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.

Conflict of interest statement

Conflict-of-interest disclosure: J.N.K. receives research funding from cooperative research and development agreements between the National Cancer Institute (NCI) and Kite Pharma Inc, and between the NCI and Bluebird Bio Inc, and also has multiple patent applications related to CARs. L.M. declares no competing financial interests.

Figures

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.