CARTs on the road for myeloma

Abstract

Chimeric antigen receptors redirect T cells to surface antigens. Discovery and validation of appropriate target antigens expands the possible indications for chimeric-antigen receptor (CAR) T cells. CS1 is expressed at high levels by multiple myeloma cells, but also to some extent on other lymphocytes. CS1 may be a viable target for CAR T cells in multiple myeloma.

Figure

Myeloma is currently treated with combinations of chemotherapy, steroids, and radiation. Novel drugs include proteasome inhibitors such as bortezomib and carfilzomib, and immunomodulatory agents such as thalidomide, lenalidomide, and pomalidomide. Elotuzumab is a monoclonal antibody targeting the glycoprotein CS1 that has been shown to have activity in combination with novel drugs. CS1 is expressed on myeloma cells and on other lymphocyte subsets, including T cells and NK cells; it is also shed into the circulation. Chimeric antigen receptors (CARs) targeting CS1 and introduced into T cells (or NK cells) can kill CS1-expressing myeloma cells, but do not appear to mediate T cell intrinsic suicide. Outstanding questions are whether CS1-directed T cells will have subtle fratricide effects on bystander T cells, and whether soluble CS1 will inactivate the CS1 CARs.