Kids Shouldn't Have Cancer Foundation

1)More effective treatments are needed for pediatric high grade gliomas (HGG). Brain tumors in the pediatric population have a poor prognosis and account for the highest mortality rate of all childhood cancers(1). Of all the pediatric brain tumors, high-grade gliomas (HGG) remain the largest challenge, with few treatment options available and an overall five-year survival rate of just 10-30 percent(1-4). Pediatric HGG are a heterogeneous group of tumors that include the World Health Organization (WHO) grade III (anaplastic astrocytoma) and grade IV (glioblastoma) neoplasms. HGG are the second most common malignant CNS tumor of childhood. Current upfront therapies include surgical resection, radiation, therapy and chemotherapy(5). Despite aggressive multimodality therapy, the long-term survival is poor. The optimal salvage treatment approach for recurrent pediatric HGG after relapse has not been determined and very few prospective clinical trials are available for this population. We have seen little improvement in the ability to cure these children in the last 30 years. The lack of effective treatment of HGG in children clearly remains a largely unmet medical need, and highlights the need for novel and effective therapies. A potential alternative to conventional cancer treatments is to utilize a patient’s own immune system to target and eliminate tumor cells. Immunotherapy has been shown to be a promising treatment for a number of types of cancer, including melanoma and non-small cell lung cancer(6, 7). However similar results have not been seen in all tumor models and it has become clear that immune suppression within the tumor microenvironment is a significant barrier to successful cancer immunotherapy outcomes, particularly within bulky and recurrent solid tumors(8-10). 2) Specific Aims: Aim1: To evaluate the safety and potential clinical benefit of neoadjuvant checkpoint blockade (PD-1 mAb) in pediatric recurrent high grade glioma patients. We hypothesize that neoadjuvant checkpoint inhibition will be safe and will lead to extended survival. Aim 2: To identify the cellular immune mechanisms by which timing of distinct checkpoint inhibitors might enhance effective anti-tumor immune responses and potential clinical benefit in pediatric recurrent high grade glioma patients. We hypothesize that neoadjuvant checkpoint inhibition will activate systemic anti-tumor immune responses that are potentiated after surgical debulking, when the immune-inhibitory tumor microenvironment is reduced and will be evident by the increased TIL activation, increased IFN-γ production, and decreased cell cycle activity by the tumor.