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

Area of Science:

• Oncology
• Immunology
• Bone Biology

Background:

• Cystatin E/M (CST6) is elevated in multiple myeloma (MM) patients lacking osteolytic lesions (OLs) and suppresses bone disease by inhibiting osteoclast activity.
• CST6 is a secreted cysteine protease inhibitor regulating lysosomal proteases and legumain.
• Osteoclast differentiation and function are critical in MM-induced bone destruction.

Purpose of the Study:

• To develop and evaluate B cell maturation antigen (BCMA) CST6 chimeric antigen receptor T cells (CAR-T cells) for targeting MM and its associated bone disease.
• To assess the efficacy of BCMA-CST6-CAR-T cells in inhibiting MM cell growth and preventing MM-induced bone damage in preclinical models.

Main Methods:

• Development of BCMA-CST6-CAR-T cells engineered to lyse MM cells and secrete CST6.
• In vitro assessment of CAR-T cell-mediated suppression of osteoclast differentiation and formation (TRAP+ osteoclasts).
• In vivo studies using xenografted MM mice with bioluminescence imaging for tumor growth and micro-computed tomography (micro-CT) for bone damage assessment.

Main Results:

• BCMA-CST6-CAR-T cells effectively lysed MM cells and released CST6 proteins in vitro.
• In vitro studies demonstrated suppression of osteoclast differentiation and formation by BCMA-CST6-CAR-T cells.
• Both BCMA-CAR-T and BCMA-CST6-CAR-T cells inhibited MM tumor growth similarly in vivo.
• BCMA-CST6-CAR-T cells, but not BCMA-CAR-T cells, prevented MM-induced bone damage and reduced osteoclast numbers in mice.

Conclusions:

• BCMA-CST6-CAR-T cells represent a novel therapeutic strategy for multiple myeloma.
• This approach combines direct tumor targeting with the delivery of an inhibitor of bone resorption, addressing both tumor burden and skeletal complications.
• The findings suggest potential for BCMA-CST6-CAR-T cells in managing MM bone disease.