Altering the Tumor Microenvironment to Augment Neuroblastoma Immunotherapy
Abstract
The work outlined in this application addresses the Topic Areas of: [1] neuroblastoma and [2] cancer in children, adolescents, and young adults. Neuroblastoma is a common solid tumor of childhood. While some children with localized tumors are cured with surgery alone or very modest chemotherapy, the majority of children with neuroblastoma have tumors that are very aggressive and spread through the body. We treat such “high-risk” children with an extremely intense and toxic combination of surgery, chemotherapy, stem cell transplant, radiation therapy and biotherapy, yet outcomes remain dismal. Only about half of such children are cured, many with lifelong complications of their treatment, and neuroblastoma is responsible for ~15% of all childhood cancer-related deaths. Better treatments are needed for these children, and immunotherapy, the use of treatments that use our own immune systems to help attack the cancer, offers the opportunity to improve outcomes. While remarkable advances in this field have been made, the use of immunotherapy for childhood solid tumors like neuroblastoma has lagged behind as much remains to be learned about how such tumors evade our immune systems. Addressing this need forms the overarching focus of our work. The Team Translational Science Award encourages studying tumor heterogeneity and its association with the tumor microenvironment (TME). While immunotherapy holds great promise for improving cancer outcomes, especially for blood cancers like leukemia, the benefit for solid tumors has lagged behind as these tumors create a fortress-like barrier that blocks the immune system. It is becoming clear, however, that how solid tumors escape their immune systems varies from tumor to tumor, and this is strongly influenced by the specific tumor-causing mutations that the cancer has. So a neuroblastoma in which the MYCN gene has become mutated to cause the cancer will have a very “MYCN-influenced” tumor environment and specific ways to avoid the immune system. Alternatively, a neuroblastoma with a different cancer gene mutated would have a different tumor environment and immune evasion tactic. Our work uses models of neuroblastoma in which different cancer genes have been activated so we can identify these differences. Further, we study how new drugs that work to alter the immune system might help restore the immune system’s ability to see and combat such tumors. Our laboratories have been studying these processes for years and are working with the largest pediatric cancer clinical trials groups in the US, the Children’s Oncology Group (COG) and the New Approaches to Neuroblastoma Therapy (NANT) consortium, to put our findings into practice in the clinic. What has been established so far is that neuroblastoma is the first pediatric solid tumor for which an immunotherapy has been shown to be effective. The immunotherapy is called dinutuximab, and it is an antibody that attaches to neuroblastoma cells to help the immune system attack the tumor. While the treatment works well enough to receive Food and Drug Administration approval, half of all patients that receive it derive little or no benefit. We are working to improve this by understanding how the individual tumors are interfering with the immune system. Our strategy is to provide patient-specific treatments that are targeted to remove the critical immune barrier created by the tumor, so the dinutuximab immunotherapy will work better. In the future, we anticipate treating children with high-risk neuroblastoma very differently than we do now. Instead of using high-dose chemotherapy alone to start treatment, we plan to begin with chemotherapy combined with immunotherapy from the very beginning. In addition, depending on the cancer genes found in the tumor, selective drugs would be added to help that specific immune system combat the tumor more potently. This will reflect a real paradigm shift and provide for more effective and les
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810418
Entities
People
- Shahab Asgharzadeh
Organizations
- United States Army