TCR engineered T cell therapies for hematologic malignancies

Division Of Basic Sciences - Nci

Investigators

Abstract

Relapsed and refractory B-cell malignancies remain deadly despite the recent advent of chimeric antigen receptor (CAR)-T cell therapies. Our project aims to incorporate novel T cell receptor (TCR)-T cell therapy to address the issues of antigen escape and inflammatory toxicities seen with existing CAR-T cell therapies. Furthermore, our research aims to establish strategies for combining TCR and CAR to synergistically and safely reduce the emergence of resistant clones, a concept applicable to other antigens and thus with ramifications for a broad array of patients suffering from various cancers. CARs bind to cell-surface antigens in the same manner as monoclonal antibodies and are able to recognize targets independently of human leukocyte antigen (HLA). However, CARs are ineffective against cancers that have lost or reduced cell-surface antigen expression. T cell receptors (TCR) recognize intracellularly processed epitopes presented on HLA and can target any antigens regardless of their cellular localization, including antigens inaccessible to CARs. As proof-of-concept that TCR can recognize CAR-escaping tumors, we discovered a novel TCR specific to an HLA-A*02:01-restricted epitope of CD22 that mediates cytotoxicity against CAR-T-resistant tumors (patent, US20240239864A1). We developed a multi-tiered strategy to efficiently isolate tumor-antigen-specific TCR clones and to effectively evaluate the safety of therapeutic TCR candidates (Science Advances 2023). Importantly, we found that T cells activated through physiological CD22 TCR signaling eradicate cancer without causing systemic toxicity in murine models, unlike CAR-T cells (Science Advances 2025). Hence, the overarching hypothesis of our ongoing project is that TCR-transduced T (TCR-T) cells can kill CAR-escaping tumors and are less proinflammatory compared to existing CAR-T cells, and that TCR's unique strengths can be combined with CAR to synergistically reduce the emergence of cell-therapy resistance and mitigate toxicities. First, we are preparing for a phase I trial to evaluate the feasibility and safety of CD22 TCR-T cells as a salvage therapy for patients with B-cell malignancies that are resistant to standard-of-care CAR-T cells. This study represents the first in the field to clinically test TCR-T cells for CAR-T resistance. In collaboration with the NCI Experimental Therapeutics Program (NExT), we successfully manufactured a clinical-grade (GMP-grade) viral vector encoding the TCR, which was a critical step forward in clinical translation. Second, we are conducting laboratory experiments to elucidate the mechanism of inflammatory toxicities triggered by CAR-T cells but not by TCR-T cells. We recently established a novel immunocompetent transgenic murine model in which both clinically relevant human-antigen-directed CD22 CAR and CD22 TCR can be directly compared in a disease-equalized context. Upon completion of the experiments and analyses, we plan to publish the results and offer the model to the public. Third, our ongoing project evaluates the synergistic effects of combining TCR and CAR against low-antigen diseases, and against heterogeneous cancers composed of pre-existing clones that are resistant to either TCR-T or CAR-T cells. This third aim will establish the pre-clinical foundation for developing TCR+CAR combination therapies that are imminently translatable to early-phase clinical trials. Lastly, our ongoing efforts include the discovery and pre-clinical development of therapeutic TCRs for other cancer-associated antigens shared across multiple cancer histology subtypes. Collectively, we aim to lay the groundwork for a new treatment paradigm of incorporating TCR-T cells to improve the current state of cellular therapies for B-cell malignancies. The concept of a TCR+CAR combination offsetting each other's limitations and mitigating toxicities is applicable to other antigens and has broader implications for improving the outcomes of various cancers.