Analysis of causes for poor persistence of CAR-T cell therapy in vivo

Abstract

Chimeric antigen receptor T-cell (CAR-T-cell) therapy has been well researched to date because of its ability to target malignant tumor cells. The most common CAR-T cells are CD19 CAR-T cells, which play a large role in B-cell leukemia treatment. However, most CAR-T cells are associated with relapse after clinical treatment, so the quality and persistence of CAR-T cells need to be improved. With continuous optimization, there have been four generations of CARs and each generation of CARs has better quality and durability than the previous generation. In addition, it is important to increase the proportion of memory cells in CAR-T cells. Studies have shown that an immunosuppressive tumor microenvironment (TME) can lead to dysfunction of CAR-T cells, resulting in decreased cell proliferation and poor persistence. Thus, overcoming the challenges of immunosuppressive molecules and targeting cytokines in the TME can also improve CAR-T cell persistence. In this paper, we explored how to improve the durability of CAR-T cell therapy by improving the structure of CARs, increasing the proportion of memory CAR-T cells and improving the TME.

Keywords: CAR-T cells; relapsed/refractory; the proportion of memory CAR-T cells; the structure of CARs; tumor microenvironment.

Figure 1

Evolution of chimeric antigen receptors (CARs). Each CAR generation contains an extracellular single-stranded variable region (scFv), an intracellular CD3 domain (CD3ζ) and a T-cell receptor transmembrane domain. The first generation of CARs has only the CD3 domain in the cell. The second generation of CARs includes the CD3 domain and the costimulatory domain (CM). Developed on the basis of second-generation CARs, the third generation of CARs has two different costimulatory domains in the cell. Developed based on the structure of second-generation of CARs, fourth-generation of CARs have an additional intracellular domain that regulates the expression of cytokines or other costimulatory molecules.

Figure 2

A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains.