Altered cancer metabolism and implications for next-generation CAR T-cell therapies

Rishab Ramapriyan; Vivasvan S Vykunta; Gust Vandecandelaere; Leland G K Richardson; Jing Sun; William T Curry; Bryan D Choi

doi:10.1016/j.pharmthera.2024.108667

Altered cancer metabolism and implications for next-generation CAR T-cell therapies

Pharmacol Ther. 2024 Jul:259:108667. doi: 10.1016/j.pharmthera.2024.108667. Epub 2024 May 17.

Authors

Rishab Ramapriyan¹, Vivasvan S Vykunta², Gust Vandecandelaere³, Leland G K Richardson³, Jing Sun³, William T Curry³, Bryan D Choi⁴

Affiliations

¹ Brain Tumor Immunotherapy Laboratory, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: rramapriyan@mgh.harvard.edu.
² Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Medical Scientist Training Program, School of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Brain Tumor Immunotherapy Laboratory, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁴ Brain Tumor Immunotherapy Laboratory, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: bchoi@mgh.harvard.edu.

PMID: 38763321
DOI: 10.1016/j.pharmthera.2024.108667

Abstract

This review critically examines the evolving landscape of chimeric antigen receptor (CAR) T-cell therapy in treating solid tumors, with a particular focus on the metabolic challenges within the tumor microenvironment. CAR T-cell therapy has demonstrated remarkable success in hematologic malignancies, yet its efficacy in solid tumors remains limited. A significant barrier is the hostile milieu of the tumor microenvironment, which impairs CAR T-cell survival and function. This review delves into the metabolic adaptations of cancer cells and their impact on immune cells, highlighting the competition for nutrients and the accumulation of immunosuppressive metabolites. It also explores emerging strategies to enhance CAR T-cell metabolic fitness and persistence, including genetic engineering and metabolic reprogramming. An integrated approach, combining metabolic interventions with CAR T-cell therapy, has the potential to overcome these constraints and improve therapeutic outcomes in solid tumors.

Keywords: CAR T-cell therapy; CRISPR Cas systems; Immunotherapy; Metabolism; Solid tumors; Tumor microenvironment.

Publication types

Review

MeSH terms

Animals
Humans
Immunotherapy, Adoptive* / methods
Neoplasms* / immunology
Neoplasms* / therapy
Receptors, Chimeric Antigen* / immunology
T-Lymphocytes / immunology
Tumor Microenvironment* / immunology

Substances

Receptors, Chimeric Antigen