Selective refueling of CAR Tcells using ADA1 and CD26 boosts antitumor immunity.

Chimeric antigen receptor (CAR) Tcell therapy is hindered in solid tumor treatment due to the immunosuppressive tumor microenvironment and suboptimal Tcell persistence. Current strategies do not address nutrient competition in the microenvironment. Hence, we present a metabolic refueling approach using inosine as an alternative fuel. CAR Tcells were engineered to express membrane-bound CD26 and cytoplasmic adenosine deaminase 1 (ADA1), converting adenosine to inosine. Autocrine secretion of ADA1 upon CD3/CD26 stimulation activates CAR Tcells, improving migration and resistance to transforming growth factor 1 suppression. Fusion of ADA1 with anti-CD3 scFv further boosts inosine production and minimizes tumor cell feeding. In mouse models of hepatocellular carcinoma and non-small cell lung cancer, metabolically refueled CAR Tcells exhibit superior tumor reduction compared to unmodified CAR Tcells. Overall, our study highlights the potential of selective inosine refueling to enhance CAR T therapy efficacy against solid tumors.

Hu, Y., Sarkar, A., Song, K., Michael, S., Hook, M., Wang, R., Heczey, A., & Song, X.

Hu, Yue||Sarkar, Abhijit||Song, Kevin||Michael, Sara||Hook, Magnus||Wang, Ruoning||Heczey, Andras||Song, Xiaotong

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