Current approaches to increase CAR T cell potency in solid tumors: targeting the tumor microenvironment

Abstract

Chimeric antigen receptor (CAR) T-cell therapy represents a revolutionary treatment for haematological malignancies (i.e. B-ALL). However, the success of this type of treatment has not yet been achieved in solid tumors. One hypothesis is that the immunosuppressive nature of the tumor microenvironment (TME) influences and affects the efficacy of adoptive immunotherapy. Understanding the role of the TME and its interaction with CAR T-cells is crucial to improve the potency of adoptive immunotherapy. In this review, we discuss the strategies and potential combinatorial approaches recently developed in mouse models to enhance the efficacy of CAR T-cells, with particular emphasis on the translational potential of these approaches.

Keywords: Adoptive immunotherapy; Chimeric antigen receptor T-cells; Tumor microenvironment.

Fig. 1

CAR structure. All different generations of CAR are composed of an extracellular antigen- binding domain (usually derived from an an antibody and engineered into an scFv), a hinge region, a transmembrane domain and various intracellular domains. First generation CARs have CD3ζ as the only signaling domain. In second generation CARs, one costimulatory domain was added, while third generation contain both CD28 and 4-1BB costimulatory signalling domains

Fig. 2

Targeting different components of the tumor microenvironment to enhance the efficacy of CAR T-cell therapy. Efforts to overcome the inhibitory effect of TME include strategies that target immunosuppressive populations (i.e. PGE₂), stroma cells, cytokine networks and immune checkpoint signals