Mechanisms of Resistance to Immunotherapy in Osteosarcoma
Abstract
Topic Areas and Military Relevance Focus Area: This project will address the Topic Areas “Immunotherapy” and “Cancer in Children, Adolescents and Young Adults,” and the Military Relevance Focus Area “Gaps in cancer prevention, early detection/diagnosis, prognosis, treatment, and/or survivorship that affect the general population but have a particularly profound impact on the health and well-being of military Service members, Veterans, and their beneficiaries.” Scientific Objective and Rationale: Our objectives are to understand when and how the immune system can be engaged to treat malignant bone cancer, called osteosarcoma. Bone cancer is rare; fewer than 1,000 cases are diagnosed yearly in the U.S. However, its impact is disproportionate because it occurs mostly in children and adolescents, it creates much suffering, and more than half of the patients with this disease die within 10 years of their diagnosis because the tumor spreads to other organs, leading to many years of life lost. The foundation for this project comes from our recent work showing that patients where the immune system “engages” the tumor have better outcomes than patients where the immune system “ignores” the tumor. However, at this point it is not possible to determine which patients with osteosarcoma will benefit from immunotherapy (a type of treatment that uses the immune system to fight cancer). For this project, we will identify how osteosarcoma becomes resistant to immunotherapy. We believe that the tumors release small bags of cargo (vesicles) with biologically active genes and proteins. In some cases, the vesicles contain molecules that turn off tumor-fighting immune cells called T cells and prevent them from responding to immunotherapy. This will not only make the treatment ineffective, but it also will increase the probability of treatment-related side effects because the therapy can still activate the rest of the patient’s T cells. Applicability of the Research: We will use a comparative approach to understand when and how treatments that activate the immune system can be used for children with bone cancer. In the short term (1-3 years), we are working to reach that vision by creating knowledge. We believe that by providing patients and families honest, reliable, and evidence-based information, we de-mystify cancer and empower their ability to make treatment decisions. This research will enhance our understanding of how osteosarcoma interacts with the immune system, helping us to develop and refine new, rational, and more personalized treatment strategies. In the medium term (3-8 years), our work will provide a foundation to match patients with new immune-based treatments. In other words, being able to predict the probability that children with osteosarcoma would respond to immune checkpoint blockade therapy would be invaluable to help us manage risks and maximize benefits of this therapy. We also expect that in the medium term, our research would support and inform new clinical trials for our novel soluble PD-1 drug for immune checkpoint blockade. And in the long term (5-20 years), our efforts will help minimize side effects from traditionally toxic chemotherapy and guide use of immune therapies in patients that will receive the most benefit. We also envision this research could lead to new therapies for osteosarcoma and other childhood cancers, and even to development of strategies that use the immune system for lifelong cancer prevention. The approach we are testing is very different from the current standard of care, and it could improve on that standard of care by decreasing the need for, and use of, conventional chemotherapy. How is the proposed research relevant to active duty Service members, Veterans, and other military beneficiaries? About 32 of every 100,000 children under age 14 years are diagnosed with cancer every year in the US. While relatively rare, the American Cancer Society still lists cancer a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810068
Entities
People
- Jaime Modiano
Organizations
- United States Army
- University of Minnesota