Role of CAR T Cell Metabolism for Therapeutic Efficacy

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2022 Nov 11

PMID 36358860

Authors

Judit Rial Saborido

Simon Volkl

Michael Aigner

Andreas Mackensen

Dimitrios Mougiakakos

Affiliations

Soon will be listed here.

Abstract

Chimeric antigen receptor (CAR) T cells hold enormous potential. However, a substantial proportion of patients receiving CAR T cells will not reach long-term full remission. One of the causes lies in their premature exhaustion, which also includes a metabolic anergy of adoptively transferred CAR T cells. T cell phenotypes that have been shown to be particularly well suited for CAR T cell therapy display certain metabolic characteristics; whereas T-stem cell memory (T) cells, characterized by self-renewal and persistence, preferentially meet their energetic demands through oxidative phosphorylation (OXPHOS), effector T cells (T) rely on glycolysis to support their cytotoxic function. Various parameters of CAR T cell design and manufacture co-determine the metabolic profile of the final cell product. A co-stimulatory 4-1BB domain promotes OXPHOS and formation of central memory T cells (T), while T cells expressing CARs with CD28 domains predominantly utilize aerobic glycolysis and differentiate into effector memory T cells (T). Therefore, modification of CAR co-stimulation represents one of the many strategies currently being investigated for improving CAR T cells' metabolic fitness and survivability within a hostile tumor microenvironment (TME). In this review, we will focus on the role of CAR T cell metabolism in therapeutic efficacy together with potential targets of intervention.

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