A Method to Enhance CAR T Efficacy through Adenosine Deaminase Overexpression

Stanford Scientists have developed an innovative approach that enhances the antitumor efficacy of CAR T cells by overexpressing Adenosine Deaminase 1 (ADA), an enzyme responsible for metabolizing adenosine into inosine, to attenuate the immunosuppressive tumor microenvironment.

Although promising, CAR T cell therapy efficacy in solid tumors is limited by hostile tumor microenvironments, limited CAR T persistence, and lack of tumor killing. Extracellular adenosine contributes to the hostile tumor microenvironment by binding the adenosine A2a receptor on immune cells. Blocking A2aR or enhancing ADA-mediated adenosine metabolism to inosine protects T cells from adenosine-mediated immunosuppression. Stanford scientists showed that human CAR T cells are also susceptible to adenosine-mediated immunosuppression. They developed an approach where they overexpressed ADA in exhausted and non-exhausted CAR T cells leading to a higher frequency of stem cell-like memory T cell effectors, and a simultaneous decrease of exhausted subpopulations. Both antigen-driven proliferation and effector function of CAR T cells also significantly improved after ADA overexpression. Therefore, overexpression of adenosine deaminase in CAR T cells is a novel and efficient way to evade immunosuppression.

Stage of Development

Research – in vitro