Redirecting B7H3 CAR T cells To Sarcoma using Midkine Receptors

Jessica Lake, MD,  University of Colorado
Recipient of the: $50,000 Sarcoma Foundation of America Research Award

Advances in pediatric oncology have occurred for some cancers, however, new therapies for sarcoma (osteosarcoma and rhabdomyosarcoma) have been sparse. The 5-year disease-free survival is 20-30% for patients with metastatic sarcoma at diagnosis or recurrent disease after front-line therapy. Cellular immunotherapy using chimeric antigen receptor (CAR) T cells has shown dramatic benefits in leukemia but has not been successful in solid tumors, including sarcoma. One limitation of CAR T cell therapy has been the inability of modified immune cells to traffic into the tumor. Thus, improved cell homing is necessary and expected to be a critical step to improve CAR T cell therapy for patients with a variety of solid tumors. Chemokines are small, secreted proteins that mediate the homing and migration of immune cells. Midkine, a heparin-binding growth factor, induces chemotaxis of neutrophils and is abnormally expressed by a variety of malignancies. In preliminary studies, midkine was shown to be highly expressed by both osteosarcoma and rhabdomyosarcoma. Syndecans, a four-member family of transmembrane proteoglycans, are cell surface receptors that bind midkine. This proposal focuses on overexpressing the syndecans (1-4) on the surface of T cells which I hypothesize will improve T cell homing into the tumor microenvironment of sarcoma. When combined with a CAR that targets sarcoma, these syndecan-expressing CAR T cells could significantly improve outcomes for patients with sarcoma.