How Can We Engineer CAR T Cells to Overcome Resistance?

Abstract

Chimeric antigen receptor (CAR) T cell therapy has achieved unrivalled success in the treatment of B cell and plasma cell malignancies, with five CAR T cell products now approved by the US Food and Drug Administration (FDA). However, CAR T cell therapies for solid tumours have not been nearly as successful, owing to several additional challenges. Here, we discuss mechanisms of tumour resistance in CAR T cell therapy and the emerging strategies that are under development to engineer CAR T cells to overcome resistance.

Keywords: T-cell; cancer; chimeric antigen receptor; immunotherapy; resistance.

Figure 1

High level overview of strategies to engineer resistance in CAR T-cells. Tumour resistance to CAR T cell therapy can be overcome by (A) improving CAR T cell fitness to enhance proliferation, persistence and cytotoxicity; (B) engineering CAR T cells to resist the suppressive TME including checkpoint inhibitors, immunosuppressive cells and cytokines and the tumour stroma, whilst enhancing tumour homing and infiltration; (C) Engineering CAR T cells to overcome tumour resistance caused by antigen loss or downregulation by promoting epitope spreading, targeting multiple antigens or introducing artificial ligands to the tumour.

Figure 2

Structural components of CAR T cells. The structure of a first generation CAR consists of an antigen binding domain attached to a transmembrane domain via a hinge/spacer, followed by a CD3ξ signalling domain. Second generation CARs have an additional co-stimulatory domain and third generation CARs contain two co-stimulatory domains. Fourth generation CARs are armoured to secrete cytokines. All structural components of CAR T cells illustrated can be refined to enhance function.

Figure 3

Structure of CARs to target multiple antigens. Tumour antigen loss can be overcome by targeting multiple antigens by various CAR T cell structures. Dual CAR T cells contain two distinct 2G CARs expressed on a single cell which recognise two different target antigens. Trivalent CAR T cells contain three distinct CARs able to recognise three different target antigens. Tandem CARs contain two distinct scFvs fused together by a flexible linker. Universal CARs consist of universal receptor and an antigen binding adaptor molecule, of which different target binders can be utilised.