Optimally engineered HLA/peptide-specific CAR-T cells outperform TCR-T cells to eradicate solid tumors.

Tumor-specific HLA/peptides (pHLA) represent attractive therapeutic targets for cancer. Two cell-based modalities can target pHLA-expressing tumors: T cell receptors (TCRs) or TCR-mimetic (TCRm) antibodies reformatted as chimeric antigen receptors (CARs). Using HLA-A2/MAGEA4₂₃₀₋₂₃₉ as a model pHLA, we discerned the relative potency of TCR-T and CAR-T cells, informing how to best deploy these for clinical benefit. Although TCR-T cells were more sensitive at detecting low-density pHLA, TCR-T cells exerted only transient in vivo antitumor efficacy followed by tumor relapse due to deficient TCR-T cell proliferation and persistence that was associated with a more differentiated and dysfunctional phenotype. By contrast, CAR-T cells with encoded costimulatory signaling fully regressed tumors. Insufficient TCR-T cell durability was overcome by coengaging 41BB or IL-2 signaling pathways, thereby enhancing tumor control in vivo. These data establish differential activities of human TCR-T and CAR-T cells targeting the same pHLA and inform the development of optimal targeting strategies to induce durable clinical responses.