Disarming CAR-Tregs with a clinical-stage natural product to supercharge CAR-T therapy

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized treatment of relapsed/refractory B-cell malignancies, yet about 60% of patients eventually relapse or become resistant.1,2 A key mechanism underlying resistance is the emergence of CAR-expressing regulatory T cells (CAR-Tregs) within infused products. These CAR-Tregs can arise from transduction of natural Tregs or from conventional T cells that acquire a regulatory phenotype upon CAR engagement. Once present, they potently suppress effector CAR-T cells by secreting IL-10 and TGF-β, expressing CTLA-4 and CD25, and metabolically disrupting the tumor microenvironment.