Deletion of the inhibitory co-receptor CTLA-4 enhances and invigorates chimeric antigen receptor T cells

Abstract

Chimeric antigen receptor (CAR) Tcell therapy targeting CD19 has achieved tremendous success treating Bcell malignancies; however, some patients fail to respond due to poor autologous Tcell fitness. To improve response rates, we investigated whether disruption of the co-inhibitory receptors CTLA4 or PD-1 could restore CART function. CRISPR-Cas9-mediated deletion of CTLA4 in preclinical models of leukemia and myeloma improved CAR Tcell proliferation and anti-tumor efficacy. Importantly, this effect was specific to CTLA4 and not seen upon deletion of CTLA4 and/or PDCD1 in CAR Tcells. Mechanistically, CTLA4 deficiency permitted unopposed CD28 signaling and maintenance of CAR expression on the Tcell surface under conditions of high antigen load. In clinical studies, deletion of CTLA4 rescued the function of Tcells from patients with leukemia that previously failed CAR Tcell treatment. Thus, selective deletion of CTLA4 reinvigorates dysfunctional chronic lymphocytic leukemia (CLL) patient Tcells, providing a strategy for increasing patient responses to CAR Tcell therapy.