Overcoming resistance to CAR-T cell therapy in hematologic malignancies: novel targets, microenvironmental barriers, and combinations

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape for several hematologic malignancies, with FDA-approved products targeting CD19 and BCMA demonstrating durable responses in patients with relapsed or refractory B cell lymphomas, acute lymphoblastic leukemia, and multiple myeloma. Despite these landmark successes, significant challenges remain. A substantial proportion of patients experience disease relapse driven by antigen loss, T cell exhaustion, or an immunosuppressive tumor microenvironment. Furthermore, CAR-T efficacy in T cell malignancies, acute myeloid leukemia, and other hematologic cancers remains limited, underscoring the need for novel therapeutic strategies.This Research Topic aims to bring together original research, reviews, and perspectives that address the current barriers to CAR-T cell therapy in hematologic malignancies and explore innovative approaches to overcome them. The Topic Editors welcome contributions spanning both preclinical and translational research, with a particular focus on the following themes:1. Identification and validation of surface antigens and molecular targets beyond CD19 and BCMA that address antigen escape, heterogeneous target expression, or limited targetability across hematologic malignancies, including AML, T cell lymphomas, and myelodysplastic syndromes.2. Mechanisms of resistance to CAR-T therapy, including antigen escape, T cell dysfunction, and microenvironmental immunosuppression, as well as strategies to detect and counteract these processes.3. CAR engineering strategies designed to overcome defined resistance mechanisms, including antigen escape, impaired trafficking, poor persistence, and T cell dysfunction.4. Combination strategies integrating CAR-T cells with checkpoint inhibitors, bispecific antibodies, small molecule inhibitors, or myeloid-targeted agents to improve response depth and durability.5. Biomarkers predictive of CAR-T response, relapse, toxicity, persistence, and long-term outcomes in hematologic cancers, including the role of the immune and cytokine milieu in shaping therapeutic efficacy.By consolidating advances in target discovery, resistance biology, and rational combination therapy, this Research Topic seeks to support the development of more durable and effective CAR-T cell therapies for patients with hematologic malignancies.Submissions must contain substantial immunological or mechanistic content. Purely in silico or computational analyses of public databases without experimental or biological validation, single retrospective case reports, studies focused exclusively on solid tumors, and clinical outcome reports without meaningful immunological analysis fall outside the scope of this collection.---Topic Editor Giacomo Tampella is an employee of Brainchild Bio, Inc. Topic Editor Maxim A. Moroz is affiliated with Seattle Children’s Therapeutics. All other Topic Editors declare no competing interests in relation to the subject of the Research Topic. Topic editors: Rajesh Kumar, Giacomo Tampella, Ph.D., Sam Saibil, Maxim A Moroz Source: https://www.frontiersin.org/research-topics/82193/overcoming-resistance-to-car-t-cell-therapy-in-hematologic-malignancies-novel-targets-microenvironmental-barriers-and-combinations