Evolving CAR-T-Cell Therapy for Cancer Treatment: From Scientific Discovery to Cures

Abstract

In recent years, chimeric antigen receptor (CAR)-T-cell therapy has emerged as the most promising immunotherapy for cancer that typically uses patients' T cells and genetically engineered them to target cancer cells. Although recent improvements in CAR-T-cell therapy have shown remarkable success for treating hematological malignancies, the heterogeneity in tumor antigens and the immunosuppressive nature of the tumor microenvironment (TME) limits its efficacy in solid tumors. Despite the enormous efforts that have been made to make CAR-T-cell therapy more effective and have minimal side effects for treating hematological malignancies, more research needs to be conducted regarding its use in the clinic for treating various other types of cancer. The main concern for CAR-T-cell therapy is severe toxicities due to the cytokine release syndrome, whereas the other challenges are associated with complexity and immune-suppressing TME, tumor antigen heterogeneity, the difficulty of cell trafficking, CAR-T-cell exhaustion, and reduced cytotoxicity in the tumor site. This review discussed the latest discoveries in CAR-T-cell therapy strategies and combination therapies, as well as their effectiveness in different cancers. It also encompasses ongoing clinical trials; current challenges regarding the therapeutic use of CAR-T-cell therapy, especially for solid tumors; and evolving treatment strategies to improve the therapeutic application of CAR-T-cell therapy.

Keywords: B-cell lymphoma; TCR-T-cell receptor; blood cancer; cancer treatment; checkpoint blockade; chimeric antigen receptor (CAR); combination therapy; cytokine release syndrome; hematological malignancies; immuno-oncology; immunomodulation; immunotherapy; solid tumor; tumor microenvironment (TME).

Figure 1

Cartoon diagram representing a typical interaction mechanism of CAR-T cells with targeted cancer cells: CAR-T cells can recognize tumor cells by binding with specific tumor-associated antigens (TAA) independent of TCR-MHC/peptide interactions. As a result, T cells are activated. CAR-T cells can induce apoptosis via the secretion of perforin, granzymes, and different pro-inflammatory cytokines, as well as the expression of the Fas ligand (FasL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).

Figure 2

Schematic representation of the basic principle of CAR architecture. (A) Cartoon diagram showing the binding moiety of CAR, where scFv comes from a TAA-specific monoclonal antibody and the signaling domain(s) comes from activating and co-stimulatory immune receptors. (B) Cartoon diagram showing the progressive evolution of CAR-T cells from first generation to fifth generation: first-generation CAR contains a single-chain variable fragment (scFv) and CD3ζ for signal transduction; an additional co-stimulatory domain (co-stimulatory domain 1: CSD 1) was added on first-generation CAR to make a second generation, whereas two additional co-stimulatory domains (CSD1 and CSD 2) were added on first-generation CAR to make third-generation CAR; one additional domain for cytokine-expression (cytokine inducer: CI) was added on second-generation CAR to make fourth-generation CAR; fifth-generation CAR contains a co-stimulatory domain (co-stimulatory domain 1) and an additional domain that activates signaling pathways such as STATE3/5. (C) Cartoon diagram showing the basic structure of a typical CAR with the functions of individual domains.

Figure 3

Cartoon diagram showing different stages of autologous CAR-T-cell production: The generation of autologous CAR-T cells started with the leukapheresis of a patient (A), followed by the separation of T cells (B); then, T cells were transduced to permanently integrate CAR transgene (C). After that, these genetically modified CAR-T cells expanded (D) and infused back into the patient (E).

Figure 4

Cartoon diagram showing the strategy of targeting two antigens using an engineered synthetic Notch receptor-CAR circuit that drives the expression of CAR.