CD229 CAR T cells eliminate multiple myeloma and tumor propagating cells without fratricide.

Multiple myeloma (MM) is a plasma cell malignancy and most patients eventually succumb to the disease. Chimeric antigen receptor (CAR) T cells targeting B-Cell Maturation Antigen (BCMA) on MM cells have shown high-response rates, but limited durability. CD229/LY9 is a cell surface receptor present on B and T lymphocytes that is universally and strongly expressed on MM plasma cells. Here, we develop CD229 CAR T cells that are highly active in vitro and in vivo against MM plasma cells, memory B cells, and MM-propagating cells. We do not observe fratricide during CD229 CAR T cell production, as CD229 is downregulated in T cells during activation. In addition, while CD229 CAR T cells target normal CD229high T cells, they spare functional CD229neg/low T cells. These findings indicate that CD229 CAR T cells may be an effective treatment for patients with MM. CD229 is expressed on the surface of multiple myeloma cells, as well as B and T lymphocytes. Here, the authors engineer CD229-specific CAR T cells and, using patient samples and mouse models, show that treatment with these cells reduces tumour burden and results in limited targeting of T cells.