CAR T-cell therapy in multiple myeloma: more room for improvement

Abstract

The emergence of various novel therapies over the last decade has changed the therapeutic landscape for multiple myeloma. While the clinical outcomes have improved significantly, the disease remains incurable, typically in patients with relapsed and refractory disease. Chimeric antigen receptor (CAR) T-cell therapies have achieved remarkable clinical success in B-cell malignancies. This scope of research has more recently been extended to the field of myeloma. While B-cell maturation antigen (BCMA) is currently the most well-studied CAR T antigen target in this disease, many other antigens are also undergoing intensive investigations. Some studies have shown encouraging results, whereas some others have demonstrated unfavorable results due to reasons such as toxicity and lack of clinical efficacy. Herein, we provide an overview of CAR T-cell therapies in myeloma, highlighted what has been achieved over the past decade, including the latest updates from ASH 2020 and discussed some of the challenges faced. Considering the current hits and misses of CAR T therapies, we provide a comprehensive analysis on the current manufacturing technologies, and deliberate on the future of CAR T-cell domain in MM.

Fig. 1. The time line of CAR T-cell development.

The history of CAR T cells and its progress and milestones achieved over the years. Red fonts are the time line for CAR T-cell development in myeloma.

Fig. 2. The basic principle of CAR T-cell therapy.

a T lymphocytes are genetically modified to express chimeric antigen receptor which is made up of monoclonal antibody targeting specific antigen of interest. ScFV Single chain variable fragment, Vh Heavy chain, VL Light chain. b ScFV portion of CAR T cell recognizes tumor-associated antigen on the surface of tumor cells, binds to them, and initiates a cascade of cytotoxic signaling, leading to tumor lysis.

Fig. 3. The depiction of different generations of CAR T cell.

First-generation CAR contains basic design with the ScFV portion of monoclonal antibody at the ectodomain, hinge at the transmembrane domain and CD3ζ signaling molecule at the endodomain. Second- and third-generation CARs comprise additional one or two co-stimulatory molecule/s in the endodomain, respectively. Fourth-generation CAR (TRUCK) follows the basic design of second-generation CAR, coupled with an added transgene encoding for a cytokine (transgenic protein).

Fig. 4. CAR T-cell manufacturing pipeline.

The process starts off with leukapheresis to obtain PBMCs from the patients. Enrichment of T cells is done prior to genetic modifications via viral or non-viral gene delivery system. This is followed by immunophenotyping analysis to determine the cytokine and cytolytic profile of the CAR T cells. Positive CAR T cells are selected to undergo ex vivo expansion in a bioreactor vessel containing growth factor-enriched media. When the required amount is obtained, the CAR T cells will be transported back to the clinic for patient infusion.

Fig. 5. CD19-antigen decoy for innovative targeting of myeloma cells.

Increased expression of CD19 is induced on the myeloma cells by artificially creating the protein-anti-BCMA antibody complex that binds to endogenous surface BCMA. Highly potent and specific anti-CD19 CAR-T can be used to target these synthetic myeloma cells.