Current progress in CAR-T cell therapy for tumor treatment

Abstract

Chimeric antigen receptor T (CAR-T) cells are a type of tumor immunotherapy that is a breakthrough technology in the clinical treatment of tumors. The basic principle of this method is to extract the patient's T cells and equip them with targeting recognition receptors of tumor cells and return them to the patient's body to recognize and kill tumor cells specifically. Most CAR-T cell therapies treat hematological diseases such as leukemia or lymphoma and achieved encouraging results. The safety and effectiveness of CAR-T cell technology in solid tumor treatment require to be improved, although it has demonstrated promising efficacy in treating hematological malignancies. It is worth noting that certain patients may experience fatal adverse reactions after receiving CAR-T cell therapy. At present, the difficulty of this therapy mainly lies in how to reduce adverse reactions and target escape effects during the course of treatment. The improvement of CAR-T cell therapy mainly focuses on improving CAR-T structure, finding suitable tumor targets and combining them with immune checkpoint inhibitors to the enhance efficacy and safety of treatment. The problems in the rapid development of CAR-T cell therapy provide both obstacles and opportunities. The present review elaborates on the clinical application of CAR-T cell technology to provide a reference for clinical practice and research on tumor treatment.

Keywords: adverse reactions; chimeric antigen receptor T cells; overcoming strategies; tumor treatment.

Figure 1.

Schematic illustrating the principle of CAR-T cell therapy: Lymphocytes are obtained from patients and T cells are isolated. These T cells are transferred into specific CAR genes through viral or non-viral vectors and thereby transformed into CAR-T cells. These CAR-T cells are expanded in vitro and returned to the patient's body to identify and kill tumor cells specifically. CAR-T, chimeric antigen receptor T-cell; VL, variable region of light chain; VH, variable region of heavy chain.

Figure 2.

Mechanisms of tumor cell recognition by T cells. In traditional CTL cell therapy, the TCR recognizes tumor antigen peptides presented by MHC molecules on the tumor cells' surface through the TCR-CD3 complex, activates with the assistance of co-stimulation molecules and releases cytotoxic substances to kill tumor cells. By contrast, CAR-T is able to recognize the antigen of tumor cells through the scFv; this recognition is not restricted by MHC molecules, which has significant advantages over the traditional CTL cell therapy. CTL, cytotoxic T lymphocyte; TCR, T cell receptor; scFv, single chain fragment variable; MHC, major histocompatibility complex; CAR-T, chimeric antigen receptor T-cell.

Figure 3.

Evolution of the development of CAR-T cell products: First-generation CAR-T cells only contain CD3ζ-derived signaling modules. Second-generation CAR-T cells contain a CD3ζ-derived signaling module and a co-stimulatory domain. Third-generation CAR-T cells contain a CD3ζ-derived signaling module and two co-stimulatory domains, including 4-1BB, CD28, OX40 or ICOS. Fourth-generation CAR-T cells contain a CD3ζ-derived signaling module, co-stimulatory domain and a cytokine (such as IL-12) producing module. Fifth-generation CAR-T cells consist of Zip CAR and zip FV with leucine adapters. The horizontal membrane in the middle is the cell membrane, which is a lipid bilayer. CAR-T, chimeric antigen receptor T-cell; VL, variable region of light chain; VH, variable region of heavy chain; FV, fragment variable; OX40, tumor necrosis factor receptor superfamily member 4; ICOS, inducible costimulatory molecule.

Figure 4.

Tumor cells and surrounding non-tumor cells form a TME; the functions of CAR-T cells are impaired by inhibitory molecules, high glucose consumption or competition of amino acids by tumor cells in the TME. TME, tumor microenvironment; CAR-T cell, chimeric antigen receptor T-cell.