Journal for Immunotherapy of Cancer最新文献

{"title":"Oncolytic viruses targeting CD47: a new road to success?","authors":"Chris H Takimoto, Michael J Wick","doi":"10.1136/jitc-2025-011550","DOIUrl":"https://doi.org/10.1136/jitc-2025-011550","url":null,"abstract":"<p><p>Clinical success in the therapeutic targeting of the CD47 signaling pathway has thus far remained elusive despite a promising scientific rationale. Use of oncolytic viruses to deliver CD47 targeting agents represents a novel approach to modulate the immunological landscape of the tumor microenvironment and to generate a systemic antitumor immune response. In recent preclinical studies, an oncolytic herpes simplex virus-1 engineered to express an inhibitory CD47-binding nanobody demonstrated promising antitumor activity. Several other oncolytic viruses engineered to express CD47 inhibitory molecules are also in preclinical development. Oncolytic viruses have the potential to mitigate drug delivery issues and may avoid systemic toxicities that have limited conventional CD47 targeting therapeutics. These novel therapeutics warrant further evaluation in clinical trials. The potential advantages, limitations, and remaining critical questions regarding this strategic approach are discussed here.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007761","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":"Correction: influenza vaccination and myocarditis among patients receiving immune checkpoint inhibitors.","authors":"","doi":"10.1136/s40425-019-0535-ycorr1","DOIUrl":"10.1136/s40425-019-0535-ycorr1","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting nerve growth factor: an Achilles' heel for tumors?","authors":"Elizabeth Repasky, Hemn Mohammadpour","doi":"10.1136/jitc-2025-011609","DOIUrl":"https://doi.org/10.1136/jitc-2025-011609","url":null,"abstract":"<p><p>A tumor's ability to attract innervation is a critical factor in tumor progression and immune escape, with the sympathetic nervous system playing a major role. Catecholamines released by sympathetic nerves activate adrenergic receptors on tumor cells, enhancing growth and resistance to therapies, while activation of adrenergic receptors on immune cells triggers immunosuppressive activity in the tumor microenvironment. Nerve growth factor (NGF) produced by tumor cells is a key driver of tumor innervation, making it a promising target for novel therapeutic strategies. In this commentary, we highlight a recent study by Yang <i>et al</i>, which examines NGF single-chain variable fragment (scFv)-secreting chimeric antigen receptor(CAR) T cells and the impact of NGF neutralization by CAR T cells on CAR T-cell function and the remodeling of the tumor microenvironment. This work shows that we may be able to exploit a tumor-derived survival factor as a vulnerability and a means to enhance antitumor immune activity.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967783","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":"Correction: Phase I study of BMS-986299, an NLRP3 agonist, as monotherapy and in combination with nivolumab and ipilimumab in patients with advanced solid tumors.","authors":"","doi":"10.1136/jitc-2024-010013corr1","DOIUrl":"https://doi.org/10.1136/jitc-2024-010013corr1","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007758","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":"FMO2⁺ cancer-associated fibroblasts sensitize anti-PD-1 therapy in patients with hepatocellular carcinoma.","authors":"Wenxin Xu, Jialei Weng, Yufei Zhao, Peiyi Xie, Minghao Xu, Shaoqing Liu, Qiang Yu, Mincheng Yu, Bugang Liang, Junbo Chen, Hui-Chuan Sun, Hui Li, Qinghai Ye, Yinghao Shen","doi":"10.1136/jitc-2025-011648","DOIUrl":"https://doi.org/10.1136/jitc-2025-011648","url":null,"abstract":"<p><strong>Background: </strong>The efficacy of immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) is limited by heterogeneity in individual responses to therapy. The heterogeneous phenotypes and crucial roles of cancer-associated fibroblasts (CAFs) in immunotherapy resistance remain largely unclear.</p><p><strong>Methods: </strong>A specific CAF subset was identified by integrating comprehensive single-cell RNA sequencing, spatial transcriptomics and transcriptome profiling of patients with HCC with different responses to antiprogrammed cell death protein 1 (anti-PD-1) therapy. Mouse orthotopic HCC models and a coculture system were constructed, and cytometry by time-of-flight analysis was performed to investigate the functions and mechanisms of specific CAFs in the immune context of HCC.</p><p><strong>Results: </strong>We identified a distinct flavin-containing monooxygenase 2 (FMO2)⁺ CAF subset associated with a favorable response to anti-PD-1 therapy and better clinical outcomes. FMO2⁺ CAFs increase anti-PD-1 treatment efficacy by promoting tertiary lymphoid structure formation and increasing the infiltration of CD8⁺ T cells and M1-like macrophages through the C-C motif chemokine ligand 19 (CCL19)-C-C motif chemokine receptor 7 axis. Mechanistically, FMO2 promotes nuclear factor kappa B/p65-mediated CCL19 expression by competitively binding to glycogen synthase 1 (GYS1) with praja ring finger ubiquitin ligase 1 (PJA1), thereby suppressing the PJA1-mediated proteasomal degradation of GYS1. CCL19 treatment potentiated the therapeutic efficacy of anti-PD-1 therapy in mouse orthotopic HCC models. A favorable immunotherapy response was observed in patients with HCC with high serum levels of CCL19.</p><p><strong>Conclusions: </strong>We identified a novel FMO2⁺ CAF subset that serves as a critical regulator of microenvironmental immune properties and a predictive biomarker of the immunotherapy response in patients with HCC. CCL19 in combination with anti-PD-1 therapy may constitute a novel therapeutic strategy for HCC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990509","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":"Combination of HDAC inhibition and cytokine enhances therapeutic HPV vaccine therapy.","authors":"Lisa K Poppe, Nicholas Roller, Miriam Marlene Medina-Enriquez, Wiem Lassoued, Daniel Burnett, Katherine E Lothstein, Asma S Khelifa, Masaya Miyamoto, James L Gulley, Caroline Jochems, Jeffrey Schlom, Sofia R Gameiro","doi":"10.1136/jitc-2024-011074","DOIUrl":"https://doi.org/10.1136/jitc-2024-011074","url":null,"abstract":"<p><strong>Background: </strong>Human papillomavirus (HPV)-associated malignancies continue to present a major health concern despite the development of prophylactic vaccines. Standard therapies offer limited benefit to patients with advanced-stage disease. Despite improved outcomes with programmed cell death protein-1 (PD-1) targeted therapies, treatment resistance and modest response rates highlight a significant unmet need to develop novel therapies for these patients. PDS0101 (designated HPV vaccine) is a liposomal nanoparticle HPV16-specific therapeutic vaccine that has been shown to generate strong HPV-specific responses in preclinical and clinical studies. Here we assess the efficacy of this HPV vaccine in combination with the tumor-targeting immunocytokine NHS-IL12 (PDS01ADC), plus either αPD-1 or the class I histone deacetylase inhibitor Entinostat.</p><p><strong>Methods: </strong>Mice bearing HPV16⁺, αPD-1 refractory TC-1 and mEER tumors were treated with HPV vaccine, NHS-IL12, and either αPD-1 or Entinostat to determine antitumor efficacy and survival benefits. A comprehensive analysis of the tumor microenvironment was performed using flow cytometry, multiplex immunofluorescence, chemokine and cytokine assessment, and single-cell RNA sequencing with T-cell receptor (TCR) enrichment.</p><p><strong>Results: </strong>Combination of HPV vaccine and NHS-IL12 with either Entinostat or αPD-1 yielded significant antitumor activity and prolonged survival in αPD-1 refractory models of HPV16⁺ cancer, with superior activity employing Entinostat versus αPD-1 combination. Entinostat triple therapy increased overall and HPV16-specific tumor CD8⁺ T-cell infiltration with heightened cytotoxicity. TCR sequencing revealed a CD8⁺ T-cell clone unique to vaccine-treated cohorts, which displayed an enriched cytotoxic transcriptional profile with triple therapy. These effects were paralleled by strong differentiation of tumor-associated macrophages (TAMs) towards pro-inflammatory, antitumor M1-like cell states. Single-cell transcriptomic analysis indicated all three agents were required for highest modulation of both CD8⁺ T cells and TAMs conducive to tumor control. A biomarker signature reflecting the preclinical findings was found to be associated with improved survival in patients with HPV-associated malignancies.</p><p><strong>Conclusion: </strong>Together, these findings provide a rationale for the combination of HPV vaccine, NHS-IL12, and Entinostat in the clinical setting for patients with HPV16-associated malignancies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981917","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":"Selection of therapeutically effective T-cell receptors from the diverse tumor-bearing repertoire.","authors":"Leonie Rosenberger, Leo Hansmann, Vasiliki Anastasopoulou, Steven P Wolf, Kimberley Drousch, Christina Moewes, Xinyi Feng, Guoshuai Cao, Jun Huang, Poh Yin Yew, Erlend Strønen, Taigo Kato, Naresha Saligrama, Johanna Olweus, Yusuke Nakamura, Gerald Willimsky, Thomas Blankenstein, Hans Schreiber, Matthias Leisegang","doi":"10.1136/jitc-2024-011351","DOIUrl":"https://doi.org/10.1136/jitc-2024-011351","url":null,"abstract":"<p><strong>Background: </strong>The development of T-cell receptor (TCR)-based T-cell therapies is hampered by the difficulties in identifying therapeutically effective tumor-specific TCRs from the natural repertoire of a patient's cancer-specific T cells.</p><p><strong>Methods: </strong>Here, we mimic experimentally near-patient conditions to analyze the T-cell repertoire in euthymic tumor-bearing mice responding to the H-2K^b-presented neoantigen p68^S551F (mp68). We temporarily separated the time point of mp68 expression from that of cancer cell transplantation to exclude the influence of injection-induced inflammation on T-cell priming. Thus, the mp68-specific T-cell response could only develop after the acute inflammatory phase had subsided.</p><p><strong>Results: </strong>We found that mp68-specific TCRs isolated from either tumor-infiltrating T cells or spleens of mice immunized with mp68-expressing cancer cells are diverse and not inherently therapeutic when introduced into peripheral T cells and used for adoptive therapy of established tumors. While measuring short-term T-cell responses in vitro was unreliable for some TCRs in predicting their therapeutic failure, assessing the persistence of cancer cell destruction by TCR-modified T cells in long-term cultures accurately predicted therapeutic outcomes. A tumor-derived TCR with optimal function was also correctly identified with this approach when analyzing human TCRs that recognize the HLA-A2-presented neoantigen CDK4^R24L.</p><p><strong>Conclusions: </strong>We show that a neoantigen-directed T-cell response in tumor-bearing hosts comprises a diverse repertoire. Infiltration and expansion of certain T-cell clonotypes in the tumor do not necessarily correlate with therapeutic efficacy of their TCRs in adoptive therapy. We propose that analysis of persistent rather than immediate responses of TCR-modified T cells in vitro serves as a reliable parameter to identify TCRs that are therapeutically effective in vivo.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144016079","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":"RAC2 inhibition enhances tumor sensitivity to NK cell-mediated cytotoxicity.","authors":"Hui Guo, Jie Hu, Zining Wang, Feifei Xu, Yongxiang Liu, Lei Cui, Huanling Zhang, Chunyuan Xie, Ruhui Yao, Huan Jin, Zixuan Guo, Tiantian Wang, Lin Li, Yanxun Lin, Xiaojuan Wang, Heping Li, Xiaojun Xia","doi":"10.1136/jitc-2024-010931","DOIUrl":"https://doi.org/10.1136/jitc-2024-010931","url":null,"abstract":"<p><strong>Background: </strong>Natural killer (NK) cells are recognized for their ability to kill tumor cells for tumor control, but tumor cells often develop resistance to evade NK cell-mediated cytotoxicity. Identification of molecular mechanisms by which tumor cells evade from NK cell-mediated killing may offer novel therapeutic strategies for potentiating NK-based cancer immunotherapy.</p><p><strong>Methods: </strong>An in vitro tumor-NK cell co-culture system was employed to identify the most significantly altered genes in tumor cells following NK cell interaction. The cell death rate of tumor cells by NK cell exposure was quantified using flow cytometry. EL4 and HCT116 tumor models in C57BL/6, BALB/c-nu, and NOD/SCID mice were used for evaluating tumor growth differences induced by <i>Rac2</i> knockdown or knockout. The cellular and molecular impact of <i>Rac2</i> knockdown or knockout on the sensitivity of tumor cells to NK cell-mediated cytotoxicity was assessed using quantitative PCR, immunofluorescence, and mutation analysis.</p><p><strong>Results: </strong>By screening expression levels of the Ras homology (Rho) GTPase family genes in tumor cells after co-culture with NK cells, we identified RAC2 as a key regulator of tumor cell resistance to NK cell-mediated cytotoxicity among the Rho GTPase family members. Furthermore, knockout of <i>RAC2</i> in human colorectal cancer cells leads to increased tumor susceptibility to NK cell-mediated cytotoxicity in a xenograft tumor model. Mechanistically, the absence of RAC2 enhances tumor cell sensitivity to NK cell-mediated killing by facilitating cell-cell contact.</p><p><strong>Conclusions: </strong>These findings indicate that the inhibition of RAC2 in tumor cells substantially enhances their susceptibility to NK cell-mediated cytotoxicity, thereby providing a potential therapeutic target for optimizing NK cell therapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035806","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":"B4GALT5 inhibits CD8⁺ T-cell response by downregulating MHC-I level through ERAD pathway in PDAC.","authors":"Xin Xing, Shi-Qi Yin, Xia-Qing Li, Hui Li, Hong-Tai Ma, Aziguli Tulamaiti, Shu-Yu Xiao, Yu-Tong Liu, Hao Zhang, Zhigang Zhang, Yan-Miao Huo, Xiao-Mei Yang, Yan Yang, Xue-Li Zhang","doi":"10.1136/jitc-2024-010908","DOIUrl":"https://doi.org/10.1136/jitc-2024-010908","url":null,"abstract":"<p><strong>Background: </strong>Immune evasion is a crucial event in the progression of pancreatic ductal adenocarcinoma (PDAC). The identification of new immunotherapeutic targets may provide a promising platform for advancing PDAC treatment. This study aims to investigate the role of beta-1,4-galactosyltransferase-5 (B4GALT5) in immune evasion by pancreatic cancer cells and evaluate its potential as an immunotherapeutic target.</p><p><strong>Methods: </strong>We conducted a comprehensive analysis using RNA sequencing data and tissue microarrays from patients with PDAC to investigate the association between B4GALT5 expression and patient prognosis. Using animal models, we further explored the impact of B4GALT5 on the quantity and activity of tumor-infiltrating CD8⁺ T cells. RNA sequencing and co-immunoprecipitation were used to explore the mechanism by which B4GALT5 regulates major histocompatibility complex (MHC-I) levels.</p><p><strong>Results: </strong>Our study demonstrates that high expression of B4GALT5 in tumor cells is significantly associated with poor prognosis in patients with PDAC and reduced cytotoxic activity of tumor-infiltrating CD8⁺ T cells. Specifically, B4GALT5 suppresses MHC-I expression in tumor cells through the endoplasmic reticulum-associated degradation pathway, enabling them to evade immune surveillance by CD8⁺ T cells.</p><p><strong>Conclusions: </strong>B4GALT5 impairs CD8⁺ T-cell recognition of tumor cells by regulating MHC-I levels, thereby promoting immune evasion. This makes B4GALT5 a highly promising immunotherapeutic target for improving the poor prognosis of patients with PDAC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144063700","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":"CD22 CAR-T cells secreting CD19 T-cell engagers for improved control of B-cell acute lymphoblastic leukemia progression.","authors":"Javier Arroyo-Ródenas, Aida Falgas, Laura Díez-Alonso, Alba Martinez-Moreno, Heleia Roca-Ho, Francisco J Gil-Etayo, Alba Pérez-Pons, Óscar Aguilar-Sopeña, Miriam Velasco-Sidro, Marina Gómez-Rosel, Beatriz Jiménez-Matías, Guillermo Muñoz-Sánchez, Yedra Pacheco, Clara Bravo-Martín, Ángel Ramírez-Fernández, Anaïs Jiménez-Reinoso, Europa Azucena González-Navarro, Manel Juan, Alberto Orfao, Belén Blanco, Pedro Roda-Navarro, Clara Bueno, Pablo Menéndez, Luis Álvarez-Vallina","doi":"10.1136/jitc-2024-009048","DOIUrl":"https://doi.org/10.1136/jitc-2024-009048","url":null,"abstract":"<p><strong>Background: </strong>CD19-directed cancer immunotherapies, based on engineered T cells bearing chimeric antigen receptors (CARs, CAR-T cells) or the systemic administration of bispecific T cell-engaging (TCE) antibodies, have shown impressive clinical responses in relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, more than half of patients relapse after CAR-T or TCE therapy, with antigen escape or lineage switching accounting for one-third of disease recurrences. To minimize tumor escape, dual-targeting CAR-T cell therapies simultaneously targeting CD19 and CD22 have been developed and validated both preclinically and clinically.</p><p><strong>Methods: </strong>We have generated the first dual-targeting strategy for B-cell malignancies based on CD22 CAR-T cells secreting an anti-CD19 TCE antibody (CAR-STAb-T) and conducted a comprehensive preclinical characterization comparing its therapeutic potential in B-ALL with that of previously validated dual-targeting CD19/CD22 tandem CAR cells (TanCAR-T cells) and co-administration of two single-targeting CD19 and CD22 CAR-T cells (pooled CAR-T cells).</p><p><strong>Results: </strong>We demonstrate that CAR-STAb-T cells efficiently redirect bystander T cells, resulting in higher cytotoxicity of B-ALL cells than dual-targeting CAR-T cells at limiting effector:target ratios. Furthermore, when antigen loss was replicated in a heterogeneous B-ALL cell model, CAR-STAb T cells induced more potent and effective cytotoxic responses than dual-targeting CAR-T cells in both short- and long-term co-culture assays, reducing the risk of CD19-positive leukemia escape. In vivo, CAR-STAb-T cells also controlled leukemia progression more efficiently than dual-targeting CAR-T cells in patient-derived xenograft mouse models under T cell-limiting conditions.</p><p><strong>Conclusions: </strong>CD22 CAR-T cells secreting CD19 T-cell engagers show an enhanced control of B-ALL progression compared with CD19/CD22 dual CAR-based therapies, supporting their potential for clinical testing.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12049870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967762","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}