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GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy.
- Source :
-
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Jul 03; Vol. 32 (7), pp. 2393-2405. Date of Electronic Publication: 2024 May 07. - Publication Year :
- 2024
-
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 IL13Rα2-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, IL13Rα2-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.<br />Competing Interests: Declaration of interests The authors declare no financial competing interests. M.S. reports research funding from Takeda Pharmaceuticals, Atara Biotherapeutics, Fate Therapeutics, and Mnemo Therapeutics, all of which are unrelated to the present research. M.S. is a scientific cofounder of Mnemo Therapeutics.<br /> (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Humans
Mice
Cell Line, Tumor
Disease Models, Animal
Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
T-Lymphocytes immunology
T-Lymphocytes metabolism
Tumor Microenvironment immunology
Glucose Transporter Type 1 genetics
Glucose Transporter Type 1 metabolism
Immunotherapy, Adoptive methods
Receptors, Chimeric Antigen genetics
Receptors, Chimeric Antigen metabolism
Receptors, Chimeric Antigen immunology
Xenograft Model Antitumor Assays
Subjects
Details
- Language :
- English
- ISSN :
- 1525-0024
- Volume :
- 32
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 38720457
- Full Text :
- https://doi.org/10.1016/j.ymthe.2024.05.006