Targeting the tumor, harboring the host: IL-7 receptor-targeted CARs to treat T-ALL

Abstract

Chimeric antigen receptor (CAR) T cell therapy has fundamentally transformed clinical outcomes in B cell malignancies; however, the success story of CAR T cells has not yet extended to T cell acute lymphoblastic leukemia (T-ALL). A primary issue lies in the fundamental biology of the disease; most target antigens are shared be-tween malignant T-ALL blasts and healthy T lymphocytes, including the CAR T cell product itself. This overlap triggers fratricide, a unique on-target, off-tumor toxicity in which CAR T cells recognize and destroy each other as well as bystander normal T cells. This self-destruction compromises the manufacturing yield, impairs in vivo persistence, and introduces the risk of prolonged severe lymphopenia.