Novel progresses of chimeric antigen receptor (CAR) T cell therapy in multiple myeloma

Abstract

Multiple myeloma (MM) is a malignant proliferative disease of plasma cells, which leads to suppressed hematopoietic and osteolytic diseases. Despite the use of traditional chemotherapy, hematopoietic stem cell transplantation (HSCT) and targeted drugs, MM still cannot be completely cured. In recent years, chimeric antigen receptor (CAR) T cells have revolutionized immunotherapy and cancer treatment. The great success of CAR-T cells in leukemia and lymphoma has promoted its development in MM. The primary requisite for developing clinically effective CAR-T cells suitable for MM is to identify the appropriate targets. In early clinical trials, CAR-T cells targeting B-cell maturation antigen (BCMA) have shown significant anti-MM activity. Currently popular targets in clinical research and preclinical research include CD138, CD38, CS1, CD19, κ light chain, CD56, CD44v6, Lewis Y, NY-ESO-1, CD229, etc. Common toxicities such as cytokine release syndrome (CRS) and neurotoxicity also occur but controllable. MM cells are mainly localized in bone marrow, therefore, the bone marrow microenvironment has a significant effect on the therapeutic effect of CAR-T cells. Targeting both MM cells and the bone marrow microenvironment is currently the most promising treatment. In this review, we provide a comprehensive overview of CAR-T cell therapy in MM, as well as outline potential targets and methods that can overcome local immunosuppression and improve the efficacy of CAR-T cells.

Keywords: B-cell maturation antigen (BCMA); Chimeric antigen receptor T cells (CAR-T cells); microenvironment; multiple myeloma (MM); target.

Figure 1

Process of CAR-T treatment. (I) Collect lymphocyte from patients’ peripheral blood and isolate T cells; (II) infect T cells with CAR lentivirus; (III) before infusion, expand CAR-T cells and control the quality; (IV) infuse CAR-T cells to patients according to weight. CAR, chimeric antigen receptor.

Figure 2

Models of bone marrow microenvironment in MM. The blue arrows indicate the pathways which can be targeted in order to achieve an immunosuppressive effect. The red signs indicate the effect of promoting or inhibiting. MM, multiple myeloma; IMiDs, immunomodulatory drugs; MDSC, myeloid-derived suppressor cells; Treg, T regulatory cells; DC, dendritic cells; CTL, cytotoxic T lymphocyte; NK, natural killer cell; Th1, type 1 helper T cells; PDE5, phosphodiesterase type 5; 5-FU, 5-fluorouracil; TGF-β, transforming growth factor beta; IL-35, interleukin-35; IL-10, interleukin-10.