Qu Y, Dunn Z, Chen X, et al. Adenosine Deaminase 1 Overexpression Enhances the Antitumor Efficacy of CAR-Engineered T Cells. Human Gene Therapy. 2021; (doi: 10.1089/hum.2021.050).
Researchers report the overexpression of adenosine deaminase 1 (ADA) is a safe and reproducible genetic modification that can be used with current chimeric antigen receptor (CAR) T cell constructs to produce an armored CAR T product with potent therapeutic potential. The team engineered CAR T cells to overexpress ADA, which catabolizes adenosine into inosine. CAR T cells expressed both ADA and modified ADA, and increased CAR T cell exhaustion resistance. The overexpressed ADA was modified with the incorporation of an albumin-binding domain and with a collagen-binding domain. Tests with a preclinical engineered ovarian carcinoma xenograft model show that, unlike albumin-binding ADA overexpression, ADA and collagen-binding ADA significantly increased CAR T cell expansion, tumor tissue infiltration, tumor growth control, and overall survival. In a syngeneic colon cancer solid tumor model, tumor burden and tumor microenvironment were significantly reduced with the overexpression of mouse ADA by cancer cells.