University of Florida Archives - Hyundai Hope On Wheels

2019

Scholar Grant

Elias Sayour

Gainesville, FL

Title: Nanoparticles targeting genetic translocations in pediatric brain tumors

Executive Summary:
Malignant brain tumors are the most common form of cancer death in children and necessitate development of new therapies. Immunotherapy promises to re-direct the host immune system with exquisite precision without toxicity. However, much of immunotherapy’s promise lies in cancers with high mutational burdens. In this regard, many childhood cancers like pediatric brain tumors are immunologically bland without a significant burden of mutations. However, many pediatric tumors like resistant supratentorial ependymomas are driven by conserved aberrant fusions (i.e. C11orf9-RELA fusion), while others are spontaneous and specific to an individual’s brain cancer. We posit that these fusions create new epitopes that can be distinctly recognized and immunologically rejected. To accomplish this, we propose development of a nanoparticle (NP) vaccine to immunologically target personalized or conserved fusions in pediatric brain cancers.

These nanoparticle vaccines will be composed of fusion specific mRNA complexed into biocompatible lipid-NPs for systemic activation of dendritic cells (DCs) and induction of therapeutic T cell immunity against fusion specific tumor antigens. We have shown that tumor derived total mRNA-NPs activate DCs and mediate robust anti-tumor immunity against several pre-clinical tumor models including settings where immune checkpoint inhibitors do not confer therapeutic benefit (Sayour et al. Nano Lett 2018). In our preclinical studies, we uncovered that RNA-NPs elicit their immunomodulating effects through release of interferon-a (IFN-a) from plasmacytoid DCs (pDCs). IFN-a is an essential antiviral cytokine and systemic administration of RNA-NPs appears to mimic viremia for induction of near immediate innate/adaptive immunity. These RNA-NPs were safe in murine acute/chronic toxicity studies, and in translational studies, RNA-NPs were therapeutically active in a client-owned canine with a spontaneous brain tumor (Sayour et al. Nano Lett 2018). In this proposal, prior to first-in-human studies, we will investigate the immunogenicity and efficacy of personalized and “off the shelf” fusion targeted RNA-NPs before translation into canine brain tumor models (pet dogs diagnosed with malignant brain tumors and enrolled through owner’s consent to receive investigational RNA-NP vaccines). We hypothesize that RNA-NPs targeting new epitopes spanning pediatric brain tumor fusions will mediate robust antigen specific immunity without induction of autoimmunity.