Driving an improved CAR for cancer immunotherapy

Abstract

The recent clinical success of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies represents a paradigm shift in cancer immunotherapy. Unfortunately, application of CAR T cell-mediated therapy for solid tumors has so far been disappointing, and the reasons for this poor response in solid tumors remain unknown. In this issue of the JCI, Cherkassky and colleagues report on their use of a murine model of human pleural mesothelioma to explore potential factors that limit CAR T cell efficacy. Their studies have uncovered the importance of the tumor microenvironment in the inhibition of CAR T cell functions, revealed a critical role for the programmed death-1 (PD-1) pathway in CAR T cell exhaustion within the tumor microenvironment, and demonstrated improved antitumor effects with a CAR T cell-intrinsic PD-1 blockade strategy using a dominant negative form of PD-1. Together, the results of this study lay the groundwork for further evaluation of mechanisms underlying CAR T cell immune evasion within the tumor microenvironment for the improvement of CAR T cell-mediated therapy for solid tumors.

Figure 1. CAR T cell design.

All CARs contain an extracellular antigen-binding domain derived from an scFv that is composed of both the heavy and light chains of a TAA-targeting monoclonal antibody and an intracellular-signaling domain that is usually derived from the TCR CD3ζ chain to activate T cells. Only the CD3ζ signaling domain is present in first-generation CARs. For second-generation CARs, one additional costimulatory domain, such as CD28 or 4-1BB, is added, while third-generation CARs contain two costimulatory domains.