Manipulating the Metabolism to Improve the Efficacy of CAR T-Cell Immunotherapy

Abstract

The adoptive transfer of the chimeric antigen receptor (CAR) expressing T-cells has produced unprecedented successful results in the treatment of B-cell malignancies. However, the use of this technology in other malignancies remains less effective. In the setting of solid neoplasms, CAR T-cell metabolic fitness needs to be optimal to reach the tumor and execute their cytolytic function in an environment often hostile. It is now well established that both tumor and T cell metabolisms play critical roles in controlling the immune response by conditioning the tumor microenvironment and the fate and activity of the T cells. In this review, after a brief description of the tumoral and T cell metabolic reprogramming, we summarize the latest advances and new strategies that have been developed to improve the metabolic fitness and efficacy of CAR T-cell products.

Keywords: Chimeric Antigen Receptor T cells; cancer; combined therapy; immunotherapy; metabolic reprogramming.

Figure 1

Tumor cell metabolism and immunosuppression. The figure shows the different ways by which the tumor cell metabolic reprogramming conditions the tumor microenvironment and affects the immune response. Treg, regulatory T cells; OXPHOS, oxidative phosphorylation; FAO, fatty acid oxidation; VEGF, vascular endothelial growth factor; ROS, reactive oxygen species, Th1, helper T cells. Created with Biorender.

Figure 2

Tumor microenvironment and chimeric antigen receptor (CAR) T-cell immunotherapy strategies. The figure shows the different strategies developed to improve CAR T-cells metabolic fitness and anti-tumor activity in response to the hostile immunosuppressive effect of the tumor metabolism. CAFs, cancer associated fibroblasts. Created with Biorender.