CAR-adapted PIK3CD base editing enhances T cell anti-tumor potency.

ABSTRACT: Insufficient functional T cell persistence impedes therapeutic success of chimeric antigen receptor (CAR) therapies. Here we performed a CAR-adapted base-editing screen of PIK3CD, a key regulator of T cell function, metabolism and fate. We identified point mutations that beneficially modulate CAR T cell profiles in 4-1BBz and 28z CAR T cells, respectively. We found that point mutations with differing effects on phosphatidylinositol-3-kinase delta (PI3Kδ) signaling activity were advantageous in distinct CAR contexts: The PI3Kδ-activating substitution E81K enhanced proliferation, metabolic fitness and effector function of 4-1BBz CARs, promoting long-term functional persistence and enhanced therapeutic efficacy in vivo. Conversely, the PI3Kδ-attenuating substitution L32P improved T cell memor

SUBMITTER: Bucher P 

PROVIDER: S-EPMC12948676 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature