BCMA- and CST6-specific CAR T cells lyse multiple myeloma cells and suppress murine osteolytic lesions

J Clin Invest. 2024 Jan 2;134(1):e171396. doi: 10.1172/JCI171396.


We have previously demonstrated that cystatin E/M (CST6), which is elevated in a subset of patients with multiple myeloma (MM) lacking osteolytic lesions (OLs), suppresses MM bone disease by blocking osteoclast differentiation and function. CST6 is a secreted type 2 cystatin, a cysteine protease inhibitor that regulates lysosomal cysteine proteases and the asparaginyl endopeptidase legumain. Here, we developed B cell maturation antigen (BCMA) CST6 chimeric antigen receptor T cells (CAR-T cells), which lysed MM cells and released CST6 proteins. Our in vitro studies show that these CAR-T cells suppressed the differentiation and formation of tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts. Using xenografted MM mice, bioluminescence images showed that both BCMA-CAR-T and BCMA-CST6-CAR-T cells inhibited MM growth to a similar extent. Reconstructed micro-computed tomography images revealed that BCMA-CST6-CAR-T cells, but not BCMA-CAR-T cells, prevented MM-induced bone damage and decreased osteoclast numbers. Our results provide a CAR-T strategy that targets tumor cells directly and delivers an inhibitor of bone resorption.

Keywords: Bone disease; Cancer immunotherapy; Hematology; Oncology.

MeSH terms

  • Animals
  • B-Cell Maturation Antigen
  • Cystatin M
  • Humans
  • Immunotherapy, Adoptive / methods
  • Mice
  • Multiple Myeloma* / pathology
  • Receptors, Chimeric Antigen*
  • T-Lymphocytes
  • X-Ray Microtomography


  • Receptors, Chimeric Antigen
  • B-Cell Maturation Antigen
  • CST6 protein, human
  • Cystatin M