Current advances and challenges in CAR T-Cell therapy for solid tumors: tumor-associated antigens and the tumor microenvironment

Abstract

The past decade has witnessed ongoing progress in immune therapy to ameliorate human health. As an emerging technique, chimeric antigen receptor (CAR) T-cell therapy has the advantages of specific killing of cancer cells, a high remission rate of cancer-induced symptoms, rapid tumor eradication, and long-lasting tumor immunity, opening a new window for tumor treatment. However, challenges remain in CAR T-cell therapy for solid tumors due to target diversity, tumor heterogeneity, and the complex microenvironment. In this review, we have outlined the development of the CAR T-cell technique, summarized the current advances in tumor-associated antigens (TAAs), and highlighted the importance of tumor-specific antigens (TSAs) or neoantigens for solid tumors. We also addressed the challenge of the TAA binding domain in CARs to overcome off-tumor toxicity. Moreover, we illustrated the dominant tumor microenvironment (TME)-induced challenges and new strategies based on TME-associated antigens (TMAs) for solid tumor CAR T-cell therapy.

Keywords: CAR T cells; Solid tumor; TAAs; TMAs; TSAs.

Fig. 1

Four generations of CAR T cells. ​An overview of the four generations of CARs displayed on the surface of a T-cell while contacting their antigens on a tumor cell. scFvs that act as ligand-binding domains in CARs mediating tumor cell recognition are shown in red, with VH and VL domains connected to intracellular signaling domains via a hinge and a transmembrane domain

Fig. 2

TAAs and TAA binding domain design strategy for developing multispecific CARs for solid tumors. TAAs and TSAs were selected as CAR T-cell targets. To overcome the challenges of tumor antigen off-target effects and heterogeneity, dual CARs or tandem CARs have been constructed to target dual TAAs. scFv affinity, steric hindrance, and stability were considered for the construction of CARs, and VHH nanobodies were applied as TAA binding domains to develop multispecific CARs for solid tumors

Fig. 3

The immunosuppressive tumor microenvironment hinders CAR T-cell therapy for solid tumors. The solid tumor microenvironment is a complex and evolving entity containing immune-suppressing cells such as Tregs, MDSCs, TAMs and TANs; there are also CAFs, endothelial cells and extracellular matrix. The immunosuppressive ligands PD-L1, ARG-1, ARG-2, CTLA-4, and IDO secreted by those cells in the TME may all quell the intrinsic antitumor immune response, as well as the CAR T-cell response that helps tumor cells evade immune cell attack. Targeting those TMAs not only leads to a direct attack on the tumor cells but also modulates the tumor microenvironment, rendering it immunocompetent and tumor-hostile. Tregs regulatory T cells; TAM tumor-associated macrophages; TAN tumor-associated neutrophils; Anti-Tregs anti-regulatory T cells; MDSC myeloid-derived suppressor cells; TEff effector T cells; CAF cancer-associated fibroblasts. PD-L1 programmed cell death 1 ligand 1; IDO indoleamine 2,3-dioxygenase; ARG-1 arginase 1; ARG2 arginase 2; CTLA-4 cytotoxic T-lymphocyte-associated protein 4