To support CAR T cell metabolism and functionality in the tumor microenvironment, Hu and Sarkar et al. developed “metabolically refueled” CAR T cells (MR-CAR-T) expressing CD26, a T cell costimulatory molecule, and ADA1, an enzyme that generates inosine as an alternative T cell energy source. ADA1 was fused to an anti-CD3 scFv to both activate and direct ADA1 to T cells. Compared to standard CAR T cells, MR-CAR-T improved in vitro migration, cytotoxicity, and proliferation; in vivo, MR-CAR-T increased tumor inosine concentration and T cell infiltration, leading to superior tumor control in HER2- or GPC3-expressing tumor models.
Contributed by Alex Najibi
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 _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 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.
Author Info: (1) Department of Translational Medical Sciences, School of Medicine, Texas A&M University, Houston, TX, USA; Center for Infectious and Inflammatory Diseases, Institute of Bioscien
Author Info: (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. (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 Biology, University of Houston, Houston, TX, USA. (4) 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. (5) 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. (6) 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. (7) Texas Children's Hospital, Houston, TX, USA; Department of Pediatric, Baylor College of Medicine, Houston, TX, USA. (8) 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.
