Journal for Immunotherapy of Cancer最新文献

{"title":"Where does ISAC (immune-stimulating antibody conjugates) go from here?","authors":"Chen Fu","doi":"10.1136/jitc-2025-012500","DOIUrl":"10.1136/jitc-2025-012500","url":null,"abstract":"<p><p>Immune-stimulating antibody conjugates (ISACs) have emerged as a promising class of therapeutics, employing design principles similar to antibody-drug conjugates (ADCs) but replacing cytotoxic payloads with immune-stimulatory agents. These agents enhance immune system activation, enabling more effective tumor targeting and elimination. However, recent clinical setbacks since 2021 have raised concerns about ISACs' viability as ADC successors. Although ISAC development remains early-stage, clinical trials have revealed significant challenges, including limited efficacy, systemic toxicity (eg, cytokine release syndrome), and anti-drug antibody generation. Current strategies to overcome these hurdles focus on optimizing payload selection (eg, toll-like receptor 7(TLR7) vs stimulator of interferon genes (STING) agonists), improving linker stability, and exploring localized delivery methods. While ISACs face substantial translational barriers, their potential to synergize with existing immunotherapies and treat \"cold\" tumors maintains therapeutic promise. Further refinement of design parameters may ultimately position ISACs as a transformative oncology modality.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954884","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":"Priming the tumor microenvironment with pembrolizumab and radiotherapy for durable cures in high-risk localized undifferentiated pleomorphic sarcoma and pleomorphic/dedifferentiated liposarcoma.","authors":"Aastha Sobti, Yvonne M Mowery","doi":"10.1136/jitc-2025-012053","DOIUrl":"https://doi.org/10.1136/jitc-2025-012053","url":null,"abstract":"<p><p>SU2C-SARC032 establishes addition of perioperative pembrolizumab as a new treatment option for high-risk localized extremity soft tissue sarcoma (STS). For patients with stage III undifferentiated pleomorphic sarcoma or dedifferentiated/pleomorphic liposarcoma, addition of neoadjuvant and adjuvant pembrolizumab to preoperative radiation therapy (RT) and surgery improved 2-year disease-free survival by 15% compared with RT and surgery alone. This commentary highlights key insights from the trial: (1) the cooperative activity between pembrolizumab and RT, (2) the need for biomarker-driven patient selection, and (3) the potential for circulating tumor DNA to guide adjuvant treatment decisions. Recognizing the heterogeneity of STS, we emphasize the importance of future trials incorporating comprehensive correlative analyses to identify predictors of response and to optimize treatment strategies. Furthermore, we highlight the need for equitable access to advanced diagnostics and personalized treatment approaches so that the benefits of SU2C-SARC032 can be realized for patients with STS throughout the world.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954969","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":"Constructing the cure: engineering the next wave of antibody and cellular immune therapies.","authors":"Stefanie R Bailey, Eric Bartee, Kyle G Daniels, Christopher R Heery, Pravin Kaumaya, Gregory B Lesinski, Timothy B Lowinger, Michelle H Nelson, Mark P Rubinstein, Megen C Wittling, Chrystal M Paulos, Avery D Posey","doi":"10.1136/jitc-2025-011761","DOIUrl":"https://doi.org/10.1136/jitc-2025-011761","url":null,"abstract":"<p><p>Immuno-oncology has revolutionized cancer treatment by mobilizing the immune system to eliminate tumors. Although immune checkpoint inhibitors and T cell therapies have mediated durable responses in hematologic malignancies and select solid tumors, most patients still relapse or fail to respond. To overcome these limitations, novel, next-generation immune constructs, including bispecific-cell therapy combinations, armored cells, tethered cytokines, immune-stimulatory antibody conjugates, and in vivo gene editing, are being developed to enhance specificity, persistence, and immune activation. This Society for Immunotherapy of Cancer roadmap highlights emerging technologies that integrate, redirect, or potentiate immune response. We examine advances in construct design, strategies for clinical translation, and opportunities for combinatorial approaches. By addressing translational barriers and real-world challenges, we outline how innovative engineering can unlock a new era of safe, durable, and accessible immunotherapies. Realizing this potential will require coordinated efforts from researchers, clinicians, industry leaders, and policymakers to deliver curative outcomes to patients worldwide.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955146","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":"Neoadjuvant PD-1 blockade: a new treatment option for patients with early-stage mismatch repair deficient solid tumors.","authors":"Kristin G Anderson, Antoni Ribas","doi":"10.1136/jitc-2025-013061","DOIUrl":"https://doi.org/10.1136/jitc-2025-013061","url":null,"abstract":"<p><p>DNA mismatch repair deficiency has been identified as a biomarker that strongly correlates with tumor response to anti-programmed cell death protein-1 (PD-1) checkpoint blockade therapy in the metastatic setting. In a promising Phase 2 study published in the <i>New England Journal of Medicine</i>, Cercek <i>et al</i> demonstrate that PD-1 checkpoint blockade also has potential in the neoadjuvant setting and may eliminate the need for surgical intervention. These results offer great hope to patients with a variety of solid malignancies because those who experience complete clinical responses may be able to safely choose non-operative management to preserve organ function and minimize side effects associated with surgery.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954886","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":"Constructing a pancancer ubiquitination regulatory network to determine tumor characteristics, immunotherapy response, and prognosis.","authors":"Zheng Zhou, Bing-Zhi Wang, Chaoqi Zhang, Guochao Zhang, Peng Wu, Xin Dong, Nan Sun, Jie He","doi":"10.1136/jitc-2025-012539","DOIUrl":"https://doi.org/10.1136/jitc-2025-012539","url":null,"abstract":"<p><strong>Background: </strong>Ubiquitination-a pivotal post-translational modification that orchestrates cellular homeostasis and oncogenic pathways-remains underexplored as a pancancer regulatory hub. Although ubiquitination dysregulation is linked to tumor progression, a comprehensive, multicancer framework integrating prognostic, molecular, and microenvironmental landscapes is lacking.</p><p><strong>Methods: </strong>This study integrated data of 4,709 patients from 26 cohorts across five solid tumor types (lung cancer, esophageal cancer, cervical cancer, urothelial cancer, and melanoma) and mapped the molecular profiles to the interaction network. Cox regression and the Kaplan-Meier survival method were employed for prognostic analysis. Functional enrichment and protein-protein interaction analyses were performed to identify the key downstream pathways and genes. Findings were validated using independent patient cohorts, cell line models, and in vivo experiments.</p><p><strong>Results: </strong>Key nodes and prognostic pathways within the ubiquitination-modification network were identified. A conserved ubiquitination-related prognostic signature (URPS) effectively stratified patients into high-risk and low-risk groups with distinct survival outcomes across all analyzed cancers. URPS may serve as a novel biomarker for predicting immunotherapy response, with the potential to identify patients who are more likely to benefit from immunotherapy in clinical settings. A comprehensive analysis of URPS-associated proteins revealed novel cancer-related interaction partners as potential drug targets. At the single-cell resolution, URPS enabled more precise classification of distinct cell types and was associated with macrophage infiltration within the tumor microenvironment. In vivo, in vitro, and patient cohort analyses, demonstrated that OTUB1-TRIM28 ubiquitination plays a crucial role in modulating MYC pathway and influencing patient prognosis.</p><p><strong>Conclusion: </strong>We constructed a pancancer ubiquitination regulatory network and prognostic model, revealing important pathways, and offering insights into predicting patient prognosis and understanding biological mechanisms.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955129","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":"Efficacy and safety of one-time autologous tumor-infiltrating lymphocyte cell therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.","authors":"Robert L Ferris, Rom S Leidner, Christine H Chung, Antonio Jimeno, Sylvia M Lee, Ammar Sukari, Jorge J Nieva, Juneko E Grilley-Olson, Rebecca Redman, Stuart J Wong, Victoria M Villaflor, Jamal Misleh, Friedrich Graf Finckenstein, Jeffrey Chou, Brian Gastman, Rana Fiaz, Melissa Catlett, Min Yi, Ezra E W Cohen","doi":"10.1136/jitc-2025-011633","DOIUrl":"10.1136/jitc-2025-011633","url":null,"abstract":"<p><strong>Background: </strong>Recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) has a high recurrence rate after first-line immunotherapy or chemoimmunotherapy. The presence of a high density of tumor-infiltrating lymphocytes (TILs) in HNSCC tumors was shown to be associated with improved clinical outcomes. One-time autologous TIL cell therapy was evaluated in patients with recurrent and/or metastatic HNSCC.</p><p><strong>Methods: </strong>C-145-03 (NCT03083873) was a phase 2 study of TIL in patients with recurrent and/or metastatic HNSCC assigned to 1 of 4 treatment cohorts: cohort 1, non-cryopreserved TIL; cohort 2, cryopreserved lifileucel (22-day manufacturing); cohort 3, cryopreserved lifileucel (16-day manufacturing); cohort 4, cryopreserved LN-145-S1 programmed cell death protein-1 (PD-1) selected. Patients underwent tumor resection for TIL generation. After preparative non-myeloablative lymphodepletion, patients received a single infusion of TIL followed by interleukin-2 (IL-2) infusion(s). The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria for Solid Tumors (RECIST) V.1.1. Secondary endpoints were investigator-assessed duration of response (DOR), disease control rate (DCR), progression-free survival, overall survival, and incidence of treatment-emergent adverse events.</p><p><strong>Results: </strong>Overall, 53 patients received TIL: cohort 1 (n=8), cohort 2 (n=17), cohort 3 (n=16), cohort 4 (n=12). Median age was 57 years and most patients were males (87%; 46/53) with stage IV disease (98%; 52/53). Patients had a median of two prior lines of systemic therapy; 87% (46/53) of patients had prior anti-PD-1/programmed cell death ligand-1 therapy and 72% (38/53) had prior chemotherapy. The ORR was 11% (6/53) with six patients achieving partial response (cohort 1, n=3; cohort 2, n=1; cohort 4, n=2). At median follow-up of 17.9 months, the median DOR was 7.6 months. The DCR was 76% (40/53); 64% (34/53) of patients had stable disease. The safety profile was consistent with known toxicities associated with non-myeloablative lymphodepletion and IL-2 administration.</p><p><strong>Conclusions: </strong>This study demonstrated the feasibility of consistently generating sufficient TIL from HNSCC tumors. Results from this study suggest TIL cell therapy may serve as a potential treatment option for patients with HNSCC and support further development, including TIL cell therapy combined with immune checkpoint inhibitors or other agents or with other TIL products.</p><p><strong>Trial registration number: </strong>NCT03083873.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954946","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":"Multiomics integration analysis identifies tumor cell-derived MIF as a therapeutic target and potentiates anti-PD-1 therapy in osteosarcoma.","authors":"Weidong Chen, Yan Liao, Hao Yao, Yutong Zou, Ji Fang, Jiongfeng Zhang, Zehao Guo, Jian Tu, Junkai Chen, Zijun Huo, Lili Wen, Xianbiao Xie","doi":"10.1136/jitc-2024-011091","DOIUrl":"https://doi.org/10.1136/jitc-2024-011091","url":null,"abstract":"<p><strong>Background: </strong>Osteosarcoma is a highly aggressive cancer, and the efficacy of existing therapies has plateaued. Multiomics integration analysis can identify novel therapeutic targets for various cancers and therefore shows potential toward osteosarcoma treatment. This study aimed to leverage multiomics integration to develop a new risk model, characterizing the immune features of osteosarcoma to uncover novel therapeutic targets.</p><p><strong>Methods: </strong>Metabolomics profiling was conducted to identify key metabolites in osteosarcoma. Transcriptomic sequencing datasets were analyzed to identify prognostic genes related to key metabolic pathways and develop a prognostic risk model. Patients were then divided into high-risk and low-risk groups with distinct clinical outcomes based on the risk model. The single-sample gene set enrichment analysis, Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) algorithm, and xCell algorithms were used to evaluate the immune cell infiltration and activity. Single-cell RNA sequencing was used to explore cell-to-cell interactions within the tumor microenvironment. In vitro coculture functional assays were performed to validate the role of macrophage migration inhibitory factor (MIF) in macrophage polarization and chemotaxis. In vivo studies were used to evaluate the effectiveness of MIF inhibition in combination with immune checkpoint blockade in murine models.</p><p><strong>Results: </strong>Elevated lactate levels in osteosarcoma patients correlated with poorer overall survival. We identified SLC7A7 and CYP27A1 as prognostic lactate metabolism genes and developed a risk model to stratify patients into high-risk and low-risk groups with distinct outcomes. Bioinformatics analyses highlighted the differences in immune infiltration patterns and activity between the groups. Notably, the infiltration and phenotype of macrophages varied significantly between the groups, and MIF was identified as a critical mediator in this process. In osteosarcoma cells, lactate regulated MIF expression through histone H3K9 lactylation. Combining the MIF inhibitor 4-IPP with a programmed cell death 1 (PD-1) monoclonal antibody treatment demonstrated a significant antitumor effect.</p><p><strong>Conclusion: </strong>MIF acts as a novel therapeutic target by regulating macrophage polarization and chemotaxis. Lactate regulated MIF expression through histone lactylation. Targeting MIF holds promise for enhancing the efficacy of anti-PD-1 treatment.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954949","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":"Immune-related adverse events of neoadjuvant immunotherapy in patients with perioperative cancer: a machine-learning-driven, decade-long informatics investigation.","authors":"Song-Bin Guo, Deng-Yao Liu, Rong Hu, Zhen-Zhong Zhou, Yuan Meng, Hai-Long Li, Wei-Juan Huang, Xiao-Peng Tian","doi":"10.1136/jitc-2024-011040","DOIUrl":"https://doi.org/10.1136/jitc-2024-011040","url":null,"abstract":"<p><p>Research on neoadjuvant immunotherapy (NAI) is increasingly focusing on immunotherapy-related adverse events (AEs). However, many unknowns remain in this field. Hence, through the machine learning (ML)-driven informatics analysis, this study aimed to profile the global decade-long scientific landscape of AEs of NAI and further reveal its critical issues and directions that deserve deeper exploration. During the past decade, the amount of research in the field of NAI safety has displayed a positive trend (annual growth rate: 30.2%), and it has achieved good global collaboration (international coauthorship: 17.43%). Using an unsupervised clustering algorithm, we identified six dominant research clusters, among which Cluster 1 (standardizing response assessment criteria for NAI to minimize its adverse reactions; average citation=34.86±95.48) had the highest impact and Cluster 6 (efficacy and safety of multiple therapy patterns combination) was an emerging research cluster (temporal central tendency=2022.43, research effort dispersion=0.52), with \"irAEs\" (s=0.4242 (95% CI: 0.01142 to 0.8371), R²=0.4125, p=0.0453), \"ICIs\" (immune checkpoint inhibitors) (s=1.127 (95% CI: 0.5403 to 1.714), R²=0.7103, p=0.0022), and \"efficacy and safety\" (s=0.5455 (95% CI: 0.1145 to 0.9764), R²=0.5157, p=0.0193) showing significant overall growth. More importantly, further hotspot burst analysis indicated \"ICI\" and \"efficacy and safety\" as the emerging research focuses, demonstrating that scholars in the field are increasingly aware of the importance of balancing NAI efficacy and safety. In conclusion, this study presents ML-derived evidence that outlines the safety challenges of NAI and highlights the importance of balancing its efficacy and safety for its application in patients with perioperative cancer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954927","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":"CD24 recruits tumor-associated neutrophils to promote the progression of hepatocellular carcinoma.","authors":"Jun Wang, Hanning Li, Yimeng Liu, Xiang Xiao, Jiapeng Li, Shu Jiang, Jincheng Wang, Yu Cheng, Zetao Song, Yuan Wu, Chaojiang Gu, Shaoyong Chen, Jing Xiong, Huimin Zhang, Yuan Xiang, Xinghua Liao","doi":"10.1136/jitc-2025-012118","DOIUrl":"10.1136/jitc-2025-012118","url":null,"abstract":"<p><strong>Background: </strong>The immunosuppressive tumor microenvironment is a significant challenge in the treatment of hepatocellular carcinoma (HCC), necessitating the urgent development of strategies to mitigate its effects.</p><p><strong>Methods: </strong>The application of bioinformatics methods to predict the expression level of CD24 in HCC and its relationship with the occurrence and development of HCC. Gene-engineered mice and flow cytometry were used to study the immune cell populations regulated by CD24. Cell metabolism analysis, western blotting, and lactate content measurement were employed to assess the impact of CD24 on lactate secretion by HCC cells. Additionally, cell counting kit 8 and colony formation assays were conducted to evaluate the effect of CD24 on the sensitivity of HCC cells to sorafenib. The integration of RNA sequencing, flow cytometry, cell chemotaxis experiments, and ELISA established a robust framework for understanding CD24-mediated neutrophils immune infiltration.</p><p><strong>Results: </strong>In this study, we found that CD24 can recruit neutrophils to infiltrate HCC tissues to form tumor-associated neutrophils (TANs) and polarize TANs to a protumor phenotype by promoting lactate secretion by HCC cells, thus promoting the progression of HCC. In addition, targeting CD24 can enhance the sensitivity of HCC cells to sorafenib by reducing the accumulation of TANs.</p><p><strong>Conclusions: </strong>Our results reveal the molecular mechanism by which CD24 promotes HCC progression through recruitment of neutrophils infiltrates, raising new insights into the role of targeting CD24 in driving HCC immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955158","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":"Interleukin-12 encoded by the oncolytic virus VSV-GP enhances therapeutic antitumor efficacy by inducing CD8+ T-cell responses with a long-lived effector cell phenotype.","authors":"Jasmin Hatami, Krishna Das, Leonie Wolf, Andreas Aufschnaiter, Janine Kimpel, Tobias Nolden, Liesa-Marie Schreiber, Brigitte Müllauer, Elke Podgorschek, Theresa Schwaiger, Bart Spiesschaert, Guido Wollmann, Knut Elbers, Dorothee von Laer, Zoltán Bánki","doi":"10.1136/jitc-2024-010675","DOIUrl":"https://doi.org/10.1136/jitc-2024-010675","url":null,"abstract":"<p><strong>Background: </strong>Vesicular stomatitis virus (VSV) pseudotyped with the glycoprotein (GP) of the lymphocytic choriomeningitis virus (VSV-GP) represents a potent oncolytic virus (OV). Oncolytic virotherapy is an emerging anticancer approach that uses viruses to eliminate cancer cells by direct cell lysis and induction of an antitumor immune response. Immunomodulatory cargos expressed by OVs hold the potential to further enhance this antitumor immune response.</p><p><strong>Methods: </strong>To evaluate interleukin-12 (IL-12) as an immunomodulatory cargo encoded by VSV-GP, we used a subcutaneous tumor model by mixing type I interferon (IFN) competent murine lung epithelial cells (TC-1), which are largely resistant to VSV-GP in vivo, with VSV-GP permissive IFN-α receptor knockout TC-1 cells (TC-1<i>ifnar1^-/</i> ^-).</p><p><strong>Results: </strong>This mixed model supports prolonged viral replication and subsequent IL-12 production. Oncolytic virotherapy with VSV-GP and VSV-GP-IL12 of parental TC-1 tumors did not lead to tumor control, whereas virus treatment in the TC-1/TC-1<i>ifnar1^-/-</i> mixed tumors showed prolonged survival. Furthermore, VSV-GP-IL12 was even more effective than VSV-GP treatment. Analysis of CD8+ T cell responses revealed phenotypic differences of activated CD8+ T cells between VSV-GP and VSV-GP-IL-12 treatment, whereby VSV-GP-IL12-induced CD8+T cells displayed a phenotype described for long-lived effector cells (LLEC). Depletion experiments indicated that CD8+ T cells, and not NK cells, were responsible for the improved efficacy observed with VSV-GP-IL12 treatment.</p><p><strong>Conclusions: </strong>Taken together, we have demonstrated that oncolytic virotherapy using VSV-GP encoding IL-12 induces CD8+ T cell responses characterized by an LLEC phenotype, a cell population that is likely a crucial component of antitumor immunity.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 8","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954938","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}