (CT) scan revealed the presence of lymph node metastases and tumor invasion in the duodenum, but no evidence of distant metastasis was found. Consequently, we performed a modified SPGJ, a complete laparoscopic SPGJ combined with No. 4sb lymph node dissection, for obstruction relief. Seven courses of adjuvant capecitabine plus oxaliplatin combined with Toripalimab (programmed death ligand-1 inhibitor) were administered thereafter. A preoperative CT showed partial response; therefore, completely laparoscopic radical subtotal gastrectomy with D2 lymphadenectomy was performed after conversion therapy, and pathological complete remission was achieved.
CONCLUSION Laparoscopic SPGJ combined with No. 4sb lymph node dissection was an effective surgical technique for initially unresectable GC with GOO.
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Affiliation(s)
- Xin-Xin Shao
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Quan Xu
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Bing-Zhi Wang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yan-Tao Tian
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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Leowattana W, Leowattana P, Leowattana T. Immunotherapy for advanced gastric cancer. World J Methodol 2023; 13:79-97. [PMID: 37456977 PMCID: PMC10348086 DOI: 10.5662/wjm.v13.i3.79] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/11/2023] [Accepted: 05/31/2023] [Indexed: 06/20/2023] Open
Abstract
Gastric cancer (GC) is believed to be the fifth most common cancer and the third most common cause of death worldwide. Treatment techniques include radiation, chemotherapy, gastrectomy, and targeted treatments are often employed. Some hopeful results from the development of GC immunotherapy have already changed treatment approaches. Along with previous combination medicines, new immunotherapies have been developed that target distinct molecules. Despite ongoing studies into the current therapeutic options and significant improvements in this field, the prognosis for the ailment is poor. Since there are few treatment options and a delay in detection, the illness actually advances, spreads, and metastasizes. The bulk of immunotherapies in use today rely on cytotoxic immune cells, monoclonal antibodies, and gene-transferred vaccines. Immune checkpoint inhibitors have become more popular. In this review, we sought to examine the viewpoint and development of several immunotherapy treatment modalities for advanced GC, as well as the clinical results thus far reported. Additionally, we outlined tumor immune escape and tumor immunosurveillance.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Pathomthep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Wattana 10110, Bangkok, Thailand
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Fei S, Lu Y, Chen J, Qi J, Wu W, Wang B, Han Y, Wang K, Han X, Zhou H, Wang J, Chen J. Efficacy of PD-1 Inhibitors in First-Line Treatment for Advanced Gastroesophageal Junction and Gastric Cancer by Subgroups: A Systematic Review and Meta-Analysis. Chemotherapy 2023; 68:197-209. [PMID: 37331333 DOI: 10.1159/000531457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 05/04/2023] [Indexed: 06/20/2023]
Abstract
BACKGROUND PD-1 inhibitors have been approved for the first-line treatment of patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. However, the results of several clinical trials are not entirely consistent, and the dominant population of first-line immunotherapy for advanced gastric/gastroesophageal junction cancer still needs to be precisely determined. OBJECTIVE This objective of this study is to evaluate the efficacy of anti-PD-1/PD-L1 therapy in advanced gastric/gastroesophageal junction adenocarcinoma patients through a systematic review and meta-analysis of relevant clinical trials. METHOD The PubMed, Embase, and Cochrane Library electronic databases were searched up to August 1, 2022, for clinical trials of anti-PD-1/PD-L1 immunotherapy for the first-line treatment of advanced gastroesophageal cancer. Hazard ratios and 95% confidence intervals for overall survival, progression-free survival, and objective response rates were extracted and pooled for meta-analysis. Prespecified subgroups included the following: agent type, PD-L1 expression, and high microsatellite instability. RESULTS This study analyzed 5 RCTs involving 3,355 patients. Compared with the chemotherapy group, the combined immunotherapy group had a significantly higher objective response rate (OR = 0.63, 95% CI: 0.55-0.72, p < 0.00001) and prolonged overall survival (HR = 0.82, 95% CI: 0.76-0.88, p < 0.00001) and progression-free survival (HR = 0.75, 95% CI: 0.69-0.82, p < 0.00001). The combination of immunotherapy and chemotherapy prolonged OS in both MSI-H (HR = 0.38, p = 0.002) and MSS (HR = 0.78, p < 0.00001) populations, but there was a significant difference between groups (p = 0.02). However, in improving ORR, the benefit of ICI combined with chemotherapy in the MSS group and MSI-H group was not significantly different between groups (p = 0.52). Combination therapy with ICIs was more effective than chemotherapy alone in prolonging OS in the subgroup with a high CPS, regardless of the CPS cutoff for PD-L1. However, when the cutoff of CPS was 1, the difference between subgroups did not reach statistical significance (p = 0.12), while the benefit ratio of the MSI-H group was higher when the cutoff was 10 (p = 0.004) than when the cutoff value was 5 (p = 0.002). CONCLUSIONS For first-line treatment of advanced gastroesophageal cancer, an ICI combination strategy is more effective than chemotherapy. The subgroup of patients with a CPS ≥10 has a more significant benefit, and CPS ≥10 has the potential to be used as an accurate marker of the dominant population of immuno-combined therapy.
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Affiliation(s)
- Shengqi Fei
- Department of Gastroenterology Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Gastrointestinal Surgery, Changxing People's Hospital, Huzhou, China
| | - Yu Lu
- Nursing Department, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Chen
- Department of Gastroenterology Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jia Qi
- Department of Gastroenterology Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wenxuan Wu
- Department of Gastroenterology Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Beidi Wang
- Department of Gastroenterology Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yaxuan Han
- Department of Gastroenterology Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kefan Wang
- Department of Gastroenterology Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaying Han
- Department of Gastroenterology Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haiyan Zhou
- Nursing Department, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Wang
- Department of Gastroenterology Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jian Chen
- Department of Gastroenterology Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Lauriola A, Davalli P, Marverti G, Santi S, Caporali A, D'Arca D. Targeting the Interplay of Independent Cellular Pathways and Immunity: A Challenge in Cancer Immunotherapy. Cancers (Basel) 2023; 15:cancers15113009. [PMID: 37296972 DOI: 10.3390/cancers15113009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 05/19/2023] [Accepted: 05/28/2023] [Indexed: 06/12/2023] Open
Abstract
Immunotherapy is a cancer treatment that exploits the capacity of the body's immune system to prevent, control, and remove cancer. Immunotherapy has revolutionized cancer treatment and significantly improved patient outcomes for several tumor types. However, most patients have not benefited from such therapies yet. Within the field of cancer immunotherapy, an expansion of the combination strategy that targets independent cellular pathways that can work synergistically is predicted. Here, we review some consequences of tumor cell death and increased immune system engagement in the modulation of oxidative stress and ubiquitin ligase pathways. We also indicate combinations of cancer immunotherapies and immunomodulatory targets. Additionally, we discuss imaging techniques, which are crucial for monitoring tumor responses during treatment and the immunotherapy side effects. Finally, the major outstanding questions are also presented, and directions for future research are described.
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Affiliation(s)
- Angela Lauriola
- Department of Biotechnology, University of Verona, 37134 Verona, Italy
| | - Pierpaola Davalli
- Department of Biomedical, Metabolic and Neural Sciences, Via G. Campi 287, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Gaetano Marverti
- Department of Biomedical, Metabolic and Neural Sciences, Via G. Campi 287, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Spartaco Santi
- Consiglio Nazionale delle Ricerche (CNR) Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza", 40136 Bologna, Italy
- IRCCS, Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Andrea Caporali
- BHF Centre for Cardiovascular Science, University of Edinburgh, Scotland EH4 2XU, UK
| | - Domenico D'Arca
- Department of Biomedical, Metabolic and Neural Sciences, Via G. Campi 287, University of Modena and Reggio Emilia, 41125 Modena, Italy
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Li G, Huo D, Guo N, Li Y, Ma H, Liu L, Xie H, Zhang D, Qu B, Chen X. Integrating multiple machine learning algorithms for prognostic prediction of gastric cancer based on immune-related lncRNAs. Front Genet 2023; 14:1106724. [PMID: 37082204 PMCID: PMC10111190 DOI: 10.3389/fgene.2023.1106724] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 02/28/2023] [Indexed: 04/07/2023] Open
Abstract
Background: Long non-coding RNAs (lncRNAs) play an important role in the immune regulation of gastric cancer (GC). However, the clinical application value of immune-related lncRNAs has not been fully developed. It is of great significance to overcome the challenges of prognostic prediction and classification of gastric cancer patients based on the current study.Methods: In this study, the R package ImmLnc was used to obtain immune-related lncRNAs of The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) project, and univariate Cox regression analysis was performed to find prognostic immune-related lncRNAs. A total of 117 combinations based on 10 algorithms were integrated to determine the immune-related lncRNA prognostic model (ILPM). According to the ILPM, the least absolute shrinkage and selection operator (LASSO) regression was employed to find the major lncRNAs and develop the risk model. ssGSEA, CIBERSORT algorithm, the R package maftools, pRRophetic, and clusterProfiler were employed for measuring the proportion of immune cells among risk groups, genomic mutation difference, drug sensitivity analysis, and pathway enrichment score.Results: A total of 321 immune-related lncRNAs were found, and there were 26 prognostic immune-related lncRNAs. According to the ILPM, 18 of 26 lncRNAs were selected and the risk score (RS) developed by the 18-lncRNA signature had good strength in the TCGA training set and Gene Expression Omnibus (GEO) validation datasets. Patients were divided into high- and low-risk groups according to the median RS, and the low-risk group had a better prognosis, tumor immune microenvironment, and tumor signature enrichment score and a higher metabolism, frequency of genomic mutations, proportion of immune cell infiltration, and antitumor drug resistance. Furthermore, 86 differentially expressed genes (DEGs) between high- and low-risk groups were mainly enriched in immune-related pathways.Conclusion: The ILPM developed based on 26 prognostic immune-related lncRNAs can help in predicting the prognosis of patients suffering from gastric cancer. Precision medicine can be effectively carried out by dividing patients into high- and low-risk groups according to the RS.
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Affiliation(s)
- Guoqi Li
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Diwei Huo
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Naifu Guo
- Department of Biological Science, College of Biological Science and Technology, Harbin Normal University, Harbin, China
| | - Yi Li
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Hongzhe Ma
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Lei Liu
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Hongbo Xie
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Denan Zhang
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Bo Qu
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- *Correspondence: Bo Qu, ; Xiujie Chen,
| | - Xiujie Chen
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
- *Correspondence: Bo Qu, ; Xiujie Chen,
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Satake H, Lee KW, Chung HC, Lee J, Yamaguchi K, Chen JS, Yoshikawa T, Amagai K, Yeh KH, Goto M, Chao Y, Lam KO, Han SR, Shiratori S, Shah S, Shitara K. Pembrolizumab or pembrolizumab plus chemotherapy versus standard of care chemotherapy in patients with advanced gastric or gastroesophageal junction adenocarcinoma: Asian subgroup analysis of KEYNOTE-062. Jpn J Clin Oncol 2023; 53:221-229. [PMID: 36533429 PMCID: PMC9991501 DOI: 10.1093/jjco/hyac188] [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: 09/09/2022] [Accepted: 11/15/2022] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE First-line pembrolizumab with/without chemotherapy versus chemotherapy was evaluated in programmed death ligand 1 combined positive score ≥1, locally advanced/unresectable or metastatic gastric cancer/gastrooesophageal junction cancer in the KEYNOTE-062 study. We present results for patients enrolled in Asia. METHODS Eligible patients were randomly assigned 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin + 5-fluorouracil or capecitabine) or placebo plus chemotherapy Q3W. End points included overall survival (primary) in combined positive score ≥1 and combined positive score ≥10 populations and safety and tolerability (secondary). RESULTS A total of 187 patients were enrolled in Asia (pembrolizumab, n = 62; pembrolizumab plus chemotherapy, n = 64; chemotherapy, n = 61). Compared with the global population, higher proportions of patients had Eastern Cooperative Oncology Group performance status 0 and a diagnosis of stomach cancer. In the programmed death ligand 1 combined positive score ≥1 population, median overall survival was numerically longer with pembrolizumab versus chemotherapy (22.7 vs 13.8 months; hazard ratio, 0.54; 95% confidence interval, 0.35-0.82) and pembrolizumab plus chemotherapy versus chemotherapy (16.5 vs 13.8 months; hazard ratio, 0.78; 95% confidence interval, 0.53-1.16). In the programmed death ligand 1 combined positive score ≥10 population, median overall survival was also numerically longer with pembrolizumab versus chemotherapy (28.5 vs 14.8 months; hazard ratio, 0.43; 95% confidence interval, 0.21-0.89) and pembrolizumab plus chemotherapy versus chemotherapy (17.5 vs 14.8 months; hazard ratio, 0.86; 95% confidence interval, 0.45-1.64). The grade 3-5 treatment-related adverse event rate was 19.4%, 75.8% and 64.9% for patients receiving pembrolizumab, pembrolizumab plus chemotherapy and chemotherapy, respectively. CONCLUSIONS This post hoc analysis showed pembrolizumab monotherapy was associated with numerically improved overall survival and a favourable tolerability profile versus chemotherapy in Asians with programmed death ligand 1-positive advanced gastric cancer/gastrooesophageal junction cancer.This study is registered with ClinicalTrials.gov, NCT02494583.
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Affiliation(s)
- Hironaga Satake
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe City, Japan and Department of Medical Oncology, Kochi Medical School, Kochi, Japan
| | - Keun-Wook Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Hyun Cheol Chung
- Department of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
| | - Jeeyun Lee
- Division of Hematology/Oncology, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital of JFCR, Tokyo, Japan
| | - Jen-Shi Chen
- Division of Hematology-Oncology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan and College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
| | - Takaki Yoshikawa
- Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Kenji Amagai
- Department of Gastroenterology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan
| | - Kun-Huei Yeh
- Department of Oncology, National Taiwan University Hospital and Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Masahiro Goto
- Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Osaka, Japan
| | - Yee Chao
- Department of Oncology, Taipei Veterans General Hospital, Taipei City, Taiwan
| | - Ka-On Lam
- Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Shi Rong Han
- Department of Medical Oncology, MSD K.K., Tokyo, Japan
| | | | - Sukrut Shah
- Department of Medical Oncology, Merck & Co., Inc., Rahway, NJ, USA
| | - Kohei Shitara
- Department of Gastrointestinal Oncology, National Cancer Center Hospital, Kashiwa, Japan.,Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Li D, Tang L, Hu J, Cao X, He Y. Immune checkpoint inhibitors' combination therapy as first-line treatment in advanced esophageal squamous cell carcinoma: a meta-analysis. J Cancer Res Clin Oncol 2023; 149:933-939. [PMID: 35751682 DOI: 10.1007/s00432-022-04066-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 05/11/2022] [Indexed: 10/17/2022]
Abstract
PURPOSE The benefit of immune checkpoint inhibitors' (ICIs) combination therapy in patients with advanced esophageal squamous cell carcinoma (ESCC) remained unclear. We performed a meta-analysis to explore the efficacy and safety of ICIs' combination therapy versus chemotherapy alone as first-line treatment in advanced ESCC. METHODS A systematic review of randomized controlled trials (RCTs) of ICIs' combination therapy as first-line treatment in advanced ESCC was conducted via searching PubMed, Embase, and Cochrane database. The data for efficacy and safety of ICIs' combination therapy were subject to meta-analysis. Subgroup analysis was performed in patients with different PD-L1 expression status. RESULTS A total of 5 RCTs and 3163 patients were included. Overall, the hazard ratio (HR) for overall survival (OS) benefit with ICIs' combination therapy was 0.68 (95% CI 0.62-0.75) compared with chemotherapy alone. The HR for progression-free survival (PFS) benefit and the odds ratio (OR) for overall response rate (ORR) increase were 0.62 (95% CI 0.56-0.68) and 2.01 (95% CI 1.70-2.38), respectively. The OS and PFS benefits with ICIs' combination therapy over chemotherapy alone were also observed in the subgroup of PD-L1 positive expression, but not in the subgroup of PD-L1 negative expression. The incidence of grade 3 or higher treatment-related adverse events was 60.4% with ICIs' combination therapy and 56.3% with chemotherapy alone (OR, 1.19; 95% CI 0.90-1.57). CONCLUSION ICIs' combination therapy showed superior OS, PFS, and ORR over chemotherapy alone with a manageable safety profile. These results suggested that ICIs' combination therapy can be considered as a new first-line treatment for advanced ESCC.
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Affiliation(s)
- Dianhe Li
- Department of Oncology, Panyu Central Hospital, No. 8 Fuyu Road East, Panyu, Guangzhou, Guangdong, People's Republic of China
| | - Ling Tang
- Department of Otolaryngology-Head and Neck Surgery, Panyu Central Hospital, Guangzhou, People's Republic of China
| | - Jiazhu Hu
- Department of Oncology, Panyu Central Hospital, No. 8 Fuyu Road East, Panyu, Guangzhou, Guangdong, People's Republic of China
| | - Xiaolong Cao
- Department of Oncology, Panyu Central Hospital, No. 8 Fuyu Road East, Panyu, Guangzhou, Guangdong, People's Republic of China
| | - Yan He
- Department of Oncology, Panyu Central Hospital, No. 8 Fuyu Road East, Panyu, Guangzhou, Guangdong, People's Republic of China.
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40
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Wu YX, Zhou XY, Wang JQ, Chen GM, Chen JX, Wang RC, Huang JQ, Chen JS. Application of immune checkpoint inhibitors in immunotherapy for gastric cancer. Immunotherapy 2023; 15:101-115. [PMID: 36597704 DOI: 10.2217/imt-2022-0080] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Gastric cancer is the fifth most common cancer worldwide. With the development of immunotherapy, especially the application of immune checkpoint inhibitors (ICIs), the prognosis of advanced gastric cancer has improved. At present, ICIs combined with other therapies or dual ICI strategies in the treatment of advanced gastric cancer have shown clinical effectiveness and controllable safety. In addition, predictive biomarkers facilitate the precise selection of patients. Therefore, it is crucial to explore rational combinations and reliable predictive biomarkers for ICI therapy. This article reviews the recent advances in ICIs and relevant predictive biomarkers in the treatment of gastric cancer.
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Affiliation(s)
- Yi-Xiang Wu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
| | - Xiao-Yu Zhou
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
| | - Jian-Qi Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
| | - Gao-Min Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
| | - Jin-Xu Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
| | - Rong-Chang Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
| | - Jiong-Qiang Huang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
| | - Jing-Song Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
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41
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Liu Y, Bao Y, Yang X, Sun S, Yuan M, Ma Z, Zhang W, Zhai Y, Wang Y, Men Y, Qin J, Xue L, Wang J, Hui Z. Efficacy and safety of neoadjuvant immunotherapy combined with chemoradiotherapy or chemotherapy in esophageal cancer: A systematic review and meta-analysis. Front Immunol 2023; 14:1117448. [PMID: 36761760 PMCID: PMC9902949 DOI: 10.3389/fimmu.2023.1117448] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 01/05/2023] [Indexed: 01/26/2023] Open
Abstract
Background Significant progress has been made in the investigation of neoadjuvant immune-chemoradiotherapy (NICRT) and neoadjuvant immune-chemotherapy (NICT) on the outcomes of esophageal cancer patients. To summarize the current developments, a systematic review and meta-analysis were conducted to evaluate the efficacy and safety of neoadjuvant immunotherapy combined with chemoradiotherapy or chemotherapy. Methods A search strategy of prospective studies on esophageal cancer receiving neoadjuvant immunotherapy was predefined to scan PubMed, Embase, Cochrane, and additional major conferences for prospective studies. Efficacy was assessed by pathological complete response (pCR), major pathological response (MPR), and R0 resection rates. Safety was evaluated based on the incidence of grade ≥ 3 treatment-related adverse events (TRAEs), neoadjuvant therapy completion rate, surgical resection rate, and surgical delay rate. Differences between the NICRT and NICT groups were also analyzed. Results A total of 38 studies qualified for the analysis. The pooled pCR, MPR, and R0 resection rates were 30, 58, and 99%, respectively. The pCR and MPR in the NICRT vs. NICT group were 38% vs. 28% (p=0.078) and 67% vs. 57% (p=0.181), respectively. The pooled incidence of grade ≥ 3 TRAEs was 24% (NICRT,58%, I2 = 61% vs. NICT,18%, I2 = 79%; p<0.001). In addition, the pooled neoadjuvant therapy completion and surgical resection rates were 92% and 85%, respectively; the difference was not statistically significant between the NICRT and NICT groups. Conclusions Neoadjuvant immunotherapy combined with chemoradiotherapy or chemotherapy is effective and safe in the short term for locally advanced esophageal cancer. However, further randomized trials are needed to confirm which combined model is more favorable. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021284266, identifier CRD42021284266.
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Affiliation(s)
- Yunsong Liu
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongxing Bao
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xu Yang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuang Sun
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Meng Yuan
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zeliang Ma
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wanting Zhang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yirui Zhai
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yang Wang
- Department of Mathematics and Statistics, Lancaster University, Lancaster, United Kingdom
| | - Yu Men
- Department of very important person (VIP) Medical Services and Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianjun Qin
- 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
| | - Liyan Xue
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Wang
- Department of Radiotherapy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zhouguang Hui
- Department of very important person (VIP) Medical Services and Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China,*Correspondence: Zhouguang Hui,
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Immune Checkpoint Inhibitors: Changing the Treatment Landscape in Esophagogastric Adenocarcinoma. Pharmaceuticals (Basel) 2023; 16:ph16010102. [PMID: 36678598 PMCID: PMC9865965 DOI: 10.3390/ph16010102] [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: 10/08/2022] [Revised: 12/18/2022] [Accepted: 12/20/2022] [Indexed: 01/12/2023] Open
Abstract
In the West, recent decades have demonstrated an epidemiological trend towards esophago-gastric adenocarcinomas (EGAC), with considerable associated mortality. Historically, chemotherapy has represented the sole systemic treatment option in the advanced EGAC setting, in addition to complementing the role of surgery and radiotherapy in the case of localized disease. Immune checkpoint inhibitors (ICIs) represent a novel systemic therapeutic choice and have revolutionized the management of other malignancies, including melanoma and renal cell carcinomas. This article considers the rationale for ICIs in EGAC, reviews the evidence supporting their role in the current standard of care in EGAC, and briefly considers ongoing trials and future directions for the ICI class in EGAC.
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Li S, Li K, Tian F, Li H, Xia Q, Li T, Dong B, Li D, Yu J, Zhang J, Wang L, Zhang C, Xu S, Zhao Y, Liu Y. A high interferon gamma signature of CD8 + T cells predicts response to neoadjuvant immunotherapy plus chemotherapy in gastric cancer. Front Immunol 2023; 13:1056144. [PMID: 36685525 PMCID: PMC9849934 DOI: 10.3389/fimmu.2022.1056144] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 12/12/2022] [Indexed: 01/07/2023] Open
Abstract
Background While the tumor microenvironment (TME) affects immune checkpoint blockade (ICB) efficacy, ICB also reshapes the characteristics of TME. Thus far, studies have focused on the TME evolution during neoadjuvant or adjuvant ICB therapy in gastric cancer (GC). However, the interaction between TME characteristics and neoadjuvant immunotherapy plus chemotherapy remains to be elucidated. Methods We performed single-cell RNA sequencing on ten GC specimens pre- and post-neoadjuvant camrelizumab plus mFOLFOX6 to determine the impact of the TME on the efficacy of the combination therapy and the remodeling of TME by the therapy. Results A high baseline interferon gamma (IFN-γ) signature in CD8+ T cells predicts better responses to the combination therapy. We also observed that the IFN-γ signature significantly decreased in multiple cell types, and the exhausted signature of CD8+ T cells was significantly suppressed during the neoadjuvant therapy. Conclusions Our data reveal interactions between the TME and neoadjuvant immunotherapy plus chemotherapy in GC. Importantly, it also highlights the signature of CD8+ T cells in predicting response to the combination therapy in GC.
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Affiliation(s)
- Sen Li
- Department of General Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Ke Li
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Fei Tian
- Department of Biological Information, Genesky Biotechnologies Inc., Shanghai, China
| | - Hongle Li
- Department of Molecular Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Qingxin Xia
- Department of Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Tiepeng Li
- Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Bing Dong
- Department of Molecular Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Danyang Li
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Juan Yu
- Department of Endoscopy Center, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Junli Zhang
- Department of General Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Li Wang
- Department of Biological Information, Genesky Biotechnologies Inc., Shanghai, China
| | - Chengjuan Zhang
- Department of Molecular Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Shuning Xu
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Yuzhou Zhao
- Department of General Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China,*Correspondence: Ying Liu, ; Yuzhou Zhao,
| | - Ying Liu
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China,*Correspondence: Ying Liu, ; Yuzhou Zhao,
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Li T, Liu T, Zhao L, Liu L, Zheng X, Wang J, Zhang F, Hu Y. Effectiveness and safety of anti-PD-1 monotherapy or combination therapy in Chinese advanced gastric cancer: A real-world study. Front Oncol 2023; 12:976078. [PMID: 36686795 PMCID: PMC9850086 DOI: 10.3389/fonc.2022.976078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 12/19/2022] [Indexed: 01/07/2023] Open
Abstract
Purpose Gastric cancer (GC) is one of the most frequently diagnosed cancers and one of the leading causes of cancer deaths worldwide, especially in eastern Asia and China. Anti-PD-1 immune checkpoint inhibitors, Pembrolizumab and Nivolumab, have been approved for the treatment of locally advanced or metastatic gastric or gastroesophageal junction cancer (GC/GEJC). Our study evaluated the effectiveness and safety of anti-PD-1-based treatment (monotherapy or combination therapy) in Chinese patients with advanced or metastatic GC/GEJCs in a real-world setting. Methods A retrospective cohort study was conducted, and 54 patients from May 31, 2015, to May 31, 2021, were included in our analysis, including 19 patients treated with anti-PD-1 monotherapy and 35 patients treated with anti-PD-1 combination therapy. Demographic and clinical information were evaluated. Clinical response, survival outcomes, and safety profile were measured and analyzed. Results Overall, the median overall survival (mOS) was 11.10 months (95% CI, 7.05-15.15), and the median progression-free survival (mPFS) was 3.93 months (95% CI, 2.47-5.39). Of the patients, 16.7% achieved a clinical response, and 72.2% achieved disease control. Prolonged overall survival (OS) and progression-free survival (PFS) and increased clinical response were observed in the combination group compared with the monotherapy group, although statistical significance was not reached. In subgroups with live metastases or elevated baseline neutrophil-to-lymphocyte ratio (NLR) levels, combination therapy outperformed anti-PD-1 alone in survival outcomes. Patients treated with anti-PD-1 monotherapy (n = 5, 26.3%) had fewer treatment-related adverse events (TRAEs) than those in the combination group (n = 22, 62.9%). There were also fewer patients with TRAEs of grades 3-5 with monotherapy (n = 2, 10.5%) than with combination therapy (n = 7, 20.0%). Pneumonitis in three patients was the only potential immune-related adverse event reported. Conclusions Anti-PD-1-based monotherapy and combination therapy showed favorable survival outcomes and manageable safety profiles in advanced or metastatic GC/GEJCs. In clinical treatment, immunotherapy should be an indispensable choice in the treatment strategy for GC/GEJC. Patients with a heavy tumor burden and more metastatic sites might benefit more from combination therapy. Elderly patients and patients with more treatment lines or high Eastern Cooperative Oncology Group (ECOG) performance scores might be more suitable for immune monotherapy, and some clinical benefits have been observed.
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Affiliation(s)
- Tao Li
- Graduate School, Medical School of Chinese People's Liberation Army (PLA), Beijing, China,Department of Oncology, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China,Chinese People's Liberation Army (PLA) Key Laboratory of Oncology, Key Laboratory for Tumor Targeting Therapy and Antibody Drugs, Ministry of Education, Beijing, China
| | - Tingting Liu
- Graduate School, Medical School of Chinese People's Liberation Army (PLA), Beijing, China,Department of Pulmonary and Critical Care Medicine, the Second Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Lei Zhao
- Institute of Translational Medicine, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Lu Liu
- Graduate School, Medical School of Chinese People's Liberation Army (PLA), Beijing, China,Department of Nutrition, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Xuan Zheng
- Graduate School, Medical School of Chinese People's Liberation Army (PLA), Beijing, China,Department of Oncology, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China,Chinese People's Liberation Army (PLA) Key Laboratory of Oncology, Key Laboratory for Tumor Targeting Therapy and Antibody Drugs, Ministry of Education, Beijing, China
| | - Jinliang Wang
- Graduate School, Medical School of Chinese People's Liberation Army (PLA), Beijing, China,Department of Oncology, The Fifth Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China,*Correspondence: Jinliang Wang, ; Fan Zhang, ; Yi Hu,
| | - Fan Zhang
- Graduate School, Medical School of Chinese People's Liberation Army (PLA), Beijing, China,Department of Oncology, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China,Chinese People's Liberation Army (PLA) Key Laboratory of Oncology, Key Laboratory for Tumor Targeting Therapy and Antibody Drugs, Ministry of Education, Beijing, China,*Correspondence: Jinliang Wang, ; Fan Zhang, ; Yi Hu,
| | - Yi Hu
- Graduate School, Medical School of Chinese People's Liberation Army (PLA), Beijing, China,Department of Oncology, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China,Chinese People's Liberation Army (PLA) Key Laboratory of Oncology, Key Laboratory for Tumor Targeting Therapy and Antibody Drugs, Ministry of Education, Beijing, China,*Correspondence: Jinliang Wang, ; Fan Zhang, ; Yi Hu,
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Cai D, Yu H, Wang X, Mao Y, Liang M, Lu X, Shen X, Guan W. Turning Tertiary Lymphoid Structures (TLS) into Hot Spots: Values of TLS in Gastrointestinal Tumors. Cancers (Basel) 2023; 15:cancers15020367. [PMID: 36672316 PMCID: PMC9856964 DOI: 10.3390/cancers15020367] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/30/2022] [Accepted: 01/04/2023] [Indexed: 01/09/2023] Open
Abstract
Tertiary lymphoid structures (TLSs) are ectopic lymphocyte aggregation structures found in the tumor microenvironment (TME). Emerging evidence shows that TLSs are significantly correlated with the progression of gastrointestinal tumors, patients' prognosis, and the efficacy of adjuvant therapy. Besides, there are still some immunosuppressive factors in the TLSs that may affect the anti-tumor responses of TLSs, including negative regulators of anti-tumor immune responses, the immune checkpoint molecules, and inappropriate tumor metabolism. Therefore, a more comprehensive understanding of TLSs' responses in gastrointestinal tumors is essential to fully understand how TLSs can fully exert their anti-tumor responses. In addition, targeting TLSs with immune checkpoint inhibitors and vaccines to establish mature TLSs is currently being developed to reprogram the TME, further benefiting cancer immunotherapies. This review summarizes recent findings on the formation of TLSs, the mechanisms of their anti-tumor immune responses, and the association between therapeutic strategies and TLSs, providing a novel perspective on tumor-associated TLSs in gastrointestinal tumors.
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Affiliation(s)
- Daming Cai
- Department of General Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China
| | - Heng Yu
- Department of General Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China
| | - Xingzhou Wang
- Department of General Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China
| | - Yonghuan Mao
- Department of General Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China
| | - Mengjie Liang
- Department of General Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China
| | - Xiaofeng Lu
- Department of General Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China
| | - Xiaofei Shen
- Department of General Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China
- Department of General Surgery, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing 210008, China
- Correspondence: (X.S.); (W.G.)
| | - Wenxian Guan
- Department of General Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing 210008, China
- Correspondence: (X.S.); (W.G.)
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Vahadane A, Sharma S, Mandal D, Dabbeeru M, Jakthong J, Garcia-Guzman M, Majumdar S, Lee CW. Development of an automated combined positive score prediction pipeline using artificial intelligence on multiplexed immunofluorescence images. Comput Biol Med 2023; 152:106337. [PMID: 36502695 DOI: 10.1016/j.compbiomed.2022.106337] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 11/05/2022] [Accepted: 11/16/2022] [Indexed: 11/25/2022]
Abstract
Immunotherapy targeting immune checkpoint proteins, such as programmed cell death ligand 1 (PD-L1), has shown impressive outcomes in many clinical trials but only 20%-40% of patients benefit from it. Utilizing Combined Positive Score (CPS) to evaluate PD-L1 expression in tumour biopsies to identify patients with the highest likelihood of responsiveness to anti-PD-1/PD-L1 therapy has been approved by the Food and Drug Administration for several solid tumour types. Current CPS workflow requires a pathologist to manually score the two-colour PD-L1 chromogenic immunohistochemistry image. Multiplex immunofluorescence (mIF) imaging reveals the expression of an increased number of immune markers in tumour biopsies and has been used extensively in immunotherapy research. Recent rapid progress of Artificial Intelligence (AI)-based imaging analysis, particularly Deep Learning, provides cost effective and high-quality solutions to healthcare. In this article, we propose an imaging pipeline that utilizes three-colour mIF images (DAPI, PD-L1, and Pan-cytokeratin) as input and predicts the CPS using AI techniques. Our novel pipeline is composed of three modules employing algorithms of image processing, machine learning, and deep learning techniques. The first module of quality check (QC) detects and removes the image regions contaminated with sectioning and staining artefacts. The QC module ensures that only image regions free of the three common artefacts are used for downstream analysis. The second module of nuclear segmentation uses deep learning to segment and count nuclei in the DAPI images wherein our specialized method can accurately separate touching nuclei. The third module of cell phenotyping calculates CPS by identifying and counting PD-L1 positive cells and tumour cells. These modules are data-efficient and require only few manual annotations for training purposes. Using tumour biopsies from a clinical trial, we found that the CPS from the AI-based models shows a high Spearman correlation (78%, p = 0.003) to the pathologist-scored CPS.
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Affiliation(s)
- Abhishek Vahadane
- Rakuten India Enterprise Private Ltd, Bagmane Pallavi Tower #20, 1st Cross, Raja Ram Mohan Roy Road, S. R. Nagar, Bengaluru, Karnataka, 560027, India
| | - Shreya Sharma
- Rakuten India Enterprise Private Ltd, Bagmane Pallavi Tower #20, 1st Cross, Raja Ram Mohan Roy Road, S. R. Nagar, Bengaluru, Karnataka, 560027, India
| | - Devraj Mandal
- Rakuten India Enterprise Private Ltd, Bagmane Pallavi Tower #20, 1st Cross, Raja Ram Mohan Roy Road, S. R. Nagar, Bengaluru, Karnataka, 560027, India
| | - Madan Dabbeeru
- Rakuten India Enterprise Private Ltd, Bagmane Pallavi Tower #20, 1st Cross, Raja Ram Mohan Roy Road, S. R. Nagar, Bengaluru, Karnataka, 560027, India
| | | | | | - Shantanu Majumdar
- Rakuten India Enterprise Private Ltd, Bagmane Pallavi Tower #20, 1st Cross, Raja Ram Mohan Roy Road, S. R. Nagar, Bengaluru, Karnataka, 560027, India
| | - Chung-Wein Lee
- Rakuten Medical Inc., 11080 Roselle Street, San Diego, CA, 92121, USA.
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Yoshida T, Ogura G, Tanabe M, Hayashi T, Ohbayashi C, Azuma M, Kunisaki C, Akazawa Y, Ozawa S, Matsumoto S, Suzuki T, Mitoro A, Fukunaga T, Shimizu A, Fujimoto G, Yao T. Clinicopathological features of PD-L1 protein expression, EBV positivity, and MSI status in patients with advanced gastric and esophagogastric junction adenocarcinoma in Japan. Cancer Biol Ther 2022; 23:191-200. [PMID: 35220884 PMCID: PMC8890430 DOI: 10.1080/15384047.2022.2038002] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
This real-world study examined the prevalence of programmed death ligand-1 (PD-L1) expression and assessed the frequency of microsatellite instability-high (MSI-H) status and Epstein-Barr virus (EBV) positivity in Japanese patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. This multicenter (5 sites), retrospective, observational study (November 2018–March 2019) evaluated Japanese patients with advanced gastric and GEJ adenocarcinoma after surgical resection (Stage II/III at initial diagnosis) or unresectable advanced cancer (Stage IV). The primary objectives were prevalence of PD-L1 expression (combined positive score [CPS] ≥1), MSI status, and EBV positivity. Tumor specimens of 389/391 patients were analyzed (male, 67.1%; mean age, 67.6 ± 12.2 years); 241/389 (62%) were PD-L1 positive, 24/379 (6.3%) had MSI-H tumors, and 13/389 (3.3%) were EBV positive. PD-L1 expression was higher in tumor-infiltrating immune cells than in tumor cells for lower CPS cutoffs. Among patients with MSI-H tumors and EBV-positive tumors, 19/24 (79.2%) and 9/13 (69.2%), respectively, were PD-L1 positive. A greater proportion of patients with MSI-H tumors (83.3% [20/24]) were PD-L1 positive than those with MSI-low/stable tumors (60.8% [216/355]; p = .0297); similarly, an association was observed between history of H pylori infection and PD-L1 expression. A higher proportion of patients with MSI-H tumors demonstrated PD-L1 expression with a CPS ≥10 (66.7% [16/24]) vs those with MSI-low/stable tumors (24.8% [88/355]; p < .0001). The prevalence of PD-L1 positivity among Japanese patients was comparable to that in previous pembrolizumab clinical trials and studies in gastric cancer. Particularly, higher PD-L1 expression was observed in MSI-H tumors.
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Affiliation(s)
- Tsutomu Yoshida
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Go Ogura
- Department of Pathology, Tokai University School of Medicine, Isehara, Japan
| | - Mikiko Tanabe
- Division of Diagnostic Pathology, Yokohama City University Medical Center, Yokohama, Japan
| | - Takuo Hayashi
- Department of Diagnostic Pathology, Main Hospital, Juntendo University, Tokyo, Japan
| | - Chiho Ohbayashi
- Department of Diagnostic Pathology, Nara Medical University, Kashihara, Japan
| | - Mizutomo Azuma
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Chikara Kunisaki
- Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Yoichi Akazawa
- Department of Gastroenterology, School of Medicine, Juntendo University, Tokyo, Japan
| | - Soji Ozawa
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Sohei Matsumoto
- Department of Surgery, Nara Medical University, Kashihara, Japan
| | - Takayoshi Suzuki
- Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Tokai University, Isehara, Japan
| | - Akira Mitoro
- Department of Gastroenterology, Nara Medical University, Kashihara, Japan
| | - Tetsu Fukunaga
- Department of Gastroenterology and Minimally Invasive Surgery, School of Medicine, Juntendo University, Tokyo, Japan
| | | | | | - Takashi Yao
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Basudan AM. The Role of Immune Checkpoint Inhibitors in Cancer Therapy. Clin Pract 2022; 13:22-40. [PMID: 36648843 PMCID: PMC9844484 DOI: 10.3390/clinpract13010003] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/18/2022] [Accepted: 12/22/2022] [Indexed: 12/29/2022] Open
Abstract
Over the years, immune checkpoint inhibitors (CPIs) have become a powerful treatment strategy in the field of cancer immunotherapy. In the last decade, the number of FDA-approved CPIs has been increasing prominently, opening new horizons for the treatment of a wide range of tumor types. Pointedly, three immune checkpoint molecules have been under extensive research, which include cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) and its ligand-1 (PD-L1). Despite remarkable success, not all patients respond positively to therapy, which highlights the complexity of the tumor microenvironment (TME) and immune system. This has led to the identification of molecular biomarkers to predict response and toxicity. In addition, there has been an emerging focus on developing new delivery and targeting approaches for better drug efficacy and potency. In this review, we highlight the mechanism of action of major CPIs, their clinical impact, variation in effectiveness, response prediction, updated clinical indications, current challenges and limitations, promising novel approaches, and future directions.
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Affiliation(s)
- Ahmed M Basudan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 12372, Saudi Arabia
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49
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Tan S, Day D, Nicholls SJ, Segelov E. Immune Checkpoint Inhibitor Therapy in Oncology: Current Uses and Future Directions: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol 2022; 4:579-597. [PMID: 36636451 PMCID: PMC9830229 DOI: 10.1016/j.jaccao.2022.09.004] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 09/07/2022] [Indexed: 12/24/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) are a major class of immuno-oncology therapeutics that have significantly improved the prognosis of various cancers, both in (neo)adjuvant and metastatic settings. Unlike other conventional therapies, ICIs elicit antitumor effects by enhancing host immune systems to eliminate cancer cells. There are 3 approved ICI classes by the U.S. Food and Drug Administration: inhibitors targeting cytotoxic T lymphocyte associated antigen 4, programmed death 1/programmed death-ligand 1, and lymphocyte-activation gene 3, with many more in development. ICIs are commonly associated with distinct toxicities, known as immune-related adverse events, which can arise during treatment or less frequently be of late onset, usually relating to excessive activation of the immune system. Acute cardiovascular immune-related adverse events such as myocarditis are rare; however, data suggesting chronic cardiovascular sequelae are emerging. This review presents the current landscape of ICIs in oncology, with a focus on important aspects relevant to cardiology.
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Affiliation(s)
- Sean Tan
- Victorian Heart Institute, Monash University, Melbourne, Victoria, Australia,Monash Heart, Monash Health, Clayton, Victoria, Australia,Address for correspondence: Dr Sean Tan, Victorian Heart Institute, Monash University, Wellington Road, Victoria 3800, Australia. @_SeanXTan
| | - Daphne Day
- School of Clinical Sciences, Monash Health, Monash University, Melbourne, Victoria, Australia,Department of Oncology, Monash Health, Clayton, Victoria, Australia
| | - Stephen J. Nicholls
- Victorian Heart Institute, Monash University, Melbourne, Victoria, Australia,Monash Heart, Monash Health, Clayton, Victoria, Australia
| | - Eva Segelov
- School of Clinical Sciences, Monash Health, Monash University, Melbourne, Victoria, Australia,Department of Oncology, Monash Health, Clayton, Victoria, Australia
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50
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Wang H, Xu Y, Zuo F, Liu J, Yang J. Immune-based combination therapy for esophageal cancer. Front Immunol 2022; 13:1020290. [PMID: 36591219 PMCID: PMC9797857 DOI: 10.3389/fimmu.2022.1020290] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 11/30/2022] [Indexed: 12/23/2022] Open
Abstract
Esophageal cancer (EC) is an aggressive malignancy raising a healthcare concern worldwide. Standard treatment options include surgical resection, chemotherapy, radiation therapy, and targeted molecular therapy. The five-year survival rate for all stages of EC is approximately 20%, ranging from 5% to 47%, with a high recurrence rate and poor prognosis after treatment. Immunotherapy has shown better efficacy and tolerance than conventional therapies for several malignancies. Immunotherapy of EC, including immune checkpoint inhibitors, cancer vaccines, and adoptive cell therapy, has shown clinical advantages. In particular, monoclonal antibodies against PD-1 have a satisfactory role in combination therapy and are recommended for first- or second-line treatments. Here, we present a systematic summary and analysis of immunotherapy-based combination therapies for EC.
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Affiliation(s)
- Huiling Wang
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Yufei Xu
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Fengli Zuo
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Junzhi Liu
- West China School of Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Jiqiao Yang
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China,Breast Center, West China Hospital of Sichuan University, Chengdu, China,*Correspondence: Jiqiao Yang,
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