Journal for Immunotherapy of Cancer最新文献

{"title":"Low-dose photodynamic therapy promotes vascular E-selectin expression in chest malignancies, improving immune infiltration and tumor control.","authors":"Louis-Emmanuel Chriqui, Damien Nicolas Marie, Alexandros Sifis, Christophe Gattlen, Matteo Ortolini, Yameng Hao, Olga De Souza Silva, Etienne Abdelnour-Berchtold, Michel Gonzalez, Thorsten Krueger, Lucas Liaudet, Etienne Meylan, Sabina Berezowska, Michel Christodoulou, Tereza Losmanova, Ren Wang Peng, Thomas Michael Marti, Johanna Joyce, Sabrina Cavin, Jean Yannis Perentes","doi":"10.1136/jitc-2024-009482","DOIUrl":"10.1136/jitc-2024-009482","url":null,"abstract":"<p><strong>Background: </strong>Chest malignancies such as non-small cell lung cancer (NSCLC) or pleural mesothelioma (PM) have an ominous prognosis. Photodynamic therapy (PDT) of NSCLC and PM improves patient survival, but the precise underlying mechanism remains unknown. Here, we hypothesized that low-dose PDT (L-PDT) alters the expression of tumor endothelial cell adhesion molecules favoring immune cell recruitment and tumor control. We explored this hypothesis in two mouse models of NSCLC and PM. We validated our findings in 82 PM patient samples.</p><p><strong>Methods: </strong>We assessed, in C56BL/6 mice bearing 344SQ-NSCLC and in BALB/c mice bearing AB12-PM, how L-PDT (400 μg/kg Visudyne administered intravenously, irradiance: 50 mW/cm², light dose: 10 J/cm²) affected tumor growth, modulated the tumor immune microenvironment and the expression of endothelial selectin cell adhesion molecule (E-selectin) using real-time multiphoton imaging, immunofluorescence staining and flow cytometry. We then blocked E-selectin, canonical nuclear factor kappa B (NF-κB) pathway or selectively depleted CD8+ lymphocytes with dedicated peptides/antibodies in mouse models to evaluate the effect of L-PDT on tumors. Finally, we assessed in 82 PM patient samples the correlation between vascular E-selectin and CD8+ lymphocyte content by immunofluorescence staining of tissue sections and their association with patient survival.</p><p><strong>Results: </strong>L-PDT induced vascular E-selectin in both NSCLC and PM, which enhanced granzyme B+/CD3+/CD8+ lymphocyte infiltration and improved tumor control. Blockade of E-selectin or immunodepletion of CD8+ lymphocytes abrogated the L-PDT-mediated cancer regression. Moreover, canonical NF-κB pathway blockade impaired enhanced vascular E-selectin expression and CD8+ T cells infiltration in tumors following L-PDT. In human malignant pleural mesothelioma samples, we found a correlation between vascular E-selectin and CD8+ T cell infiltration, which was associated with improved patient outcome.</p><p><strong>Conclusion: </strong>L-PDT remodels the vasculature of chest tumors and favors a cytotoxic immune microenvironment promoting tumor control. This approach could complement current immunotherapy approaches in these malignancies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12161339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-4-STAT6-induced high Siglec-G/10 expression aggravates the severe immune suppressive tumor microenvironment and impedes the efficacy of immunotherapy in head and neck squamous cell carcinoma.","authors":"Wenyi Yang, Zhaoyang Guo, Houyu Ju, Yusheng Lu, Yifan Fei, Yuanchen Yin, Guoxin Ren, Ming Yan, Chaofeng Han, Jingzhou Hu","doi":"10.1136/jitc-2025-011474","DOIUrl":"10.1136/jitc-2025-011474","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint blockade therapy has shown limited efficacy in head and neck squamous cell carcinoma (HNSCC). Sialic acid binding immunoglobulin-like lectin (Siglec)-15 has been identified as a novel immune evasion biomarker, while the role of Siglec-10 in the specific immune suppressive tumor microenvironment remains largely unknown.</p><p><strong>Methods: </strong>Immunohistochemical assays were employed to investigate the correlation of the expressions of Siglec-10 and Siglec-15 with the clinicopathological features as well as the prognosis of immunotherapy in patients with HNSCC. The Gene Expression Omnibus datasets were used to identify the upstream transcriptional regulators of <i>SIGLEC10</i> in tumor-associated macrophages (TAMs) and the downstream biological functions it mediates. These findings were then validated through in vitro and in vivo experiments. The impact of <i>Siglecg</i> deficiency on the efficacy of immunotherapy and the activation of CD8+T cells was analyzed in mouse HNSCC tumor-bearing models.</p><p><strong>Results: </strong>The expression of Siglec-G/10, rather than that of Siglec-15, was positively correlated with immune suppressive marker programmed death-ligand 1 (PD-L1) expression and was associated with cervical lymph node metastasis, poorer pathologic stage, and lower sensitivity to immunotherapy. <i>Siglecg</i> deficiency rescued the immune suppressive tumor microenvironment, as evidenced by decreased TAM-associated phenotype and increased CD8+T cell infiltration and activation, which inhibited tumor growth significantly. Single-cell sequence and transcription factor prediction revealed that signal transducer and activator of transcription 6 (STAT6) could induce Siglec-G/10 transcription. Interleukin (IL)-4 could upregulate Siglec-G/10 expression significantly via STAT6 activation, as proved by overexpression and inhibition of STAT6. Signal transduction mechanism revealed that Siglec-G/10 could promote TAM differentiation and activation via increasing HIF1α (hypoxia-inducible factor 1α) expression. Furthermore, <i>Siglecg</i> deficiency could enhance the efficacy of immune checkpoint inhibitor, and increase the infiltration and cytotoxic functions of CD8+T cells.</p><p><strong>Conclusions: </strong>Our results suggest that high Siglec-G/10 expression aggravates the immune suppressive tumor microenvironment and impedes the immunotherapy efficacy in HNSCC, which indicates that targeting Siglec-G/10 may represent a promising therapeutic option for improving the immunotherapy efficacy in HNSCC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12161403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical and clinical evaluation of intratumoral injection of an IL-12 expressing SKV-012 oncolytic virus for advanced solid tumors.","authors":"Zheng Jiang, Nian Yang, Jing Jin, Zongliang Zhang, Huaqing Lu, Long Xu, Yongdong Chen, Liyuan Jin, Liangxue Zhou, Hui Yang, Jun Liu, Weiwei Zhang, Aiping Tong, Xingchen Peng","doi":"10.1136/jitc-2025-011642","DOIUrl":"10.1136/jitc-2025-011642","url":null,"abstract":"<p><strong>Background: </strong>SKV-012 is a novel engineered oncolytic virus (containing the viral neurovirulence ICP34.5 gene transcribed by the Survivin promoter with an upstream genetic component of interleukin-12 (IL-12) driven by the cytomegalovirus promoter) that preferentially replicates in tumors and helps stimulate antitumor immune responses.</p><p><strong>Methods: </strong>We evaluated SKV-012's safety and efficacy in preclinical models. In a phase I trial, patients with advanced solid tumors received intratumoral injections of escalating doses of SKV-012. Primary endpoints were safety and tolerability, while secondary endpoints were antitumor response and changes in the tumor microenvironment (TME), assessed by RECIST v1.1 criteria and multiplex immunohistochemistry and single-cell transcriptome analysis.</p><p><strong>Results: </strong>SKV-012-infected tumor cells secreted high levels of IL-12 and exhibited increased ICP34.5 expression. The combination of oncolytic herpesvirus and IL-12 was proven to reshape the TME by increasing the infiltration of immune cells, thereby significantly inducing immune cell-mediated cytolysis of tumor cells both in vitro and in animal models. Based on this, we then tested the safety, efficacy and immunogenicity of SKV-012 in patients with advanced solid cancers in a phase I clinical trial (NCT06080984). No dose-limiting toxicities were observed, and adverse events were mild. Three patients achieved partial responses; one had stable disease and two had progressive disease. SKV-012 altered the TME, increasing CD8+ T cells, conventional dendritic cells, and programmed death-ligand 1 expression.</p><p><strong>Conclusions: </strong>Intratumoral SKV-012 injections demonstrated a favorable safety profile and promising efficacy in animal models and patients with advanced cancers, thereby implicating its potential for clinical application in treatment-resistant advanced solid tumors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12161328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperglycemia in patients treated with immune checkpoint inhibitors: key clinical challenges and multidisciplinary consensus recommendations.","authors":"Linda Wu, Venessa Tsang, Roderick Clifton-Bligh, Matteo S Carlino, Tim Tse, Yiting Huang, Meredith Oatley, Ngai Wah Cheung, Georgina V Long, Alexander Maxwell Menzies, Jenny Gunton","doi":"10.1136/jitc-2024-011271","DOIUrl":"10.1136/jitc-2024-011271","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have an expanding role in the management of numerous cancers. Hyperglycaemia is commonly seen in patients treated with ICIs. However, the differential diagnosis for hyperglycaemia is broad, and incorrect diagnosis can have serious consequences. Herein we review the available literature on causes of hyperglycaemia in ICI treated patients and expert guidelines on management and provide an updated synthesis of expert multidisciplinary recommendations. Our key recommendations are as follows: Intensity of screening for hyperglycaemia should be based on a patient's risk level, including assessment of factors such as corticosteroid use, pre-existing diabetes, baseline HbA1c and fasting blood glucose levels (BGL). People with new onset hyperglycaemia should undergo initial assessment to determine severity and aetiology, including bedside capillary BGL, and formal bloods including lipase, C-peptide with matching glucose, electrolytes and renal function and in some cases type 1 diabetes autoantibodies. People with BGL >15mmol/L (or those receiving SGLT2 inhibitors with BGL >10mmol/L) should additionally have ketones measured. Patients with a high risk of diabetic ketoacidosis (BGL>15 mmol/L, ketones >2 mmol/L) and/or risk of hyperosmolar hyperglycaemic state (BGL persistently >20 mmol/L or reading 'HI') should be referred directly to hospital for emergency assessment and management. Further management of hyperglycaemia should be tailored to the underlying cause(s).</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12161310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting TBK1 potentiates oncolytic virotherapy via amplifying ICAM1-mediated NK cell immunity in chemo-resistant colorectal cancer.","authors":"Xin Guo, Huolun Feng, Zhihui Xi, Ji Zhou, Zuda Huang, Jieqing Guo, Jiabin Zheng, Zejian Lyu, Yongfeng Liu, Jianlong Zhou, Yucheng Zhang, Yuhan Zhang, Yong Li, Fan Xing","doi":"10.1136/jitc-2024-011455","DOIUrl":"10.1136/jitc-2024-011455","url":null,"abstract":"<p><strong>Background: </strong>Tumor resistance is the primary reason for treatment failure in patients with cancer, while oncolytic viruses (OVs), as a novel therapy, have been rapidly advancing through clinical evaluation and are typically assessed in recurrent tumors that are refractory to standard chemotherapy. However, whether the adaptive process that fosters chemotherapy resistance influences the efficacy of OV therapy is unknown.</p><p><strong>Methods: </strong>We analyzed chemo-resistant colorectal cancer (CRC) using in vitro, in vivo, and patient-derived organoid models to assess sensitivity to OVs. Through RNA sequencing analysis and immunohistochemistry were performed in clinical samples that indicated TANK-binding kinase 1 (TBK1) expression. Using single-cell RNA sequencing, flow cytometry, and in vivo neutralization assays to demonstrate that the combination of TBK1 inhibitor (TBK1i) and OVs reprograms the tumor immune microenvironment, particularly by activating natural killer (NK) cells. Through RNA sequencing analysis, we identified intercellular cell adhesion molecule-1 (ICAM-1) as a potential target responsible for NK cell activation. Subsequently, we designed and conducted rescue experiments, both in vitro and in vivo, to validate the influence of ICAM-1 on NK cell activity.</p><p><strong>Results: </strong>We demonstrated that chemo-resistant CRC showed decreased sensitivity to the OV in vitro, in vivo, and patient-derived organoids. Further investigation revealed aberrant activation of TBK1 in chemo-resistant CRC, which mediated the activation of the type I interferon pathway and impaired viral replication. TBK1 inhibition enhanced intratumor viral replication and direct oncolysis effect in vitro and augmented the antitumor immunity elicited by OVs in vivo. Immune cell profiles presented that OV/TBK1i combination reshaped the tumor microenvironment and especially activated the NK cell response. Immune cell depletion studies demonstrated that NK cells were required for the synergistic therapeutic activity of the OV/TBK1i combination. Mechanistically, TBK1 inhibition synergized with VSVΔ51 to increase ICAM1 expression in a RIPK1-dependent manner, promoting NK cell-mediated tumor killing.</p><p><strong>Conclusion: </strong>This study presents a promising approach for treating chemo-resistant CRC by combining OVs and TBK1i.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12161417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting IL13Rα2 in melanoma with a bispecific T-cell engager: expression profiling and preclinical evaluation.","authors":"Shushu Zhao, Yeqing Chen, Pratik S Bhojnagarwala, Cory Livingston, Joshua Jose, Yangcheng Gao, Daniel H Park, Meenhard Herlyn, David B Weiner","doi":"10.1136/jitc-2024-011073","DOIUrl":"10.1136/jitc-2024-011073","url":null,"abstract":"<p><strong>Background: </strong>Melanoma is a highly aggressive skin cancer, especially in advanced stages. While current treatments such as targeted therapies and immunotherapies have made significant progress, challenges like drug resistance and limited effectiveness in some patients persist. Therefore, ongoing development of novel therapies, particularly for late-stage melanoma, is crucial.</p><p><strong>Methods: </strong>In this study, we explored the expression of interleukin-13 receptor subunit alpha-2 (IL13Rα2) in melanoma patient-derived xenograft models. We investigated IL13Rα2 as a potential target for melanoma treatment by employing an IL13Rα2-CD3 bispecific T-cell engager (BTE). We tested the effect of IL13Rα2-CD3 BTE on T cell activity by flow cytometry. We studied the potency of IL13Rα2-CD3 BTE in tumor killing assay in vitro. For in vivo studies, we administered DNA expression cassettes encoding IL13Rα2-CD3 BTE (IL13Rα2-CD3 DNA encoding BTE (dBTE)) into immunodeficient mice for direct in vivo expression. The mice were challenged with A375 cells and then treated with IL-13Rα2-CD3 dBTE versus control and reconstituted with human peripheral blood mononuclear cells (PBMCs) or T cells. Tumor development was monitored, and T cell infiltration in the tumor was analyzed throughflow cytometry.</p><p><strong>Results: </strong>Our findings revealed heterogeneous expression of IL-13Rα2, particularly in samples from advanced stages of melanoma. The IL13Rα2-CD3 BTE facilitated T-cell activation and proliferation by bridging melanoma cells and T cells. We also observed the ability of IL13Rα2-CD3 BTE to direct T cells to kill multiple melanoma patient-derived cell lines through xCELLigence assay in vitro, including those with various mutations associated with late-stage metastatic melanoma. IL13Rα2-CD3 dBTE expressed in vivo led to notable tumor regression through inducing increased T-cell infiltration and activation within the tumor microenvironment.</p><p><strong>Conclusions: </strong>These promising findings underscore the potential of targeting IL13Rα2 as a relevant target for the development of biologics including dBTE aimed at treating specific subsets of melanoma.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12161313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C5a/C5aR pathway blocking promoted CuS-mediated cancer therapy effect by inhibiting cuproptosis resistance.","authors":"Hong Yang, Boshao Deng, Xiao Han, Lulu Wang, Jing Zhao, Yunpei Zhao, Zihan Sun, Siyi Wang, Guokang Liu, Yuzhang Wu, Jian Chen","doi":"10.1136/jitc-2025-011472","DOIUrl":"10.1136/jitc-2025-011472","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer is the most diagnosed malignancy and a leading cause of cancer-related deaths among women globally. Cuproptosis plays a significant role in tumor progression and therapeutic response. Increasing studies suggest that targeting cuproptosis presents a promising strategy for cancer therapy, such as through the development of copper nanoparticles as therapeutic agents. However, resistance to cuproptosis has emerged as a critical hallmark of cancer. Therefore, it is essential to further investigate the mechanisms underlying cuproptosis resistance to enhance its therapy effect.</p><p><strong>Methods: </strong>The relationship between breast cancer progression and the C5a/C5aR pathway or cuproptosis was determined by single-cell RNA sequencing analyses, RNA-sequence analyses, bioinformatic analyses, survival analyses and immunohistochemistry. The antitumor effects of CuS nanoparticles and C5a receptor antagonists (C5aRA) were assessed by in vitro and in vivo strategies including cell counting kit-8, colony formation assay, relative reactive oxygen species level assay, western blots, real-time quantitative PCR, immunohistochemistry, immunofluorescence assay, flow cytometry and the xenograft mice models. Complement system activation by CuS nanoparticles was tested by ELISA.</p><p><strong>Results: </strong>Our results indicated that activation of the C5a/C5aR pathway contributes to cuproptosis resistance by upregulating ATP7B expression via the Wnt/β-catenin pathway. Consequently, combining CuS nanoparticles with lazer treatment and C5aRA markedly enhanced the antitumor efficacy of CuS nanoparticles by overcoming cuproptosis resistance, leading to a synergistic effect in cancer therapy that included cuproptosis-targeting therapy, immunotherapy, and photothermal therapy.</p><p><strong>Conclusions: </strong>This study reports, for the first time, proved C5a/C5aR pathway-mediated cuproptosis resistance in cancer cells, and combining CuS nanoparticles and C5aRA offers a superior and novel therapeutic strategy for cancer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12161435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trials.","authors":"Christopher R Cabanski, EnJun Yang, Mark D Stewart, Jeff D Allen, John E Connolly, Ute Dugan, Philip D Greenberg, Crystal L Mackall, Carl H June, Alexander Marson, Marcela V Maus, Antoni Ribas","doi":"10.1136/jitc-2024-011301","DOIUrl":"10.1136/jitc-2024-011301","url":null,"abstract":"<p><p>Cell-based gene therapies, including chimeric antigen receptor-T, T-cell receptor-T, and tumor-infiltrating lymphocyte therapies, have transformed the treatment landscape for certain cancers, yet their efficacy in solid tumors remains limited. Next-generation therapies aim to overcome biological barriers, enhance potency and safety, and streamline development timelines through innovative approaches. Recent advances in genome editing technologies have identified hundreds of gene edits that improve T-cell functionality in preclinical models. However, the limited direct translatability of these findings and the impracticality of testing each of the individual edits in a traditional clinical trial highlight the need for more efficient strategies.This article provides an overview of genome-wide screens that identify gene knockouts and knock-ins to enhance T-cell function and the limitations with translating these results to human trials. Next, we propose a novel clinical trial design for testing multiple gene modifications simultaneously within a single T-cell infusion product. This approach would enable head-to-head evaluation of edits in an internally controlled setting, accelerating the identification of promising candidate edits. Key considerations for Chemistry, Manufacturing, and Controls, non-clinical evaluation, and clinical protocols are discussed, with an emphasis on patient safety and ethical transparency.This framework is informed by insights shared at the \"Unlocking Complex Cell-based Gene Therapies\" workshop, held on May 6, 2024. Co-hosted by Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy, the event brought together participants from academia, the US Food and Drug Administration, and patient advocacy groups. By fostering collaboration among these stakeholders, this innovative approach aims to accelerate the development of effective cell-based therapies for complex diseases.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAR-T cell therapy in older adults with relapsed/refractory LBCL: benefits and challenges.","authors":"Leyla Shune, Matthew J Frigault, Peter A Riedell","doi":"10.1136/jitc-2024-009793","DOIUrl":"10.1136/jitc-2024-009793","url":null,"abstract":"<p><p>Patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) have poor prognosis with a high unmet need for efficacious treatment options. Most patients with r/r large B-cell lymphoma (LBCL) are elderly, which adds to the complexity of choosing the appropriate and effective therapy in these patients. Recently approved therapies, such as CD19-targeted chimeric antigen receptor-T cell therapy, have shown improvements in the outcomes of patients with r/r DLBCL. Several real-world studies also support the use of these newer therapies in elderly patients. However, given the frailty, variability in the risk factors in each elderly patient, and the increased susceptibility for adverse events, a comprehensive geriatric assessment and a multidisciplinary approach could be helpful in guiding the management and treatment choices for these vulnerable patients. Individualized care can aid in giving elderly patients with r/r LBCL the best possible outcome with their chosen treatment regimen.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-depth characterization of vaccine-induced neoantigen-specific T cells in patients with IDH1-mutant glioma undergoing personalized peptide vaccination.","authors":"Henning Zelba, Borong Shao, Armin Rabsteyn, Annekathrin Reinhardt, Carsten Greve, Lisa Oenning, Simone Kayser, Christina Kyzirakos, Pauline Latzer, Tabea Riedlinger, Oliver Bartsch, Julian Wünsche, Johannes Harter, Magdalena Feldhahn, Yannick Bantel, Janina Johänning, Jiri Ködding, Dirk Hadaschik, Martin Schulze, Florian Battke, Olga Maksimovic, Veit Scheble, Alexandra M Miller, Michael Castro, Deborah T Blumenthal, Martin Glas, David Reardon, Saskia Biskup","doi":"10.1136/jitc-2024-011070","DOIUrl":"10.1136/jitc-2024-011070","url":null,"abstract":"<p><p>Isocitrate dehydrogenase (IDH) mutant glioma is a malignant primary brain tumor diagnosed in adults. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors. The first targeted IDH-inhibitor was approved by the US Food and Drug Administration in August 2024 for grade 2 gliomas, in light of results of a phase III trial which showed significant advantages in progression-free survival. However, biologic therapy is not curative, and subsequent treatment options offer only limited clinical benefit and often result in long-term toxicities. In addition, targeted treatment options for grade 3 and grade 4 IDH-mutant gliomas are still missing. In this study, we present n=52 patients with glioma (grade 2, 3 and 4) with confirmed IDH1 mutation (mutIDH1) in the newly diagnosed and recurrent setting who, in addition to standard-of-care, received a personalized neoantigen-targeting peptide vaccine. Each tumor was initially analyzed for somatic mutations by whole exome sequencing, and a peptide vaccine containing potential neoepitopes was designed, manufactured and vaccinated. Each vaccine consisted of peptides derived from numerous somatic mutations, including at least one peptide targeting the mutIDH1.Vaccine immunogenicity was determined by intracellular cytokine staining and simultaneous measurement of four T-cell activation markers (Interferon-γ, Tumor Necrosis Factor, Interleukin-2, CD154) after 12-day in vitro expansion of pre and post vaccination peripheral blood mononuclear cells. Extracellular CD154 staining was used to sort mutIDH1-specific CD4+T cells.Immunomonitoring revealed that the vaccines were immunogenic and induced mainly CD4 but also CD8 T cell responses. Vaccine-induced immune responses were robust and polyfunctional. Immunogenicity against mutIDH1 was high (89%). We implemented an assay which allowed us to isolate functional antigen-specific CD4+T cells in an HLA-independent manner. Subsequent T cell receptor (TCR) repertoire sequencing revealed that CD4+T cells reacting on mutIDH1 stimulation were polyclonal. Strikingly, we detected two mutIDH1-specific TCRβ candidate sequences in three different patients. These three patients had the same human leukocyte antigen (HLA) DQA-DQB alleles. The obtained TCRβ sequences could be tracked in autologous ex-vivo single-cell transcriptomic data. Our results provide a rationale for pursuing vaccination and T cell transfer strategies targeting IDH1. Furthermore, our findings indicate that personalized neoantigen-targeting vaccines might be considered for the treatment of IDH1-mutant gliomas.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12142095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}