A Metabolism Toolbox for CAR T Therapy

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.

αKG inhibits Regulatory T cell differentiation by coupling lipidome remodelling to mitochondrial metabolism

“…As such, aKG can potentially alter the activity of endogenous or adoptively-transferred tumor-specific T lymphocytes. Indeed, CAR-T cell metabolism, modulated as a function of the CAR co-stimulatory domain, has been shown to alter anti-tumor function (Kawalekar et al, 2016;Xu et al, 2019) and here, we find that short-term ex vivo aKG treatment enhances the in vivo persistence of CAR-T cells in a murine tumor model. aKG increased intra-tumoral infiltration of Treg-polarized CAR-T cells and moreover, was associated with levels of IFNg secretion that were similar to those induced by Th1-polarized CAR-T cells.…”

Revisiting Glycogen in Cancer: A Conspicuous and Targetable Enabler of Malignant Transformation

“…Consistent with this role of glycogen metabolism in immune system responses, disruption of glycogenolysis in the Tm cell compartment caused growth of subcutaneous melanoma cell xenografts and reduced survival of tumor-bearing mice (60). Disruption of the glycogen axis is thought to impair nascent anti-tumor immunity to drive cancer progression and also inhibit immunotherapeutic responses mediated by T-cells (61,62). Here, it is important to note that immune system responses can elicit both pro-and anti-tumoral actions, and metabolic reprogramming underlies this fine balance (54,63,64).…”

Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction

“…as one of the hallmarks of human cancer, and of the activation of oncogenic signalling pathways that enable tumour cells to reprogram nutrient-acquisition and nutrient-metabolism pathways to meet the additional bioenergetic, biosynthetic and redox demands of cell transformation and proliferation [25][26][27] . The TME of solid tumours represents a dramatic example of metabolic stress, wherein the high metabolic demands of cancer cells can restrict the function of T eff cells through competition for nutrients, including glucose, and by producing immunosuppressive metabolites [28][29][30][31][32] . As such, a better understanding of the metabolic modulation of T eff cells that relieves the immunosuppressive barriers in the TME will enable us to devise rational and effective approaches to enhance cancer immunotherapy via improvement of the metabolic fitness of T cells.…”