Toward improvement of BCMA/CST6-CAR-T therapy to target both myeloma cells and bone resorption
Fenghuang Zhan
MD, PhDUniversity of Arkansas for Medical Sciences
Project Term: July 1, 2024 - June 30, 2027
We have observed that non-glycosylated CST6 proteins suppress osteoclast differentiation and function without causing immunosuppression. We aim to determine whether BCMA-CAR-T cells which are engineered to secret CST6 proteins kill myeloma cells and suppress bone lytic lesions without immune suppressive effects in myeloma. Our ultimate goal is to develop a CAR-T-cell based immune therapy to prevent bone loss and disease progression in myeloma patients.
Multiple myeloma (MM) predominantly effects bone leading to severe osteolytic disease. Currently, bisphosphonates, which have been approved by the FDA, are the most prescribed agents to prevent and treat osteolytic bone diseases in MM. However, one noticeable side effect of bisphosphonates is bone and cartilage necrosis after long-term usage, and there is no convincing evidence that they show any effect on cancer cell itself. Therefore, there is an unmet demand for novel therapies to both repair bone damage and kill MM. Our goal in this application is to develop novel treatments to accomplish both actions. We recently discovered that elevated expression of cystatin M/E (CST6) in about 20% MM patients was significantly associated with the absence of osteolytic lesions based on combined PET-CT and gene expression profiling of purified CD138+ MM cells from 512 newly diagnosed MM patients. We further determined that CST6 protein prevented osteolytic bone disease in MM mouse models. Both recombinant CST6 protein (rCST6) and bone marrow serum from MM patients with high CST6 expression significantly inhibited activity of osteoclast-specific protease cathepsin K, and blocked osteoclast differentiation and function. Such inhibitory effects of CST6 on osteoclasts were not only observed in MM mice but also in an osteoporotic mouse model. However, rCST6 decreased CD8+ T cells, suggesting that MM cells promote their growth and/or survival, through CST6’s immunosuppressive effects in the tumor microenvironment. We further found that N-glycosylation of CST6 proteins, but not non-N-glycosylation of CST6 proteins, showed strong immunosuppression of T cell proliferation in myeloma. We also identified that a mutant of CST6 (CST6Mu) protein showed suppression of osteoclast formation and function without decrease in immune responsive T cells. BCMA-CAR-T cell therapies represent a promising new treatment strategy for MM. We have developed a new therapy that targets BCMA and at the same time releases CST6 protein. In this proposed study, we will further establish a CST6 mutant (CST6Mu) without glycosylation as a biological agent to prevent MM bone disease and progression; we will also determine therapeutic effects of BCMA/CST6Mu -CAR-T cells in targeting MM cells and suppressing MM cells-induced bone damage. Our studies will provide a novel strategy based on CAR-T cells that targets tumor cells directly and delivers an inhibitor of bone resorption in myeloma.