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

Abstract

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 CD229 high T cells, they spare functional CD229 neg/low T cells. These findings indicate that CD229 CAR T cells may be an effective treatment for patients with MM.

CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions

“…Intriguingly, CD229 is expressed on myeloma-precursor cells responsible for the relapse after treatment. CD229 CAR-T cells have been developed and tested in pre-clinical studies with promising results (136,137).…”

Immune Functions of Signaling Lymphocytic Activation Molecule Family Molecules in Multiple Myeloma

“…Moreover, the blockade of SLAMF3-mediated self-ligation between MM cells suppresses cell proliferation and facilitates melphalan-induced apoptosis [ 63 ]. Atanackovic’s group developed an innovative CAR-T cell therapy specific for SLAMF3 on MM cells [ 70 ]. Those CAR-T cells efficiently killed SLAMF3 high plasma cells but not SLAMF3 low T cells or native B cells.…”

“…Those CAR-T cells efficiently killed SLAMF3 high plasma cells but not SLAMF3 low T cells or native B cells. Interestingly, SLAMF3 CAR-T cells more effectively eliminated SLAMF3-positive, BCMA-negative memory B cells (which include putative clonotypic MM progenitor cells) when compared with BCMA CAR-T cells [ 70 ]. Thus, SLAMF3-targeted CAR-T therapy could potentially prevent posttreatment MM relapse, unlike BCMA CAR-T therapy.…”

Contribution of Macrophages and T Cells in Skeletal Metastasis

“…Despite that, this study shows that CD19-CAR-T cell therapy could be adapted for patients with myeloma. Alternative treatments are developed and tested by CARs recognizing other surface antigen on myeloma cells such as CD138, SLAMF7, the κ light chain, BCMA, or CD229 [341][342][343]. CAR-T cells could also be used for the treatment of carcinoma if the appropriate antigen is targeted.…”