RNA-Nanoparticles Targeting H3.3 K27M Epitopes in Diffuse Intrinsic Pontine Glioma
Abstract
Malignant primary brain tumors currently represent the most common cause of cancer death in children and young adults. Despite aggressive surgery, radiation, and chemotherapy delivered at toxic doses, most patients with diffuse intrinsic pontine glioma (DIPG) live little more than 1 year from the time of diagnosis. The development of more effective and specific therapies that will not add further toxicity to existing treatments is critical in improving clinical outcomes for children affected by these tumors. Targeted therapy, using RNA nanoparticle vaccines, to redirect the immune system against tumor cells is a promising treatment strategy that meets this clear and urgent need. Nanoparticles are small enough to deliver information to the immune system teaching it to fight cancer, providing a more effective and specific therapy for cancer patients without toxicity. Moreover, the nanoparticles we are investigating have been used for other purposes in ongoing clinical trials without major side effects. Additionally, our preliminary data using these nanoparticles have shown very effective immune responses with improved survival including long-term cures in tumor-bearing mice. We propose engineering these particles in such a way that will make them highly effective in teaching the immune system to eradicate brain tumors in children. To achieve this end, we will investigate where these particles travel, and the kind of immune responses they generate. We will then investigate how to improve these vaccines before establishing the most effective formulation. We plan on modifying the nanoparticles to improve vaccine delivery by making them better targets of the most effective immune cells of the body, called dendritic cells or DCs, in an attempt to activate the immune system to recognize the difference between normal brain tissue and malignant tumor tissue leading towards the specific killing of altered cancer cells. We will also incorporate viral constructs into the nanoparticle that mimic a smoldering infection, augmenting the immune system to generate potent anti-tumor responses. We will examine the safety profile of these nanoparticle vaccines while investigating anti-tumor immunity of our optimized formulation in mouse models for pediatric brain cancer. Through these experiments, we aim to establish the preclinical feasibility, efficacy, and toxicity data to support the rationale for clinical development of tumor RNA-loaded nanoparticle vaccines that we can further investigate in pediatric clinical trials. We anticipate the generation of sufficient data by the end of the funding period for a U.S. Food and Drug Administration Investigational New Drug application for the first-in-human evaluation of nanoparticle vaccines for the treatment of pediatric brain tumors. New therapies are paramount for pediatric patients with brain tumors. The study proposed here is responsive to the healthcare needs of all children and young adults who are afflicted with this devastating disease, including civilians and military personnel. We propose engineering nanoparticles in such a way that will make them highly effective in teaching the immune system to eradicate the most common type of malignant brain tumors in children. We have pioneered techniques developed at our institution for making suitable cancer vaccines from as few as 100 tumor cells, making possible the ability to offer cancer immunotherapy to the majority of patients from which small amounts of tumor tissue can be obtained during surgery or biopsy. Leveraging this technology with novel nanoparticle vaccines can provide a more effective and specific therapy against brain tumors without toxicity for the exceptional children with this devastating disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710510
Entities
People
- Elias J Sayour
Organizations
- United States Army
- University of Florida