Role of CAR T Cell Metabolism for Therapeutic Efficacy

SIMPLE SUMMARY: Chimeric antigen receptor (CAR) T cell therapy has heralded a new era in cancer treatment, in particular for hematological malignancies. Despite the current progress in CAR T cell research and development, frequent occurrence of exhausted and/or terminally differentiated CAR T cells can lead to poor tumor infiltration, limited persistence, lack of effector functions, and finally tumor immune escape. In fact, key functions and even the differentiation of T cells are tightly interconnected with the cells’ bioenergetics. Tumor cells and their microenvironment (TME) in turn can impact T cell metabolism in a variety of ways, including depletion of critical nutrients (e.g., glucose or tryptophan), accumulation of bioactive metabolites (e.g., lactic acid or reactive oxygen species) or via immunological checkpoints. Given this strong link between T cell metabolism and functional features that represent prerequisites for an efficient CAR T cell therapy, it is of great interest to explore metabolic modulation as a mean to improve clinical efficacy and even tolerability. 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(SCM)) cells, characterized by self-renewal and persistence, preferentially meet their energetic demands through oxidative phosphorylation (OXPHOS), effector T cells (T(EFF)) 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(CM)), while T cells expressing CARs with CD28 domains predominantly utilize aerobic glycolysis and differentiate into effector memory T cells (T(EM)). 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.