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

Immunity. 2023 Oct 10;56(10):2388-2407.e9. doi: 10.1016/j.immuni.2023.09.001. Epub 2023 Sep 29.

Abstract

Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has achieved tremendous success treating B cell malignancies; however, some patients fail to respond due to poor autologous T cell 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 T cell proliferation and anti-tumor efficacy. Importantly, this effect was specific to CTLA4 and not seen upon deletion of CTLA4 and/or PDCD1 in CAR T cells. Mechanistically, CTLA4 deficiency permitted unopposed CD28 signaling and maintenance of CAR expression on the T cell surface under conditions of high antigen load. In clinical studies, deletion of CTLA4 rescued the function of T cells from patients with leukemia that previously failed CAR T cell treatment. Thus, selective deletion of CTLA4 reinvigorates dysfunctional chronic lymphocytic leukemia (CLL) patient T cells, providing a strategy for increasing patient responses to CAR T cell therapy.

Keywords: CAR T cells; CRISPR-Cas9; CTLA4; PD-1; T cell exhaustion; acute lymphoblastic leukemia; cancer immunotherapy; checkpoint blockade; chronic lymphocytic leukemia; resistance.

MeSH terms

  • Antigens, CD19
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / metabolism
  • Humans
  • Immunotherapy, Adoptive
  • Leukemia, Lymphocytic, Chronic, B-Cell*
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Chimeric Antigen*
  • T-Lymphocytes

Substances

  • Receptors, Chimeric Antigen
  • Receptors, Antigen, T-Cell
  • CTLA-4 Antigen
  • Antigens, CD19