CAR T cells in solid tumors: challenges and opportunities

Abstract

Background: CARs are simulated receptors containing an extracellular single-chain variable fragment (scFv), a transmembrane domain, as well as an intracellular region of immunoreceptor tyrosine-based activation motifs (ITAMs) in association with a co-stimulatory signal.

Main body: Chimeric antigen receptor (CAR) T cells are genetically engineered T cells to express a receptor for the recognition of the particular surface marker that has given rise to advances in the treatment of blood disorders. The CAR T cells obtain supra-physiological properties and conduct as "living drugs" presenting both immediate and steady effects after expression in T cells surface. But, their efficacy in solid tumor treatment has not yet been supported. The pivotal challenges in the field of solid tumor CAR T cell therapy can be summarized in three major parts: recognition, trafficking, and surviving in the tumor. On the other hand, the immunosuppressive tumor microenvironment (TME) interferes with T cell activity in terms of differentiation and exhaustion, and as a result of the combined use of CARs and checkpoint blockade, as well as the suppression of other inhibitor factors in the microenvironment, very promising results were obtained from the reduction of T cell exhaustion.

Conclusion: Nowadays, identifying and defeating the mechanisms associated with CAR T cell dysfunction is crucial to establish CAR T cells that can proliferate and lyse tumor cells severely. In this review, we discuss the CAR signaling and efficacy T in solid tumors and evaluate the most significant barriers in this process and describe the most novel therapeutic methods aiming to the acquirement of the promising therapeutic outcome in non-hematologic malignancies.

Keywords: CAR T cells; Cell therapy; Chimeric antigen receptor; Solid tumors.

Fig. 1

CAR T cell engineering. The design of the CAR T cell has evolved by combining existing immune cell components to facilitate direct targeting of tumor antigens. scFv of CAR-induced light and heavy chains of the antibody variable region, whereas the CAR amplitude CD3ζ has been derived from the intracellular signaling domains of the TCR

Fig. 2

CAR T cell engineering. The specificity of T cells against tumor cells is mediated by CAR proteins. CAR is a combination of extracellular proteins and is usually derived from antibodies and intracellular signaling modules derived from T cell signaling proteins. First-generation CARs have been composed of CD3ζ, while adding  a costimulatory endodomain including CD28 or 4BB to CD3ζ has led to the creation of second-generation CARs. Third-generation cars include two costimulatory domains fused to CD3ζ. VH, variable heavy chain; VL, variable light chain; scFv, single-chain variable fragment. Generation of CAR T cells leads to the initiation of different signaling pathways which caused cell survival, proliferation, and cytokine production

Fig. 3

T cell-mediated antitumor effects by chimeric antigen receptors. CAR-modified T cells can detect tumor cells by CAR binding to TAA independent of the TCR-MHC/peptide interaction

Fig. 4

T cell-mediated antitumor effects by chimeric antigen receptors. T cells are activated and can kill tumor cells by secreting granzymes and perforin, as well as the expression of TRAIL and FasL. Moreover, immune cells that invade the tumor can be activated by secreting various cytokines

Fig. 5

Isolation of CAR T cells and its interaction with tumor-associated antigens (TAA) in solid tumors. T cells are collected from patients’ peripheral blood via leukophores and are designed to express chimeric antigen receptors to tumor-specific antigens. These cells proliferate before being re-injected. After injection, autologous CAR-engineered T cells detect TAA and binds to its corresponding ligand, leading to the secretion of cytokines and the interaction of some apoptosis-related ligands, which ultimately leads to the destruction of tumor cells