Decker et al. compared TCR-T (expressing true TCR) and CAR-T (expressing anti-pHLA Aab with CD28 or 4-1BB costimulation) targeting the same peptide antigen, MAGEA4. Compared to the TCR, the CARs were less sensitive to low antigen density on target cells, but more effectively controlled tumors in vivo, accompanied by greater T cell expansion and tumor accumulation with the 4-1BB CAR-T. In an in vitro coculture model, TCR-T cells also had inferior long-term tumor killing and greater exhaustion compared to CAR-T. Supporting TCR-T with 4-1BBL or IL-2 (via fusion to an anti-PD-1 Ab) improved functionality and efficacy.
Contributed by Alex Najibi
ABSTRACT: 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/MAGEA4(230-239) 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.
Author Info: (1) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (2) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (3) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (4) Regenero
Author Info: (1) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (2) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (3) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (4) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (5) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (6) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (7) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (8) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (9) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (10) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (11) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (12) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (13) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (14) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (15) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (16) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA. (17) Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA.
