Clinical trials, challenges, and changes in TCR-based therapeutics for hematologic malignancies

T cells engineered to express antigen-specific T cell receptors (TCR; TCR-T) are a promising class of immunotherapeutic for patients with hematologic malignancies. Like chimeric antigen receptor-engineered T cells (CAR-T), TCR-T are cell products with defined specificity and composition. Unlike CAR-T, TCR-T can recognize targets arising both from intracellular and cell surface proteins and leverage the sensitivity of natural TCR signaling machinery. A growing number of TCR-T targeting various antigens in different hematologic malignancies are in early-phase clinical trials, and more are in preclinical development.

This review covers results from early-phase TCR-T clinical trials for hematologic malignancies. Challenges in the field are reviewed, including identifying optimal targets, engaging CD4⁺ help for CD8⁺ T cells, and overcoming tumor-induced suppression; recent innovations to overcome these challenges are also highlighted.

In the future, TCR-T's promise for hematologic malignancies will be borne out in later-phase clinical trials and approvals for clinical use. Improved antigen discovery methods will help build the toolbox of targets needed for broadly applicable TCR-T. Rationally designed TCR-T modifications including incorporation of accessory receptors and gene editing will enhance TCR-T function. New hybrid receptors combining features of TCR and CAR will enter the clinic.