Most children with brain tumors experience low survival rates even with maximal invasive treatment such as surgery, intensive chemotherapy, and radiation therapy. To avoid such invasive and potentially toxic therapies, scientists have been developing ways to help the body’s own immune system recognize cancer cells and kill them. One of the biggest developments in this area so far has been in the design of checkpoint inhibitor drugs that are able to block cancer cells’ protective mechanisms. An example of such a successful drug is the PD-1 inhibitor. Unfortunately, PD-1 inhibitors have proven ineffective for the treatment of pediatric brain tumors. There is, however, one possible way to make PD-1 inhibitors effective at killing pediatric tumor cells by combining them with drugs that mimic viral infection. These “viral mimicry” drugs can prime cancer cells to be killed by the immune system’s T-cells. In this project, the team proposes to combine these “viral mimicry” drugs with PD-1 inhibitors to see if this combination is effective in pediatric brain cancer models. The studies they propose will be carried out in mice engineered to grow aggressive, malignant pediatric brain tumors. This team’s work promises to help establish whether this novel combination therapy is safe and feasible for future clinical trials and will lead directly to future human trials in the 15-member Collaborative Network of Neuro-oncology Clinical Trials (CONNECT).
This proposal fills a critical, unmet need for children with poor-prognosis brain tumors by exploring the combination of CDK4/6 inhibitors or DNMT inhibitors and immune checkpoint blockade judiciously administered on the backbone of current therapies. Promising results in this pre-clinical research study will a) lead to a paradigm shift in the treatment of children with high-risk brain tumors for whom further intensification of conventional therapies is not an option, and b) accelerate information leading to clinical trials to determine feasibility and define efficacy.
Maryam Fouladi, MD, MSc, Cincinnati Children’s Hospital Medical Center
James Olson, MD, PhD, Fred Hutchinson Cancer Research Center
Nada Jabado, MD, PhD, The Research Institute of the McGill University Health Centre
Annie Huang, MD, PhD, The Hospital for Sick Children
Keith Desserich, Cure Starts Now