Journal for Immunotherapy of Cancer最新文献

{"title":"Allele-specific HLA LOH in solid tumors: distinct patterns by tumor type and potential prognostic relevance.","authors":"Tomasz Sewastianik, Christian Roy, Michael V Gormally, Meagan Montesion, Patrick Halvey, Aastha Jindal, Hubert Lam, Adam Schoenfeld, Christopher A Klebanoff, Gregory J Opiteck, Dirk Nagorsen","doi":"10.1136/jitc-2025-012435","DOIUrl":"10.1136/jitc-2025-012435","url":null,"abstract":"<p><p>T-cell receptors (TCRs) recognize antigens derived from fragments of somatically expressed proteins that are degraded by the proteasome and presented by specific human leukocyte antigen (HLA) molecules. Recent therapeutic advances using the TCR as a tumor-targeting moiety have focused attention on <i>HLA</i> loss of heterozygosity (LOH) as a potential resistance mechanism. Allele-specific LOH, rather than allele-agnostic, is particularly pertinent, but rarely evaluated. Using a real-world dataset comprising 78,418 cases, we demonstrate that allele-specific LOH occurs at a relatively low frequency (<10%) across all patients with cancer. We observed a modest increase in allele-specific <i>HLA</i> LOH in cancers harboring associated neoantigen driver mutations (eg, <i>KRAS</i> or <i>TP53</i> mutations), but the overall frequency remained consistently low. Furthermore, using an orthogonal dataset, we integrated clinical outcomes with <i>HLA</i> LOH and identified distinct impacts on overall survival in colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) cohorts. For instance, <i>A*02:01</i>-specific LOH was linked to worse survival in CRC (HR 0.5355, 95% CI 0.2991 to 0.9589, p=0.0094) but showed a trend toward improved survival in NSCLC (HR 1.249, 95% CI 0.7778 to 2.005). These findings underscore the relevance of allele-specific <i>HLA</i> LOH assessments and reveal nuanced differences in its clinical implications, which should be accounted for in the optimization of TCR-based immunotherapies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033357","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":"Comparative efficacy and safety of PSCA CAR-engineered Vδ1 γδ T cells for immunotherapy of pancreatic cancer.","authors":"Zhixin Li, Ningyuan Liu, Zahir Shah, Lewei Jin, Lei Tian, Xiaolei Sun, Jianying Zhang, Zhiyao Li, Michael A Caligiuri, Jianhua Yu","doi":"10.1136/jitc-2025-011890","DOIUrl":"10.1136/jitc-2025-011890","url":null,"abstract":"<p><strong>Background: </strong>γδ T cells possess unique immunological features including tissue tropism, major histocompatibility complex-independent antigen recognition, and hybrid T/natural killer cell properties that make them promising candidates for cancer immunotherapy. However, the therapeutic potential of Vδ1 γδ T cells, particularly when engineered with chimeric antigen receptors (CARs), remains underexplored in solid tumors such as pancreatic cancer (PC), largely due to their low abundance in peripheral blood and challenges in ex vivo expansion. This study aims to directly compare the preclinical safety and efficacy among CAR-engineered Vδ1 γδ T cells, Vδ2 γδ T cells, and conventional αβ T cells.</p><p><strong>Methods: </strong>We developed a CAR targeting prostate stem cell antigen (PSCA) and engineered it into human blood-derived Vδ1 γδ T cells. These PSCA CAR-Vδ1 T cells were evaluated for antitumor activity against PSCA-expressing pancreatic tumor cells using both in vitro cytotoxicity assays and in vivo xenograft mouse models. Comparative analyses were conducted using PSCA CAR-Vδ1 γδ T cells, PSCA CAR-Vδ2 γδ T cells, and PSCA CAR-αβ T cells. Safety assessments of these CAR-engineered T cell subsets were conducted to evaluate graft-versus-host disease (GvHD) and cytokine release syndrome (CRS), while exhaustion profiles were assessed using single-cell RNA sequencing.</p><p><strong>Results: </strong>Our study demonstrated that PSCA CAR-Vδ1 γδ T cells, PSCA CAR-Vδ2 γδ T cells, and PSCA CAR-αβ T cells exhibited similar antitumor efficacy. However, PSCA CAR-Vδ1 T cells did not exhibit GvHD or CRS compared with CAR-αβ T cells. PSCA CAR-Vδ1 T cells also had lower scores for exhaustion when compared with PSCA CAR-Vδ2 T cells by single-cell transcriptomic analysis.</p><p><strong>Conclusion: </strong>PSCA CAR-Vδ1 γδ T cells represent a potent and safe therapeutic modality for PSCA⁺ PC, with efficacy comparable to other CAR T cell types and potential advantages in safety and persistence. These findings support further development of CAR-Vδ1 T cell immunotherapy for solid tumors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033393","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":"Reprogramming the immunologically cold landscape of prostate cancer through MAOA inhibition.","authors":"Anil K Singh, Boyang Jason Wu","doi":"10.1136/jitc-2025-012567","DOIUrl":"10.1136/jitc-2025-012567","url":null,"abstract":"<p><p>Prostate cancer (PC) is notoriously known for exhibiting an immunologically cold phenotype in the tumor immune microenvironment (TIME), leading to the need for interventions to enhance immunotherapy efficacy. Recent findings by Zhao <i>et al.</i> in the <i>Journal for ImmunoTherapy of Cancer</i> identified stromal monoamine oxidase A (MAOA), a key enzyme that degrades monoamine neurotransmitters and plays a role in the neuroendocrine system, as a critical regulator of the immune response to PC. Altering MAOA levels in myofibroblastic cancer-associated fibroblasts, either genetically or pharmacologically, can reprogram PC's TIME to modulate CD8⁺ T cell-mediated cytotoxicity through the WNT5A-Ca²⁺-NFATC1 signaling axis, highlighting the stromal influences on CD8⁺ T cell cytotoxic activity within the TIME. The inactivation of MAOA synergizes with immune checkpoint blockade therapies to reverse the trajectory of prostate tumor growth. This work offers a promising therapeutic avenue for PC by positioning MAOA as a stromal modulator of immune response as well as a target for combination immunotherapies. The current commentary aims to present our perspective on how a metabolic enzyme can change the immune landscape of the tumor microenvironment, what we have learned, and what we can develop in the future.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033377","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":"Tandem CAR-T cells targeting mesothelin and MUC16 overcome tumor heterogeneity by targeting one antigen at a time.","authors":"Diego Salas-Benito, Filippo Birocchi, Sangwoo Park, Cassidy E Ho, Alexander Armstrong, Aiyana L Parker, Amanda A Bouffard, Jessica A Frank, Eugene Kim, Tamina Kienka, Kiana Graham, Christopher Kelly, Sadie Goncalves, Mark B Leick, Giulia Escobar, Bo Rueda, Trisha R Berger, Marcela V Maus","doi":"10.1136/jitc-2025-012822","DOIUrl":"10.1136/jitc-2025-012822","url":null,"abstract":"<p><strong>Background: </strong>Tumor heterogeneity and antigen escape are mechanisms of resistance to chimeric antigen receptor (CAR)-T cell therapy, especially in solid tumors. Targeting multiple antigens with a unique CAR construct could be a strategy for a better tumor control than monospecific CAR-T cells on heterogeneous models. To overcome tumor heterogeneity, we targeted mesothelin (meso) and Mucin 16 (MUC16), two antigens commonly expressed in solid tumors, using a tandem CAR design.</p><p><strong>Methods: </strong>We designed a series of tandem CAR constructs based on various anti-meso (SS1) and anti-MUC16 ectodomain (MUC16ecto) (4H11) single-chain variable fragment (scFv) arrangements and G4S linker lengths. Then we determined the best tandem CAR design based on binding of soluble antigens, steric hindrance, avidity and functionality against cell lines expressing one or both antigens in vitro. Finally, we compared the tandem CAR to monospecific CAR-T cells in mixed tumor models in vitro (two-dimensional and three-dimensional models) and in vivo.</p><p><strong>Results: </strong>We show that the scFv arrangement and linker length impacted antigen binding and CAR expression in T cells. Tandem CAR configuration (TanCAR1) (with SS1 scFv located distally and one G4S repeat as the linker between scFvs) had the best binding and activation profile in vitro and outperformed SS1 and 4H11 monospecific CAR-T cells in mixed tumor models in vitro and in vivo, showing an antigen-driven killing of tumor cells based on antigen density. Moreover, acoustic force microscopy, using tumor cells with different levels of antigen expression, revealed that TanCAR1-T cells likely bind to one antigen at a time rather than simultaneously.</p><p><strong>Conclusions: </strong>This is the first time using a tandem CAR design targeting meso and MUC16, and demonstrating a benefit on tumor control over monospecific CAR-T cells. Tandem CAR-T cells targeting meso and MUC16ecto could be employed as a strategy to overcome tumor cell heterogeneity in ovarian and pancreatic tumors, and may help to design therapeutic approaches relying on its one-antigen-at-a-time binding properties and on its antigen-driven killing of tumor cells based on antigen density.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033382","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":"Randomized clinical efficacy and safety study of peltopepimut-S plus cemiplimab compared to cemiplimab alone in patients with recurrent/metastatic HPV16-positive head and neck cancer.","authors":"Caroline Even, Kevin J Harrington, Erminia Massarelli, Simon Laban, Jérôme Fayette, Marc Oliva, Marielle Klein Hesselink, Sonja Visscher, Matthew G Fury, Anna-Sophia Wiekmeijer, Lisa Licitra, Bohuslav Melichar, Lot A Devriese, Irene Braña, Petra Jankowska, Marshall Posner, Bonnie Glisson, Anthony Kong, Leon Hooftman, Cornelis J M Melief, Renata Ferrarotto","doi":"10.1136/jitc-2025-012555","DOIUrl":"10.1136/jitc-2025-012555","url":null,"abstract":"<p><strong>Background: </strong>Peltopepimut-S is a therapeutic vaccine, which induces specific expansion of both CD4+helper and CD8+cytotoxic T-cells against human papillomavirus type 16 (HPV16) E6/E7 oncoproteins.</p><p><strong>Patients and methods: </strong>In a randomized phase 2 trial, we evaluated the efficacy and safety of peltopepimut-S plus cemiplimab compared with cemiplimab alone as first-line or second-line therapy in recurrent/metastatic HPV16-positive head and neck cancer. The primary efficacy endpoint was the objective response rate (ORR) by an independent review (Response Evaluation Criteria in Solid Tumors version 1.1, RECIST v1.1), while the primary safety endpoint was frequency and severity of adverse events. Secondary endpoints included progression-free survival (PFS) and overall survival (OS).</p><p><strong>Results: </strong>Overall, 198 anti-programmed cell death protein-1 therapy-naïve patients with confirmed HPV16-positive recurrent/metastatic oropharyngeal cancer were randomized to receive cemiplimab plus peltopepimut-S (n=100) or placebo (n=99). The trial did not meet its primary objective (ORR, 25.3% in peltopepimut-S arm vs 22.9% in placebo arm; p=0.735). The median OS (mOS) and PFS in the placebo arm were unexpectedly longer than in the peltopepimut-S arm (26.9 vs 15.8 months) and (20.3 vs 5.5 months), respectively. In predefined exploratory analyses this was associated with an excess death rate from progressive disease in patients with pre-treatment programmed death-ligand 1 (PD-L1) combined positive score (CPS) <20. In contrast, patients with CPS ≥20 had a higher ORR of 51.7% (95% CI, 32.5% to 70.6%) vs 25.8% (95% CI, 11.9% to 44.6%) and a longer mOS in the peltopepimut-S arm (34.8 vs 28.8 months) compared with the placebo arm, respectively. If patients had received all three vaccine or placebo doses, the ORR in patients with CPS ≥20 was 70.0% (95% CI, 45.7% to 88.1%) vs 29.2% (95% CI, 12.6% to 51.1%) in the peltopepimut-S arm and placebo arms, respectively, associated with mOS not reached (after 42 months) versus 23.3 months. The addition of peltopepimut-S to cemiplimab did not increase cemiplimab's toxicity.</p><p><strong>Conclusion: </strong>Adding peltopepimut-S to cemiplimab did not improve ORR and worsened mOS in the primary analysis. Divergent outcomes were seen in patients with pretreatment PD-L1 CPS <20 (worse ORR and mOS compared with placebo) and CPS ≥20 (higher ORR and longer mOS compared with placebo) values. Future drug development is justifiable in the CPS ≥20 patient population.</p><p><strong>Trial registration number: </strong>NCT03669718.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023318","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":"CD33^KO-CD33-mesothelin Loop CAR design avoids fratricide and improves efficacy of iNK cells against acute myeloid leukemia.","authors":"Yao Wang, Xiujuan Zheng, Zhiqian Wang, Ziyun Xiao, Yunqing Lin, Fan Zhang, Yanhong Liu, Pengcheng Liu, Qitong Weng, Leqiang Zhang, Chengxiang Xia, Dehao Huang, Lijuan Liu, Yanping Zhu, Qi Zhang, Hanmeng Qi, Yi Chen, Yiyuan Shen, Chenyuan Zhang, Jiacheng Xu, Yaoqin Zhao, Jiaxin Wu, Tongjie Wang, Mengyun Zhang, Minming Li, Wenbin Qian, Aibin Liang, Xin Du, Wenyu Yang, Tianyuan Hu, Qi Chen, Xiaofan Zhu, Fangxiao Hu, Jinyong Wang","doi":"10.1136/jitc-2025-011887","DOIUrl":"10.1136/jitc-2025-011887","url":null,"abstract":"<p><strong>Background: </strong>Patients with acute myeloid leukemia (AML) are often older, which brings challenges of endurance and persistent efficacy of autologous chimeric antigen receptor (CAR)-T cell therapies. Allogenic CAR-natural killer (NK) cell therapies may offer reduced toxicities and enhanced anti-leukemic potential against AML. CD33 CAR-NK cells have been investigated for AML therapy. However, the fratricide-mediated lysis of CD33-expressing NK cells by CD33 CAR-NK cells limits the expansion and efficacy of CD33 CAR-NK cells. Mesothelin (MSLN), a tumor differentiation antigen, is highly expressed in a fraction of patients with AML, making it a promising target for AML therapy.</p><p><strong>Methods: </strong>We designed a novel CD33-MSLN Loop CAR (Loop CAR) and evaluated its antitumor efficacy in human umbilical cord blood-derived NK (UCB-NK) cells and human pluripotent stem cell-derived NK (hPSC-iNK) cells. To further avoid fratricide caused by endogenous CD33 expression in NK cells, we established an hPSC-derived cell line via knockout of the <i>CD33</i> gene (CD33^KO) and engineered Loop CAR. We generated CD33^KO-Loop CAR-iNK cells using an organoid induction approach. The efficacy of CD33^KO-Loop CAR-iNK cells against tumor cells expressing CD33 and MSLN was investigated both in vitro and in AML xenograft mice.</p><p><strong>Results: </strong>Loop CAR-NK cells exhibited superior cytotoxicity against dual-antigen-positive tumor cell lines and primary AML cells compared with CD33 CAR-NK and MSLN CAR-NK cells. Moreover, Loop CAR-NK cells showed upregulated signaling pathways related to NK cell activation and cytotoxic function. The loss of CD33 in iNK cells effectively avoided fratricide, improved expansion ability, and significantly enhanced CD33 and MSLN-mediated specific cytotoxicity of Loop CAR-iNK cells. Moreover, the CD33^KO-Loop CAR-iNK cells demonstrated superior tumor-killing activity in AML xenograft mouse models and significantly prolonged mouse survival.</p><p><strong>Conclusion: </strong>Loop CAR empowered both UCB-NK cells and hPSC-iNK cells with superior cytotoxicity against CD33⁺MSLN⁺ tumor cells. Genetic disruption of CD33 avoided fratricide and improved efficacy of Loop CAR-iNK cells against AML. This innovative strategy possesses unique advantages and translational potential for treating AML.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023358","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":"Differential phagocytosis induces diverse macrophage activation states in malignant gliomas.","authors":"Senthilnath Lakshmanachetty, Kent Riemondy, Bridget Sanford, Andrew Donson, Vincent Chen, Ilango Balakrishnan, Eric W Prince, Todd Hankinson, Nathan Dahl, Rajeev Vibhakar, Nicholas Foreman, Sujatha Venkatraman, Siddhartha S Mitra","doi":"10.1136/jitc-2025-012211","DOIUrl":"10.1136/jitc-2025-012211","url":null,"abstract":"<p><strong>Background: </strong>Diffuse midline glioma (DMG) and glioblastoma (GBM) are aggressive brain tumors with limited treatment options. Macrophage phagocytosis is a complex, tightly regulated process governed by competing pro-phagocytic and anti-phagocytic signals. CD47-SIRPα signaling inhibits macrophage activity, while radiotherapy (RT) can enhance tumor immunogenicity. How RT and CD47 blockade together modulate macrophage \"appetite\" and activation states remains poorly understood, particularly in the context of glioma immune evasion and therapy resistance.</p><p><strong>Methods: </strong>Human and mouse glioma cell lines were exposed to fractionated RT, anti-CD47 monoclonal antibody, or both. Flow cytometry and ELISA quantified the induction of immunogenic cell death (ICD) and expression of damage-associated molecular patterns (DAMPs). In vitro, phagocytosis assays were performed using peripheral blood mononuclear cell-derived and bone marrow-derived macrophages. Single-cell RNA sequencing (scRNA-seq) was used to analyze transcriptional changes in macrophage subsets that phagocytosed (\"eaters\") or did not phagocytose (\"non-eaters\") glioma cells. In vivo, efficacy of combination therapy was assessed using orthotopic xenograft and syngeneic mouse models of DMG and GBM.</p><p><strong>Results: </strong>RT induced ICD in glioma cells, evidenced by dose-dependent increases in DAMPs such as phosphatidylserine, calreticulin, HSP70/90, and HMGB1. RT and anti-CD47 each promoted macrophage-mediated phagocytosis, with a synergistic effect observed when combined. scRNA-seq of phagocytic macrophages revealed transcriptionally distinct subpopulations associated with each treatment, characterized by enrichment in inflammatory, metabolic, and antigen presentation pathways. In vivo, combination therapy significantly reduced tumor burden, extended survival, and polarized tumor-associated macrophages toward a pro-inflammatory (M1-like) phenotype. Distinct macrophage markers (CLEC7A, CD44, CD63) validated scRNA-seq findings in vivo.</p><p><strong>Conclusions: </strong>This study highlights that macrophage fate is intimately linked to the molecular properties of what they phagocytose. Phagocytosis is not a singular, uniform process but a dynamic and context-dependent event that drives macrophage specialization and plasticity. By demonstrating that RT and anti-CD47 therapy shape distinct macrophage phenotypes through their effects on tumor immunogenicity, this study provides a framework for understanding how to harness and reprogram macrophage activity for therapeutic benefit. These findings underscore the potential of targeting macrophage plasticity as a strategy to enhance antitumor immunity and improve outcomes in malignant gliomas and other diseases.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006180","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":"High transposable element expression in sarcomas is associated with increased immune infiltrates and improved outcomes including after immunotherapy.","authors":"Benjamin A Nacev, Martina Bradic, Hyung Jun Woo, Allison L Richards, Ciara M Kelly, Mark A Dickson, Mrinal M Gounder, Mary L Keohan, Ping Chi, Sujana Movva, Robert G Maki, Emily K Slotkin, Evan Rosenbaum, Viswatej Avutu, Jason E Chan, Lauren B Banks, Travis Adamson, Samuel Singer, Cristina R Antonescu, William D Tap, Mark Ta Donoghue, Sandra P D'Angelo","doi":"10.1136/jitc-2025-012357","DOIUrl":"10.1136/jitc-2025-012357","url":null,"abstract":"<p><strong>Background: </strong>Response to immune checkpoint inhibition (ICI) in sarcomas is overall low and heterogeneous. Understanding determinants of ICI outcomes may improve efficacy and patient selection. Thus, we investigated whether the expression of transposable elements (TEs), which are epigenetically silenced and can stimulate antitumor immunity, influence ICI outcomes and immune infiltrates in common sarcoma subtypes.</p><p><strong>Methods: </strong>We used transcriptomic data to assign immune enhanced versus immune depleted status to 67 pretreatment and on-treatment biopsies of sarcomas from patients treated on ICI trials, along with additional cohorts from The Cancer Genome Atlas (TCGA) and an independent ICI trial (SARC028). A machine learning technique (lasso-penalized logistic regression) controlled for sarcoma subtype was used to determine if TE and epigenetic regulatory gene expression predict immune infiltrates. Correlations between top features in these models and sarcoma immune infiltrates, immune pathway expression, and clinical outcomes were explored.</p><p><strong>Results: </strong>Expression of TEs and epigenetic regulators significantly predicted immune enhanced status. TE subfamilies and Ikaros family zinc finger 1 (<i>IKZF1</i>), a chromatin-modulating transcription factor, were significantly contributory. TE and <i>IKZF1</i> expression positively correlated with tumor immune infiltrates, inflammatory pathways, and improved clinical outcomes, and increased in tumors that gained immune infiltrates during ICI treatment. TE and <i>IKZF1</i> expression similarly correlated with overall survival and immune features in a TCGA cohort. In an additional cohort of patients with sarcoma treated with ICI, <i>IKZF1</i> expression correlated with progression-free survival and inflammatory features.</p><p><strong>Conclusions: </strong>TE and <i>IKZF1</i> expression warrant further translational investigation as potential biomarkers of tumor immune infiltrates and outcomes following ICI treatment, and as therapeutic targets in sarcomas.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006113","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":"The spontaneous neoantigen-specific CD4⁺ T-cell response to a growing tumor is functionally and phenotypically diverse.","authors":"Ryan Q Griswold, Spencer E Brightman, Karla Soria Zavala, Manuel Azaid Ordaz-Arias, Navid Djassemi, Rukman R Thota, Martin S Naradikian, Hannah Dose, Suzie Alarcon, Pandurangan Vijayanand, Bjoern Peters, Aaron M Miller, Ezra E W Cohen, Stephen P Schoenberger","doi":"10.1136/jitc-2025-012209","DOIUrl":"10.1136/jitc-2025-012209","url":null,"abstract":"<p><strong>Background: </strong>CD4⁺ T cells play a critical role in the positive and negative regulation of cellular immunity through the many functional subsets they comprise. The progressive growth of immunogenic tumors which nonetheless generate mutation-specific T cells suggests that effective immune control may be avoided or suppressed at the level of the neoantigen-specific CD4⁺ T-cell response. Despite their importance, little is known about the ontogeny, architecture, and development of the CD4⁺ NeoAg-specific repertoire induced by progressively growing tumor.</p><p><strong>Methods: </strong>We used a tetramer specific for a validated neoantigen, CTLC_H129>Q/I-A^k, to characterize the ontogeny of natural CD4⁺ T-cell responses to an aggressive and poorly immunogenic major histocompatibility complex class II-deficient tumor, squamous cell carcinoma VII (SCC VII), during progressive growth or following therapeutic peptide vaccination using a combination of flow cytometry, single-cell genomics, and T-cell receptor (TCR) gene engineering.</p><p><strong>Results: </strong>We find that the natural CD4⁺ T-cell response to a growing tumor is phenotypically and functionally diverse, with distinct subsets including type 1 helper, T follicular helper-like, and regulatory T cell (Treg) lineages appearing as early as 9 days after tumor implantation. Therapeutic vaccination using the CLTC_H129>Q peptide in adjuvant plus α-programmed cell death protein-1 reduces the frequency of CLTC_H129>Q-specific Treg in both tumor and tumor-draining lymph node. Single-cell transcriptomic analysis of CLTC-specific CD4⁺ T cells recapitulated and extended the diversity of the response, with TCRs of varying affinity found within each functional subset. The TCR affinity differences did not strictly correlate with function, however, as even the lowest affinity TCRs isolated from Treg can mediate therapeutic efficacy against established tumors in the setting of adoptive cellular therapy (ACT).</p><p><strong>Conclusions: </strong>These findings offer unprecedented insight into the functional diversity of a natural neoantigen-specific CD4⁺ T-cell response and show how immunotherapeutic intervention influences the phenotype, magnitude, and efficacy of the antitumor immune response. This information could lead to new approaches to immune monitoring in the clinical setting of checkpoint blockade immunotherapy and cancer vaccines. Furthermore, we show that Treg can be a potent source of TCRs that can mediate therapeutic benefit in the setting of ACT.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000667","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 evaluation of antitumor activity and toxicity of TROP2-specific CAR-T cells for treatment of triple-negative breast cancer.","authors":"Shiyu Sun, Xiaojia Wang, Yongchen Chen, Ziwei Liang, Zuomin Nian, Wanni Xu, Wenzhou Wang, Li Yan, Fei Wu, Huizi Wu, Yiwei Jia, Lu Zhang, Shuqun Zhang, Yang Xu, Xingcong Ma","doi":"10.1136/jitc-2025-012442","DOIUrl":"10.1136/jitc-2025-012442","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) represents a subtype of breast cancer with poorest prognosis due to limited effective targeted therapies. Chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable efficacy in treating hematological cancers, but its application in TNBC requires further development. One major obstacle is the lack of suitable tumor-specific target in TNBC. Inspired by recent success of trophoblast cell-surface antigen 2 (TROP2) antibody-drug conjugate in TNBC, we developed a second-generation CAR that specifically targets TROP2 and formally evaluated its antitumor activity and safety profile using in vitro and in vivo models.</p><p><strong>Methods: </strong>A CAR molecule targeting TROP2 was constructed based on the clinically-validated humanized antibody Sacituzumab and expressed in primary human T cells using a retroviral vector. Tumor cytotoxicity, cytokine production and T-cell proliferation of TROP2 CAR-T cells were tested against multiple TNBC cell lines in vitro. Antitumor efficacy was evaluated using orthotopic and metastatic models of cell line-derived xenograft in NSG mice and in patient-derived xenograft (PDX) model. The safety profile of TROP2 CAR-T cells was assessed using TROP2-humanized immunocompetent mice and an \"AND\"-logic gated SynNotch CAR targeting B7-H3 and TROP2 was engineered to minimize off-tumor, on-target toxicity of TROP2 CAR-T cells.</p><p><strong>Results: </strong>Human TROP2 CAR-T cells demonstrated robust antitumor activity in vitro and in orthotopic/metastatic/PDX xenograft mouse models. TROP2 CAR-T cells caused lethal on-target, off-tumor toxicity in TROP2-humanized immunocompetent mice, causing severe tissue damage in lungs and systemic inflammation. The B7-H3/TROP2 \"AND\"-logic gated SynNotch CAR-T cells showed comparable antitumor efficacy without causing apparent adverse effects as in TROP2 CAR-T cells.</p><p><strong>Conclusions: </strong>These data indicate that while CAR-T therapy targeting TROP2 possesses potent antitumor activity against TNBC cell lines and PDX, its potential side effects could be lethal due to TROP2 expression in vital organs such as the lung. Using an \"AND\"-logic gated CAR is a viable solution to overcome its in vivo toxicity. Our study lays the groundwork for future development of TROP2 CAR-T cell therapy for TNBC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992757","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}