By overexpressing the glucose transporter GLUT1 in two clinically relevant CAR T cells (19-28z and IL13Rα2-BBz), Shi and Kotchetkov et al. asked if improved glucose uptake by the CAR T cells in a glucose-low TME would enhance their efficacy. In a low glucose milieu, GLUT1 increased glycolytic and mitochondrial capacity, and enhanced CAR T cell numbers and cytolytic activity with repetitive Ag stimulation. In mouse models, GLUT1 prolonged survival and increased T stem cell-like memory cells (NALM6 ALL), and improved tumor control with memory (RCC PDX). In an orthotopic GBM model, IL-13Ra2-BBz GLUT1 CAR T cells prolonged survival and decreased exhaustion markers.
Contributed by Katherine Turner
ABSTRACT: The tumor microenvironment presents many obstacles to effective chimeric antigen receptor (CAR) T cell therapy, including glucose competition from tumor and myeloid cells. Using mouse models of acute lymphoblastic leukemia (ALL), renal cell carcinoma (RCC), and glioblastoma (GBM), we show that enforced expression of the glucose transporter GLUT1 enhances anti-tumor efficacy and promotes favorable CAR-T cell phenotypes for two clinically relevant CAR designs, 19-28z and IL13R_2-BBz. In the NALM6 ALL model, 19-28z-GLUT1 promotes T stem cell-like memory formation and prolongs survival. RNA sequencing of these CAR-T cells reveals that the overexpression of GLUT1, but not GLUT3, enriches for genes involved in glycolysis, mitochondrial respiration, and memory precursor phenotypes. Extending these data, 19-28z-GLUT1 CAR-T cells improve tumor control and response to rechallenge in an RCC patient-derived xenograft model. Furthermore, IL13R_2-BBz CAR-T cells overexpressing GLUT1 prolong the survival of mice bearing orthotopic GBMs and exhibit decreased exhaustion markers. This novel engineering approach can offer a competitive advantage to CAR-T cells in harsh tumor environments where glucose is limiting.
Author Info: (1) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (2) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York,
Author Info: (1) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (2) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (3) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (4) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (5) Orthopedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (6) Orthopedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (7) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: m-sadelain@ski.mskcc.org.
