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Review
. 2019 Apr 30:9:322.
doi: 10.3389/fonc.2019.00322. eCollection 2019.

A Metabolism Toolbox for CAR T Therapy

Xuequn Xu  1 , J N Rashida Gnanaprakasam  1 , John Sherman  1 , Ruoning Wang  1
Affiliations
Review

A Metabolism Toolbox for CAR T Therapy

Xuequn Xu et al. Front Oncol. .

Abstract

The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) through genetic engineering is one of the most promising new therapies for treating cancer patients. A robust CAR T cell-mediated anti-tumor response requires the coordination of nutrient and energy supplies with CAR T cell expansion and function. However, the high metabolic demands of tumor cells compromise the function of CAR T cells by competing for nutrients within the tumor microenvironment (TME). To substantially improve clinical outcomes of CAR T immunotherapy while treating solid tumors, it is essential to metabolically prepare CAR T cells to overcome the metabolic barriers imposed by the TME. In this review, we discuss a potential metabolism toolbox to improve the metabolic fitness of CAR T cells and maximize the efficacy of CAR T therapy.

Keywords: anti-tumor immune response; chimeric antigen receptor (CAR); immunotherapy; metabolism; tumor microenvironment (TME).

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Figures

Figure 1
Figure 1
(A) CART design and structure. (B) Metabolic antagonism between tumor and CAR T cells in the tumor microenvironment (TME). Tumor cells may suppress CAR T cells proliferation and function by competing for key nutrients with CAR T cells and excreting immune-suppressive metabolites into the TME.
Figure 2
Figure 2
Metabolic tool box of the CAR T cell manufacturing process and therapy. A variety of metabolic strategies are proposed to be integrated into standard work flow to optimize the manufacturing process and maximize the therapeutic efficacy of CAR T cells.
Figure 3
Figure 3
Important strategy for promoting CAR T cell therapy in immune suppressive TME. Manipulations during CAR T manufacturing HIF-CAR, TAN-CAR, and iCAR will promote CAR T function in immune suppressive TME. HIF-CAR T cells are activated by low oxygen concentrations. Inhibitory CAR (iCAR) limits T cell activation in the presence of off-target cells. Tandem CARs (Tan CAR) requires bispecific activation which reduces off target effects. A2AR−/− CAR T cells are resistant to adenosine mediated INF-γ suppression.
See this image and copyright information in PMC

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