Chimeric antigen receptor T-cell therapies for multiple myeloma

Abstract

Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells, so new approaches to treatment are needed. T-cell therapies are a promising approach for treating MM, with a mechanism of action different than those of standard MM treatments. Chimeric antigen receptors (CARs) are fusion proteins incorporating antigen-recognition domains and T-cell signaling domains. T cells genetically engineered to express CARs can specifically recognize antigens. Success of CAR-T cells (CAR-Ts) against leukemia and lymphoma has encouraged development of CAR-T therapies for MM. Target antigens for CARs must be expressed on malignant cells, but expression on normal cells must be absent or limited. B-cell maturation antigen is expressed by normal and malignant plasma cells. CAR-Ts targeting B-cell maturation antigen have demonstrated significant antimyeloma activity in early clinical trials. Toxicities in these trials, including cytokine release syndrome, have been similar to toxicities observed in CAR-T trials for leukemia. Targeting postulated CD19⁺ myeloma stem cells with anti-CD19 CAR-Ts is a novel approach to MM therapy. MM antigens including CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain are under investigation as CAR targets. MM is genetically and phenotypically heterogeneous, so targeting of >1 antigen might often be required for effective treatment of MM with CAR-Ts. Integration of CAR-Ts with other myeloma therapies is an important area of future research. CAR-T therapies for MM are at an early stage of development but have great promise to improve MM treatment.

Figure 1.

A diagram of a CAR is shown. The antigen-binding domain of a CAR is attached to intracellular T-cell signaling moieties by an extracellular hinge domain and a transmembrane region. The CAR antigen-binding domain is usually a scFv derived from a monoclonal antibody. Examples of costimulatory domains are CD28 and 4-1BB. The T-cell activation domain is usually from the CD3Zeta molecule. Professional illustration by Patrick Lane, ScEYEnce Studios.

Figure 2.

A representation of the CAR-T therapy process is shown. Cells are harvested from patients by apheresis. T cells are activated and genetically modified with a CAR gene that will lead to expression of a CAR protein on the T cells. Genetic modification is carried out with a gene-therapy vector such as a γ-retrovirus or a lentivirus. CAR-expressing T cells proliferate ex vivo. Patients often receive a chemotherapy conditioning regimen to deplete endogenous leukocytes with a goal of enhancing CAR-T activity. After completion of the conditioning chemotherapy regimen, CAR-Ts are infused. Professional illustration by Patrick Lane, ScEYEnce Studios.