Current developments in T-cell receptor therapy for acute myeloid leukemia

Abstract T-cell receptor (TCR) therapies are a promising modality for the treatment of cancers, with significant efforts being directed toward acute myeloid leukemia (AML), a particularly challenging disease. Chimeric antigen receptor (CAR) T cells targeting single surface antigens have shown remarkable efficacy for B-cell lymphoblastic leukemia, lymphomas, and multiple myeloma. However, AML presents formidable obstacles to the effectiveness of CAR T cells because of the widespread expression of heterogenous leukemia immunophenotypes and surface antigen targets additionally present on normal myeloid cells. TCR therapies are an evolving field of cell therapies that allow targeting intracellular antigenic peptides presented via HLA molecules. The development of TCR therapy for AML is progressing rapidly through preclinical research and successful clinical trials. This review specifically explores the antigens targeted in AML, the diverse methodologies and strategies used in TCR identification, and preclinical TCR T-cell development. The review also discusses innovative molecular designs to improve functional efficacy, mitigate safety concerns, and overcome HLA restrictions. Specific outcomes of early clinical trials targeting important antigens Wilms tumor gene 1, preferentially expressed antigen in melanoma, and minor histocompatibility antigen HA-1 are also highlighted. Ultimately, this review underscores why TCR therapy is poised to become an indispensable component of AML immunotherapy.