L15/TGF-beta trap fusokine for treatment of pediatric sarcomas
Mentor Name: Christian Capitini
Relapsed sarcomas remain an essentially incurable disease for many children, adolescents and young adults with cancer, with 5-year survival rates of less than 10%. Natural killer (NK) cells have been previously utilized to treat pediatric sarcomas but no complete remissions or durable responses were observed. Despite development of a variety of methods to activate NK cells, including interleukin (IL)-2, IL-12, IL-15, IL-18, IL-21, or artificial antigen presenting cells expressing CD137L or MICA, none of these approaches have been successful in achieving a potent enough anti-tumor response against pediatric sarcomas. One major obstacle may lie in the tumor microenvironment, specifically production of the immunosuppressive cytokine transforming growth factor-beta (TGF-beta), which inhibits NK cell proliferation and cytotoxicity. In fact, pediatric sarcomas like rhabdomyosarcoma and osteosarcoma were one of the first cancers that were found to express this cytokine and show its role in carcinogenesis. Inhibiting TGF-beta has thus become a potential treatment strategy for these and many other tumors. Simultaneously activating NK cells could provide a powerful "one-two" punch for inducing regression of sarcomas that are resistant to chemotherapy. Recently, a fusion protein called FIST15 has been designed that combines IL-15/IL-15 receptor alpha (IL-15Ra) with a TGF-beta receptor that can “trap” free TGF-beta and prevent it from engaging cells, and has been shown to mediate anti-tumor activity of murine melanoma via stimulation of NK cells. We have obtained FIST15 and verified IL-15 levels by ELISA. However, FIST15 has never been studied on pediatric sarcomas. In this proposal, we hypothesize that rhabdomyosarcoma and osteosarcoma can be cured with administration of FIST15 through activation of NK cells and reduction in serum TGF-beta.
