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.

Figure 1.

TCR and CAR. TCR αβ subunits combine with γ, δ, ε, and ζ subunits of the CD3 to form the multisubunit TCR complex. Peptide-HLA binding to the TCR αβ combined with the other subunits and with either CD4 or CD8 coreceptor initiates downstream signaling, T-cell activation, and effector functioning. Proteins involved in signaling such as LCK and ZAP70 are indicated and the activating motifs within the subunits are represented as horizontal bars. A typical CAR molecule comprises an antigen-specific scFv from a monoclonal antibody linked to a spacer, costimulatory domain (CD28 or 4-1BB shown in this example) and signaling CD3ζ domain. Figure created with BioRender.com: Gore S. (2025); https://BioRender.com/o91f055

Figure 2.

Pipeline of TCR T-cell preclinical development. (A) Antigens can either be overexpressed self-antigens seen on normal tissues or those that belong to the cancer testis antigen family with restricted expression; neo-antigens arising from mutations and gene rearrangements; or those belonging to the minor histocompatibility complex. (B) Donor PBMCs containing either auto- or allo-HLA–restricted TCR-expressing T cells can be stimulated with antigenic peptides; and activated or reactive T cells can be identified, isolated, and expanded in the laboratory. (C) Sequencing of reactive cells identifies the precise αβ sequences of the TCR that are introduced into T cells after modifications to ensure proper pairing. Newly generated TCR T cells are tested for function and efficacy against tumor cells and tested for specificity and safety using in silico and experimental analyses. CDX, cell line-derived xenograft; DCs, dendritic cells; PDX, patient-derived xenograft. Figure created with BioRender.com: Gore S (2025); https://BioRender.com/o91f055