Epigenetic Enhancement of MHCI to Augment Neuroblastoma Immunotherapy
Half of all neuroblastoma patients are diagnosed with high-risk neuroblastoma. Even with the recent addition of immunotherapy, which has been proven to help, only ~ 50% of children with high-risk disease are cured. Laboratory studies have identified three characteristics that make high-risk-neuroblastoma harder to cure using the current clinical regimen of chemotherapy, surgery, radiation and immunotherapy. These 3 characteristics include: 1) amplification of the MYCN gene, which makes the cancer divide and resist chemotherapy and immunotherapy; 2) a low number of mutations, which limits the number of targets the immune system can see on the neuroblastoma; and 3) a loss of MHC molecules on the neuroblastoma, making the neuroblastoma cells “invisible” to the immune cells. We are developing a combination therapy regimen to treat high-risk neuroblastoma, and testing it in mice that have a neuroblastoma (called 9464D-GD2) that mimics these 3 features of clinical high-risk neuroblastoma. Although the standard clinical regimen can’t cure mice with even a small 9464D-GD2 tumor, we cure mice with small 9464D-GD2 tumors using a novel combination radio-immunotherapy regimen. In order to improve this to enable cures of mice with larger tumors, or with tumors in more than one location, we are now adding to this regimen additional drugs that we are showing can restore expression of MHC molecules, to better enable immune cells to recognize and destroy the neuroblastoma. This project will systematically test this approach in mice with larger, or multiple tumors, using agents that could translate to clinical testing, and that influence MHC on clinical neuroblastoma.
We hypothesize that high-risk neuroblastoma can resist current immunotherapy because: A) it has low/absent MHC (making it “invisible” to immune cells); and B) the immune system is inhibited by the MYCN pathway that characterizes high-risk neuroblastoma. This project uses the 9464D-GD2 neuroblastoma, which mimics the genetics and clinical behavior of the human disease, to test these hypotheses and develop a multipronged approach to circumvent these problems, by pursuing 3 related research aims: Aim 1) Analyze how the MHC genes are turned off in both human and mouse neuroblastoma, and expand on our initial work showing that appropriate epigenetic-modifying (EM) drugs can get MHC genes turned back on, enabling sufficient expression of MHC molecules to allow immune recognition. Aim 2) Determine the best way to give these EM drugs to mice with 9464D-GD2 tumors to induce an adequate level of MHC on the neuroblastoma, while maintaining immune function and not causing toxicity to the mouse. Aim 3) Develop a combination therapy regimen that includes agents that can activate and expand tumor-reactive immune cells in combination with EM drugs that enable neuroblastoma cells to be better seen and destroyed by immune cells. Overall, our goal is to better understand why high-risk neuroblastoma is so resistant to immune recognition and destruction, to develop a more effective immunotherapeutic strategy that can cure mice with large or metastatic 9464D-GD2 neuroblastomas that simulate children with this disease, in order to establish a regimen for clinical testing that is designed to substantially improve the cancer-free survival for children with high-risk neuroblastoma.