CTLA4 Deletion Boosts CAR T-Cell Efficacy

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CTLA4 deletion shows promise as a strategy to overcome T-cell dysfunction and may increase the efficacy of chimeric antigen receptor (CAR) T-cell therapy.¹

According to findings published in Immunity, CTLA4 deletion in CAR T cells improves the antitumor efficacy and surface of CAR expression under stress. This enhanced efficacy comes from the uninhibited activation of CD28 signaling in CTLA4-deficient CAR T cells. When CTLA4 is deleted, CD28 signaling remains unopposed, leading to enhanced CAR T-cell function.

The study also showed that CTLA4 deletion can rescue the function of nonresponding CAR T cells that come from patients with chronic lymphocytic leukemia (CLL). Further, PD-1 deficiency nullifies the CD28 signaling enabled by CTLA4 deletion in CAR T cells.

"Surprisingly we observed that CRISPR-Cas9-mediated deletion of CTLA4, but not deletion of CTLA4 and/or PDCD1, improved CAR T-cell anti-tumor activity in preclinical models of leukemia and myeloma. Additional we demonstrated that CTLA4 deficiency permitted unopposed CD28 signaling and rescued the function of T cells from patients with CLL that had previously failed CAR T-cell therapy,” Regina M. Young, PhD, adjunct associate professor, scientific director June Academic Laboratory, Department of Pathology and Laboratory Medicine, told Targeted Oncology^TM.

Investigators tested whether single or dual CRISPR-Cas9-mediated deletion of PDCD1 and CTLA4could prevent CAR T-cell dysfunction. This was characterized by gradual loss of effector function or cytokine expression, and sustained expression of inhibitory receptors.

“In this study we sought to understand whether CRISPR-Cas9 mediated depletion of PD-1 and CTLA4 in T cells would improve CAR T-cell function,” said Young.

CTLA4-deficient CART19 cells generated enhanced antitumor activity in both an in vitro model of CAR T dysfunction and in xenograft mouse models while PD-1-deficient CART19 cells and CART19 cells deficient for both PD-1 and CTLA4 did not.

Longer expression, increased proliferation, and enhanced CART19 effector function supported by unopposed CD28 costimulation were observed with CTLA4-disrupted CART19 cells.

Additionally, these findings showed that dysfunctional CART19 cells from patients with CLL can be invigorated by CTLA4-deficiency in the starting T-cell population, and the deletion of CTLA4 in CART19 cell products can potentially lead to improvements in clinical efficacy in a subset of patients with CLL that do not respond to currently available treatments.

This technology may also increase the feasibility of manufacturing CAR T-cell products from heavily pretreated patient T cells. By alleviating the inhibitory effects of CTLA4, CTLA4 deletion can show the full potential of CAR T cells, leading to more effective cancer treatment.

"Despite the tremendous success with CART19 therapy, many patients with hematological malignancies fail to achieve durable responses. In patients with CLL, the primary mechanism of failure of CART19 therapy is lack of initial response. CTLA4-deletion reinvigorates dysfunctional CLL patient T cells, providing a potential strategy to increase the efficacy of CART19 therapy,” added Young.

REFERENCE

Agarwal S, Aznar MA, Rech AJ, et al. Deletion of the inhibitory co-receptor CTLA-4 enhances and invigorates chimeric antigen receptor T cells. Immunity. 2023;56(10):2388-2407.e9. doi:10.1016/j.immuni.2023.09.001