Special Chimeric Antigen Receptor (CAR) Modifications of T Cells: A Review

Abstract

Chimeric antigen receptor (CAR) -T cell therapy has become one of the hot topics in tumor immunity research in recent years. Although CAR-T cell therapy is highly effective in treating hematological malignancies, there are numerous obstacles that prevent CAR-T cells from having anti-tumor effects. Traditional CARs, from the first to the fourth generation, are incapable of completely overcoming these challenges. Therefore, identifying ways to boost the efficacy of CAR-T cells by utilizing the limited tumor surface antigens has become an urgent area of research. Certain special CARs that have special structures, special systems, or are greatly improved on the basis of traditional CARs, such as tandem CAR, dual-signaling CARs, AND-gate CARs, inhibitory CAR, AND-NOT CARs, CARs with three scFvs, ON/OFF-switch CARs, and universal CARs have been introduced. This study aims to use these special CARs to improve the anti-tumor ability, accuracy, and safety of CAR-T cells. In addition to summarizing various special CARs of T cells, this paper also expounds some of our own conjectures, aiming to provide reference and inspiration for CARs researchers.

CAR-T cell potency: from structural elements to vector backbone components

“…Therefore, efforts to develop CAR-T cell immunotherapy must confront this high diversity of potential target antigen expression; otherwise, treatment failure or tumor recurrence may occur [ 33 ]. Designing CARs with two scFvs in which two corresponding scFvs target two different antigens, such as tandem CARs (TanCAR), dual CARs, loop CARs, AND-gate CARs (synNotch-CAR), and inhibitory CARs (iCARs), is a common strategy to improve the specificity of CARs [ 30 , 34 ]. In the TanCAR concept, also referred to as OR-gate CAR, two different scFvs are connected outside the cell (in series), usually by a glycine-serine linker [ 35 , 36 ].…”

A promising antitumor method: Targeting CSC with immune cells modified with CAR

“…Mohammadmahdi Sabahi et al proposed a tandem ANDgate CAR-T cell which utilized a combination of a modular synthetic Notch receptor (synNotch) and a tandem CAR-T cells to target glioblastoma CSCs (79). Additionally, some other special CARS, such as dual-signaling CARs, inhibitory CARs, AND-NOT CARs, CARs with three scFvs, ON/OFF-switch CARs, and universal CARs, have been proposed and proven their success and advantages in tumor therapy (80). However, these CARs mainly target common tumor cells, not CSC.…”

Tumor Microenvironment Immunosuppression: A Roadblock to CAR T-Cell Advancement in Solid Tumors

“…Many variations have been made to the structure or composition of CARs and CAR T cells to improve their efficacy in solid tumors, the extent of which is beyond this review (see cited reviews for extensive detail on many different CAR varieties and applications) [ 5 , 113 , 114 , 115 ]. These modifications range from multi-specific CARs which bind multiple antigens to logic gated CAR T cells to cytokine secreting CAR T cells and CARs engineered into other cell types besides T cells [ 5 ].…”