Tinkering under the Hood: Metabolic Optimisation of CAR-T Cell Therapy

Abstract

Chimeric antigen receptor (CAR)-T cells are one of the most exciting areas of immunotherapy to date. Clinically available CAR-T cells are used to treat advanced haematological B-cell malignancies with complete remission achieved at around 30-40%. Unfortunately, CAR-T cell success rates are even less impressive when considering a solid tumour. Reasons for this include the paucity of tumour specific targets and greater degree of co-expression on normal tissues. However, there is accumulating evidence that considerable competition for nutrients such as carbohydrates and amino acids within the tumour microenvironment (TME) coupled with immunosuppression result in mitochondrial dysfunction, exhaustion, and subsequent CAR-T cell depletion. In this review, we will examine research avenues being pursued to dissect the various mechanisms contributing to the immunosuppressive TME and outline in vitro strategies currently under investigation that focus on boosting the metabolic program of CAR-T cells as a mechanism to overcome the immunosuppressive TME. Various in vitro and in vivo techniques boost oxidative phosphorylation and mitochondrial fitness in CAR-T cells, resulting in an enhanced central memory T cell compartment and increased anti-tumoural immunity. These include intracellular metabolic enhancers and extracellular in vitro culture optimisation pre-infusion. It is likely that the next generation of CAR-T products will incorporate these elements of metabolic manipulation in CAR-T cell design and manufacture. Given the importance of immunometabolism and T cell function, it is critical that we identify ways to metabolically armour CAR-T cells to overcome the hostile TME and increase clinical efficacy.

Keywords: CAR-T cells; immunometabolism; metabolism; oncometabolism; tumour microenvironment.

Figure 1

T cell metabolism and the tumour microenvironment. T cells face various metabolic challenges within the TME. Direct competition for nutrients arises such as glucose, glutamine, and amino acids, with the tumour outcompeting T cells. The tumour can also produce immunosuppressive nutrients such as lactate and kynurenine, and intrinsically modulate T cell metabolism through PD-1 checkpoint ligation and the production of TGF-β. This metabolic modulation of T cells within the TME results in an impaired anti-tumoural response. IDO, indoleamine 2,3-dioxygenase; OXPHOS, oxidative phosphorylation; PD-1, programmed cell death-1; PD-L1, programmed cell death-ligand 1; TCA cycle, tricarboxylic acid cycle; TGF-β, transforming growth factor-beta; and TME, tumour microenvironment.

Figure 2

Metabolic optimisation of CAR-T cells. Various strategies are currently being investigated to enhance the metabolic program of CAR-T cells and overcome the metabolic hostility of the TME. This includes improving CAR-T cell design, optimising ex vivo culture conditions, manipulating signalling pathways, and modulating various metabolic enzymes. These strategies increase OXPHOS levels and mitochondrial fitness in CAR-T cells leading to an enhanced central memory T cell compartment, resulting in a fitter CAR-T cell product with improved anti-tumoural immunity. ACAT1, cholesterol acyltransferase 1; BH4, tetrahydrobiopterin; CAR-T cell, chimeric antigen receptor T cell; LDH, lactate dehydrogenase; OXPHOS, oxidative phosphorylation; PGC1-α, PPAR-gamma coactivator 1-α; S-2HG, S-2-hydroxygluterate; TCA cycle, tricarboxylic acid cycle; TME, tumour microenvironment; and TRUCKs, T-cells redirected for unrestricted cytokine-mediated killing.