Selective refueling of CAR T cells using ADA1 and CD26 boosts antitumor immunity

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

doi:10.1016/j.xcrm.2024.101530

Selective refueling of CAR T cells using ADA1 and CD26 boosts antitumor immunity

Cell Rep Med. 2024 Apr 22:101530. doi: 10.1016/j.xcrm.2024.101530. Online ahead of print.

Authors

Yue Hu¹, Abhijit Sarkar¹, Kevin Song², Sara Michael³, Magnus Hook¹, Ruoning Wang⁴, Andras Heczey⁵, Xiaotong Song⁶

Affiliations

¹ Department of Translational Medical Sciences, School of Medicine, Texas A&M University, Houston, TX, USA; Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA.
² Department of Translational Medical Sciences, School of Medicine, Texas A&M University, Houston, TX, USA; Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA; Department of Biology, University of Houston, Houston, TX, USA.
³ Department of Translational Medical Sciences, School of Medicine, Texas A&M University, Houston, TX, USA; Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA; Department of Synthesis Biology, University of Houston, Houston, TX, USA.
⁴ Center for Childhood Cancer Research, Hematology/Oncology & BMT, Abigail Wexner Research Institute at Nationwide Children's Hospital, Department of Pediatrics at The Ohio State University, Columbus, OH, USA.
⁵ Texas Children's Hospital, Houston, TX, USA; Department of Pediatric, Baylor College of Medicine, Houston, TX, USA.
⁶ Department of Translational Medical Sciences, School of Medicine, Texas A&M University, Houston, TX, USA; Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA. Electronic address: xsong@tamu.edu.

PMID: 38688275
DOI: 10.1016/j.xcrm.2024.101530

Abstract

Chimeric antigen receptor (CAR) T cell therapy is hindered in solid tumor treatment due to the immunosuppressive tumor microenvironment and suboptimal T cell 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 T cells 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 T cells, improving migration and resistance to transforming growth factor β1 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 T cells exhibit superior tumor reduction compared to unmodified CAR T cells. Overall, our study highlights the potential of selective inosine refueling to enhance CAR T therapy efficacy against solid tumors.

Keywords: ADA; ADA1 autocrine secretion; CAR T cell; CD26; T cell engager; adenosine; anti-CD3 scFv; inosine; metabolic reprogramming; solid tumor.