Journal for Immunotherapy of Cancer最新文献

{"title":"VISTA neutralization by immunization reprograms immunosuppression and augments vaccine efficacy in renal carcinoma.","authors":"Jiawei Wang, Zhenzhen Wang, Wanting Zhao, Haomin Chen, Bowen Lu, Yingxiang Shao, Yanyan Zheng, Shanshan Liu, Meng Wang, Lin Fang, Huizhong Li, Praveen Neeli, Hui Tian, Gang Wang, Dafei Chai","doi":"10.1136/jitc-2026-015052","DOIUrl":"https://doi.org/10.1136/jitc-2026-015052","url":null,"abstract":"<p><strong>Background: </strong>Renal carcinoma remains a highly lethal malignancy, and tumor vaccine efficacy is frequently hampered by a profoundly immunosuppressive tumor microenvironment. V-domain Ig suppressor of T-cell activation (VISTA), an inhibitory immune checkpoint enriched in myeloid cells and regulatory T cells (Tregs), represents a critical barrier to effective antitumor immunity. Targeting VISTA may therefore provide a promising strategy to overcome immune suppression and enhance tumor vaccine efficacy.</p><p><strong>Methods: </strong>Recombinant adenoviral vaccines encoding carbonic anhydrase IX (CAIX) and VISTA (Ad-CAIX and Ad-VISTA) were constructed and validated for efficient antigen expression. The antitumor efficacy of Ad-VISTA/CAIX co-immunization was evaluated in subcutaneous, lung metastatic, orthotopic, and anti-programmed cell death protein 1-resistant renal carcinoma models. Vaccine-induced immune responses were assessed by flow cytometry, immunohistochemistry, ELISA, cell proliferation assays, cytotoxic T lymphocyte (CTL) assays, and in vivo immune cell depletion experiments.</p><p><strong>Results: </strong>Ad-VISTA immunization markedly potentiated the therapeutic efficacy of CAIX-targeted vaccination, resulting in significant tumor growth inhibition and prolonged survival across multiple renal carcinoma models. Mechanistically, VISTA-targeting remodeled the tumor microenvironment by enhancing the infiltration and activation of dendritic cells (DCs) and CD8⁺ T cells while reducing immunosuppressive myeloid cells and Tregs. Ad-VISTA/CAIX co-immunization promoted the expansion and maturation of multiple DC subsets, characterized by increased expression of CD40, CD80, CD86, and major histocompatibility complex molecules, thereby facilitating efficient antigen presentation. VISTA immunization elicited robust antigen-specific antibody and neutralizing responses, restored CD8⁺ T-cell proliferation, and enhanced CTL-mediated tumor cell killing. Depletion of CD8⁺ T cells abrogated therapeutic efficacy of Ad-VISTA/CAIX vaccine, establishing its essential role in tumor control. Furthermore, combined vaccination induced durable memory CD8⁺ T-cell responses capable of preventing tumor recurrence on rechallenge.</p><p><strong>Conclusions: </strong>These results indicated that vaccine-induced VISTA blockade effectively amplifies DC-mediated CD8⁺ T-cell immunity and synergistically enhances tumor vaccine efficacy. Targeting VISTA represents a promising immunotherapeutic strategy for improving vaccine-based treatments in renal carcinoma.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 5","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase 1 multicenter study of the NKG2A targeting antibody S095029 as a single agent and in combination with anti-PD-1 in patients with advanced malignancies.","authors":"Aung Naing, Anna Spreafico, Minal Barve, Amita Patnaik, Xenophon Ianopoulos, Pauline Drean, Niels Jorgen Skartved, Agnes Hemon, Chahrazade Kantari-Mimoun, Peng He, Vasileios Askoxylakis, Nehal Lakhani","doi":"10.1136/jitc-2025-014325","DOIUrl":"https://doi.org/10.1136/jitc-2025-014325","url":null,"abstract":"<p><strong>Background: </strong>NKG2A is a C-type lectin that heterodimerizes with CD94 creating an inhibitory immunoreceptor. S095029 is a fully human monoclonal IgG1 anti-NKG2A antibody with attenuated Fc-effector functions that specifically binds the NKG2A/CD94 heterodimer, blocking the interaction with its ligand HLA-E. Sym021 is an anti-programmed cell death protein 1 (PD-1) IgG1 antibody. Preclinical data demonstrated that S095029 combined with Sym021 increases antitumor activity.</p><p><strong>Methods: </strong>This first-in-human, open-label, multicenter study (NCT05162755) evaluated safety, tolerability, preliminary efficacy, pharmacokinetics and pharmacodynamics (PD) of S095029 as monotherapy or in combination with Sym021 in patients with advanced solid tumors. Monotherapy regimen included two doses of S095029 every 2 weeks (Q2W) followed by single-agent Sym021 (Q2W). Adverse events were defined per Common Terminology Criteria for Adverse Events V.5.0. Antitumor activity was evaluated per Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1. Cytokine secretion as PD markers and target engagement/receptor occupancy were assessed in peripheral blood. Selected immune markers were assessed by multiplex immunofluorescence on tumor biopsies.</p><p><strong>Results: </strong>As of July 25, 2025, 21 patients with heavily pretreated solid tumors were treated with S095029 as a single agent (10, 30, 100, 300, 750 and 1,500 mg) and 20 patients were treated with S095029 (30, 100, 300, 750 and 1,500 mg) in combination with Sym021 (200 mg). S095029 was well tolerated without dose-limiting toxicities for both monotherapy and combination with anti-PD-1. A maximum tolerated dose was not reached. Two patients (9.5%; uterine sarcoma, porocarcinoma) who received one cycle of S095029 monotherapy followed by Sym021 and two patients (10%; leiomyosarcoma, squamous cell carcinoma of unknown primary) who received S095029 in combination with Sym021 showed confirmed partial responses. None of these patients had received prior anti-PD-1 treatment. The clinical benefit rate (complete response+partial response+stable disease ≥6 months) by RECIST V.1.1 in all enrolled patients was 19.5%. S095029 serum concentrations increased with dose for both monotherapy and combination with Sym021. Full receptor occupancy was achieved starting at 30 mg Q2W. Increases in levels of monokine induced by gamma interferon, macrophage inflammatory protein 1-beta and tumor necrosis factor-α in peripheral blood were detected following treatment with S095029+Sym021 suggesting immune cell activation on treatment.</p><p><strong>Conclusions: </strong>The anti-NKG2A antibody S095029 in combination with anti-PD-1 Sym021 demonstrated a favorable safety profile and exhibited signal of antitumor activity in unselected, heavily pretreated patients with advanced malignancies.</p><p><strong>Trial registration number: </strong>NCT05162755.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 5","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PSCA CAR Vδ1 T cells: a safer off-the-shelf CAR T therapy for pancreatic cancer?","authors":"Joseph A Fraietta, Jason J Lohmueller","doi":"10.1136/jitc-2025-014088","DOIUrl":"https://doi.org/10.1136/jitc-2025-014088","url":null,"abstract":"<p><p>Pancreatic cancer remains among the deadliest malignancies, with a 5-year survival of ~13%. Chimeric antigen receptor (CAR) T -cell therapy offers hope, but conventional αβ T cells can trigger severe toxicities, including graft-versus-host disease (GvHD) when used for allogeneic therapy. By contrast, γδ T cells recognize tumors without MHCmajor histocompatibility complex restriction and are unlikely to cause GvHD, making them attractive candidates for \"off-the-shelf\" immunotherapy. Li <i>et al</i> engineered the Vδ1 subset of γδ T cells with a CAR targeting prostate stem cell antigen (PSCA) and compared these cells to CAR-engineered Vδ2 γδ and conventional αβ T cells in preclinical pancreatic cancer models. All three groups showed comparable tumor killing efficacy, but the CAR Vδ1 T cells induced none of the GvHD or systemic toxicity seen with CAR αβ T cells. They also displayed lower exhaustion than CAR Vδ2 cells, suggesting potential for greater persistence. Vδ1 CAR T cells could be expanded robustly ex vivo and remained highly potent even after cryopreservation, a key \"off-the-shelf\" requirement. These findings position CAR Vδ1 T cells as a safer alternative to traditional CAR T cells. Future rigorous clinical evaluation will be needed to confirm superior safety and efficacy of this promising approach in patients.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 5","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sensory neuron-derived CCL5 orchestrates an immunosuppressive niche via regulatory T cells to fuel head and neck tumor progression.","authors":"Kailiu Wu, Zhen Zhang, Xing Qin, Guanying Feng, Huasheng Li, Ruiyu Guo, Yuhua Hu, Yikang Ji, Yang Wang, Ming Yan, Chenping Zhang","doi":"10.1136/jitc-2025-013958","DOIUrl":"https://doi.org/10.1136/jitc-2025-013958","url":null,"abstract":"<p><strong>Background: </strong>Perineural invasion (PNI) is a hallmark of malignancy in solid tumors, including oral squamous cell carcinoma (OSCC), and is closely associated with poor prognosis. Emerging evidence suggests a critical association between PNI and the tumor immune microenvironment (TME).</p><p><strong>Methods: </strong>In this study, we used spatial transcriptomics, in vitro and in vivo experiments, and clinical specimen validation to systematically study the interplay between neural infiltration and immune modulation in OSCC.</p><p><strong>Results: </strong>Our results suggest that intratumoral nerves may enhance the recruitment of regulatory T cells (Tregs) through C-C motif chemokine ligand 5 (CCL5)-mediated chemotaxis and further promote the acquisition of an immunosuppressive phenotype in Tregs by activating the RAMP1 signaling pathway. Through these coordinated mechanisms, neural components in the TME contribute to immune suppression and facilitate tumor progression. Therapeutically, both combination of CCL5 blockade with anti-CTLA-4 antibody and the combination of RAMP1 blockade with anti-PD-1 antibody exhibited significantly enhanced anti-tumor efficacy.</p><p><strong>Conclusions: </strong>This study highlights a previously underappreciated neural-Treg axis in the TME and provides new insights into potential combinatorial strategies for cancer immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 5","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LGALS9 blockade augments vaccine-induced immune responses against prostate cancer.","authors":"Bowen Lu, Ning Liu, Wanting Zhao, Haomin Chen, Yingxiang Shao, Haosen Lu, Shanshan Liu, Jie Yang, Yanyan Zheng, Jiage Ding, Dafei Chai, Lijun Mao","doi":"10.1136/jitc-2025-014141","DOIUrl":"https://doi.org/10.1136/jitc-2025-014141","url":null,"abstract":"<p><strong>Background: </strong>Prostate-specific membrane antigen (PSMA)-based vaccination represents a promising immunotherapeutic strategy for prostate cancer; however, its efficacy remains constrained by tumor-induced immune evasion and insufficient activation of antigen-presenting cells. Galectin-9 (LGALS9), an immunoregulatory lectin that contributes to immune suppression, is therefore an attractive target for overcoming tumor-induced immune tolerance.</p><p><strong>Methods: </strong>Recombinant adenoviral vaccines encoding PSMA and LGALS9 (Ad-PSMA and Ad-LGALS9) were generated and validated for antigen expression in vitro and in vivo. Therapeutic efficacy was evaluated in murine subcutaneous, bone metastatic, and humanized prostate cancer models. Vaccine-induced immune responses were characterized by flow cytometry, ELISA, enzyme-linked immunospot (ELISpot), immunohistochemistry, EdU proliferation assays, cytotoxic T lymphocyte assays, and cell depletion experiments.</p><p><strong>Results: </strong>Pre-immunization with Ad-LGALS9 significantly potentiated the therapeutic efficacy of the Ad-PSMA vaccine in subcutaneous, bone metastatic, and humanized prostate cancer models, resulting in pronounced tumor growth inhibition and prolonged survival. Mechanistically, LGALS9 targeting enhanced dendritic cell (DC) activation and maturation, upregulating CD80, CD86, major histocompatibility complex-II, and CD40 expression and promoting efficient antigen cross-presentation. This facilitated robust priming and expansion of multifunctional CD8⁺ T cells producing interferon-γ, interleukin-2, and tumor necrosis factor-α, which mediated potent cytotoxicity against PSMA-expressing tumor cells. Furthermore, LGALS9 immunization induced high-titer neutralizing antibodies that disrupted the LGALS9/TIM-3 inhibitory axis, alleviating T-cell exhaustion. Combined Ad-LGALS9/PSMA vaccination established durable memory CD8⁺ T-cell responses that conferred protection against tumor rechallenge.</p><p><strong>Conclusions: </strong>Targeting LGALS9 enhances DC-mediated CD8⁺ T-cell immunity and synergistically augments the therapeutic efficacy of tumor vaccines, representing a promising immunotherapeutic strategy for prostate cancer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 5","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endogenous neoantigen-specific antibodies mediate antitumor responses and determine vaccine efficacy.","authors":"Sirajbir S Sodhi, John S Wang, David T Severson, Joey V Ragusa, Nicole Moon, Timothy Trotter, Li-Chung Tsao, Herbert Kim Lyerly, Zachary Conrad Hartman","doi":"10.1136/jitc-2025-014671","DOIUrl":"https://doi.org/10.1136/jitc-2025-014671","url":null,"abstract":"<p><strong>Background: </strong>The contribution of B cells to antitumor immunity remains controversial, with studies reporting varied effects across cancer types. Even less is known about the role of the endogenous humoral response, including when tumor-elicited antibodies are protective, when they are deleterious, and how they might be modulated to influence antitumor immunity. Critically, it remains unclear whether specific antigenic features govern the efficacy of humoral immune responses against cancer. We aim to define the conditions under which endogenous antibodies mediate antitumor immunity and to leverage these principles to improve neoantigen-directed immunotherapies, including cancer vaccines.</p><p><strong>Methods: </strong>We performed a pan-cancer analysis of The Cancer Genome Atlas (TCGA) to assess associations between intratumoral IgG and clinical outcomes. Using syngeneic mouse tumor models expressing membrane or cytoplasmic neoantigens, we examined how antigen localization influences endogenous antibody responses. We evaluated strategies to enhance humoral immunity via cytokine and chemokine modulation and assessed antibody responses in the context of cancer vaccination.</p><p><strong>Results: </strong>Our pan-cancer TCGA analysis revealed marked heterogeneity in the prognostic impact of intratumoral IgG. In vivo, expression of membrane-localized, but not cytoplasmic, neoantigens drove potent class-switched IgG responses, activated myeloid cells, and restricted tumor growth independently of CD8 T cells. Notably, membrane-restricted antigen expression was sufficient to convert tumor types such as colorectal cancer, where IgG correlates with poor prognosis, into settings in which antibodies mediate tumor suppression. These effects required CD4 T-cell help, antigen-specific IgG, and Fc receptor engagement. Enhancing B-cell recruitment (C-X-C motif chemokine ligand 13) or B-cell help (interleukin (IL)-21) further amplified antibody-mediated tumor control, with co-expression providing the strongest benefit. Finally, we establish that antigen localization dictates vaccine efficacy: the point-mutated trophoblast cell-surface antigen 2 (Trop2) T256R, which exhibits impaired membrane localization and reduced antibody binding relative to wild-type Trop2, failed to elicit comparable vaccine-induced tumor control.</p><p><strong>Conclusions: </strong>These findings identify antigen subcellular localization as a key regulator of endogenous antibody-mediated antitumor immunity and cancer vaccine efficacy, providing a mechanistic framework for leveraging humoral immunity in immunotherapeutic strategies. CXCL13 and IL-21 emerge as candidate approaches to selectively enhance antibody-mediated tumor control in settings where membrane-bound antigens are present.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 5","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147838117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correlation between recognition of autologous tumor organoids by tumor-infiltrating lymphocytes from metastatic epithelial cancers and clinical response.","authors":"Alexandra M Gustafson, Aarushi Bhasin, Billel Gasmi, Brian D Bui, Catherine Marie Ade, Ken-Ichi Hanada, Hyunmi K Halas, Jared J Gartner, Todd D Prickett, Jon Salazar, Maria R Parkhust, Paul Robbins, Nicholas D Klemen, Mei Li Kwong, Stephanie L Goff, Steven A Rosenberg, James C Yang","doi":"10.1136/jitc-2025-014644","DOIUrl":"10.1136/jitc-2025-014644","url":null,"abstract":"<p><strong>Background: </strong>Neoantigen-specific tumor-infiltrating lymphocytes (TILs) have the ability to mediate responses in patients with metastatic epithelial cancers. While some identified factors are associated with response, there is a need for ways to determine which patients will benefit from adoptive cell therapy with TIL. Patient-derived tumor organoids (PDTO) retain the genetic makeup of the tumor from which they are derived, and are a useful tool in personalized medicine to test the effectiveness of anticancer therapies.</p><p><strong>Methods: </strong>Tumor organoids were grown from patients with metastatic epithelial cancers treated on a TIL protocol. TIL recognition of autologous PDTO by enzyme-linked immunosorbent spot assays and 4-1BB upregulation, as well as objective Response Evaluation Criteria in Solid Tumors (RECIST) responses to treatment, were measured in a cohort of treated patients. The most common histologies were colorectal (20 patients, 67%), pancreatic (4 patients, 13%), and breast (2 patients, 7%) cancer.</p><p><strong>Results: </strong>Recognition of PDTO was driven by major histocompatibility complex (MHC) class I-restricted reactivity and upregulation of MHC in response to interferon-γ was not associated with response. There were no responders in the 9 patients who lacked PDTO recognition on their initial TIL screening compared with seven responses in 18 patients with initial reactivity (p=0.059). After TIL were selected and expanded for administration, 15 infusion products showed organoid recognition, with 8 of these patients achieving objective responses (53%), while only 1 of 15 patients without organoid recognition responded (7%; p=0.014).</p><p><strong>Conclusions: </strong>TIL reactivity against autologous tumor organoid appears to be associated with objective clinical response in patients with metastatic epithelial cancers.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 5","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13150870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147838120","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":"Characterization of aberrant alternative splicing landscape in patients with metastatic renal cell carcinoma.","authors":"Ameish Govindarajan, Nathaniel Hansen, Benjamin D Mercier, Sara A Byron, Apurva Hegde, Krystine Garcia-Mansfield, Kristin Leskoske, Neal Chawla, Luis Meza, Zeynep Zengin, Regina Barragan-Carillo, Hedyeh Ebrahimi, Daniela V Castro, Nazli Dizman, JoAnn Hsu, Alexander Chehrazi-Raffle, Abhishek Tripathi, Nicholas J Salgia, Sumanta K Pal, Patrick Pirrotte","doi":"10.1136/jitc-2025-012427","DOIUrl":"10.1136/jitc-2025-012427","url":null,"abstract":"<p><strong>Purpose: </strong>Aberrant alternative splicing (AS) events have been implicated in cancer progression; however, their role in metastatic renal cell carcinoma (mRCC) remains underexplored. This study aims to identify AS events associated with clinical benefits from immune checkpoint inhibitors and targeted therapies in mRCC.</p><p><strong>Materials and methods: </strong>We conducted a retrospective analysis on 101 patients with mRCC who received systemic therapy and underwent RNA sequencing. Patients were divided into subgroups based on ICIs (alone or in combination) and targeted therapies. Responders and non-responders were classified according to Response Evaluation Criteria in Solid Tumors V.1.1 criteria. Differential gene expression and splicing analyses were performed between responders and non-responders in each cohort. Novel AS events were analyzed for their potential to generate peptide neoantigens through major histocompatibility complex (MHC) class I binding predictions.</p><p><strong>Results: </strong>Outlier splicing analysis identified 10 aberrant splice events specific to mRCC. AS analysis revealed 461 differentially spliced events between responders and non-responders in the ICI cohort and 253 in the targeted therapy cohort, with intron retention as the predominant motif. Thirteen unique AS events were enriched in responders, including <i>PTPN6</i> and <i>ACTN1</i>. Predictive neoantigen analysis identified high MHC class I binding potential in peptides from AS events in <i>IFFO1</i> and <i>ZNF692</i>. High splice burden was linked to an immunogenic tumor microenvironment, characterized by enriched antigen processing and adaptive immune responses.</p><p><strong>Conclusions: </strong>This study provides a comprehensive analysis of AS events in mRCC, highlighting intron retention as potential biomarkers for treatment response. Identified AS-derived neoantigens may serve as potential targets for adoptive cell therapy strategies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 5","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13150895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147838084","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":"Discontinuation of combo immunotherapy and outcome of patients with melanoma brain metastases.","authors":"Mario Mandalà, Monica F Chen, Ryan J Sullivan, Maria Chiara Sergi, Michael Postow, Aleigha R Lawless, Derek Effiom, Tobias Peres, Paul C Lorigan, Patricio Serra-Bellver, Reinhard Dummer, Teresa Amaral, Marie-Lena Rasch, Diana Giannarelli, Maria Grazia Vitale, Hildur Helgadottir, Caroline Robert, Martina Ubaldi, Douglas B Johnson, Michele Del Vecchio, Alice Indini, Karijn P M Suijkerbuijk, Paul Nathan, Thomas Carter, Bart Neyns, Iris Dirven, Ines Pires da Silva, Alexander Maxwell Menzies, Lisa Zimmer, Elisabeth Livingstone, Roberta Depenni, Katharina Kähler, Axel Hauschild, Francesco Spagnolo, Anna Maria Di Giacomo, Ana Arance, Barbara Merelli, Pietro Quaglino, Ernesto Rossi, Marco Tucci, Michele Guida, Eva Muñoz-Couselo, Georgina V Long, James Larkin, Paolo A Ascierto","doi":"10.1136/jitc-2026-015063","DOIUrl":"https://doi.org/10.1136/jitc-2026-015063","url":null,"abstract":"<p><strong>Background: </strong>Nivolumab plus ipilimumab (COMBO) is the standard treatment for asymptomatic melanoma brain metastases (MBM), but current guidelines do not provide specific recommendations for treatment discontinuation in responding patients. This study aimed to evaluate outcomes after COMBO discontinuation within 24 months and the role of continuing treatment beyond 24 months.</p><p><strong>Methods: </strong>Patients with MBM treated with COMBO who discontinued treatment within 24 months for reasons other than disease progression or continued beyond this time point were retrieved. Overall survival (OS), objective response, progression-free survival (PFS) and toxicities were analyzed.</p><p><strong>Results: </strong>465 patients were included: 392 discontinued COMBO within 24 months, while 73 continued beyond 24 months. Treatment was discontinued due to complete response (CR, n=47), partial response (PR, n=45), stable disease (SD, n=12), toxicity after SD (n=59), toxicity after CR (n=99), or toxicity after PR (n=130). At multivariable analysis, the line of treatment (>first vs first: HR 2.65 (1.62-4.32)), the immune-related adverse events (irrespective of anti-tumor necrosis factor-alpha) (HR 0.18 (0.07-0.42)); COMBO discontinuation after CR (HR 0.15 (0.05-0.40)), or PR (HR 0.08 (0.03-0.26)), as well as stopping due to toxicity after CR (HR 0.14 (0.07-0.27)) or PR (HR 0.51 (0.32-0.82)), were associated with OS. Notably, at a median follow-up of 51 months (IQR 31-70), patients with CR/PR who discontinued COMBO within 24 months had PFS and OS comparable to those who continued treatment beyond this time point. 4-year OS exceeded 83% in patients discontinuing COMBO after CR, PR, or toxicity following CR, compared with 66.4% in those discontinuing due to toxicity after PR; median PFS was not reached in the former groups but was 18.6 months in the toxicity after PR group.</p><p><strong>Conclusion: </strong>Discontinuation of COMBO within 24 months appears safe in patients with CR and in selected cases of PR, with no survival disadvantage versus prolonged therapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 5","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13141176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147838110","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-engineering of innate and innate-like immune cells: a new horizon in adoptive cell therapy for solid tumors.","authors":"Giuseppe Nardo, Francesca Putti, Alice Indini, Michele Del Vecchio, Filippo De Braud, Massimo Di Nicola, Francesca De Santis","doi":"10.1136/jitc-2025-014592","DOIUrl":"https://doi.org/10.1136/jitc-2025-014592","url":null,"abstract":"<p><strong>Background: </strong>Chimeric antigen receptor (CAR) therapies have revolutionized cancer immunotherapy, particularly in hematologic malignancies, but their efficacy in solid tumors remains limited. Key barriers include tumor antigen heterogeneity, on-target/off-tumor toxicity, impaired trafficking, and an immunosuppressive tumor microenvironment.</p><p><strong>Methods: </strong>We conducted a narrative review of preclinical and clinical studies investigating CAR-engineered innate and innate-like immune cells, including CAR-natural killer, CAR-γδ T, CAR-natural killer T (NKT), and CAR-macrophages, focusing on their biological features, therapeutic potential, and current clinical development in solid tumors.</p><p><strong>Results: </strong>These alternative platforms exhibit distinct advantages over conventional CAR-T cells, including reduced risk of severe toxicities, improved trafficking, overcoming antigen loss, and higher allogeneic potential. Emerging clinical data suggest favorable safety profiles, although limited persistence and variable efficacy remain key challenges. Advances in cell engineering, such as cytokine armoring and non-viral gene transfer, are further enhancing their therapeutic potential.</p><p><strong>Conclusions: </strong>CAR-engineered innate and innate-like immune cells represent a promising next-generation strategy to overcome the limitations of conventional CAR-T therapies in solid tumors. Among these, CAR-NKT and CAR-γδ T cells may offer particular advantages for clinical translation, warranting further investigation in future trials.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 5","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13140957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147838054","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}