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Principal Investigator: Elias Sayour
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $601,230
Funding agency: National Cancer Institute
Project Summary
While activated T cells cross the blood-brain barrier (BBB), immunotherapy has yet to be harnessed for targeted
therapy due to GBM’s heterogeneity and immunosuppressive microenvironment. Unleashing immunotherapy
against GBM requires new technologies that activate the tumor microenvironment (TME), while concomitantly
engaging both innate and adaptive arms to generate sustained cellular immunity.
We developed a novel RNA-nanoparticle (RNA-NP) formulation to simultaneously orchestrate innate/adaptive
response against a heterogeneous cohort of personalized tumor derived mRNA. By layering tumor mRNA into
a multi-lamellar nano-lipid formulation (for systemic administration), we can deliver increased antigenic load (per
particle) triggering potent innate activation which then facilitates adaptive effector responses. Our technology
unlocks activity in poorly immunogenic small animal and spontaneous large animal glioma models.
RNA-NPs activate systemic/intratumoral dendritic cells (DCs), upregulate critical innate gene signatures in the
glioma TME, and induce glioma-specific T cell immunity. In murine tumor models resistant to immune checkpoint
inhibitors, RNA-NPs induce robust anti-tumor efficacy with long-term survivor benefits. We have previously
demonstrated safety of RNA-NPs in acute/chronic murine GLP toxicity studies, and launched a large animal
canine glioma trial (IACUC#201609430). Our canine trial demonstrated that RNA-NP administration is feasible,
safe and immunologically active with improvement in overall survival in pet dogs with terminal gliomas (compared
with historical controls). We have since received FDA-IND approval (BB-IND#19304, Sayour) for first-in-human
studies in GBM patients.
In this proposal, we will explore mechanistic underpinnings for innate modulation and adaptive response
following RNA-NPs. Our experiments will be conducted in clinically relevant small and large animal glioma
models, which recapitulate many human GBM features before translation into a human clinical trial. We
hypothesize that RNA-NPs reprogram the glioma microenvironment unlocking vaccine response across the
BBB. Our SPECIFIC AIMS will be to:
1. Establish RNA-NPs as innate biomodulators of glioma immunogenicity.
2. Elucidate mechanistic interactions between innate and adaptive anti-glioma immunity following tumor
specific RNA-NPs.
3. Determine in a neoadjuvant clinical trial design the modulating effects and immunogenicity of RNA-
NPs in recurrent GBM patients.
Terms: <(IFN) α><(IFN)-α><(IFN)α><Abscission><Acute><Adjuvant><Alferon><Animal Model><Animal Models and Related Studies><Animals><BBB crossing><Biological><Biological Response Modifiers><Biomodulators><Biopsy><Blood><Blood - brain barrier anatomy><Blood Reticuloendothelial System><Blood Serum><Blood-Brain Barrier><CCL2><CCL2 gene><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Canine Species><Canis familiaris><Cell Body><Cell Communication and Signaling><Cell Mediated Immunology><Cell Signaling><Cell-Mediated Immunity><Cells><Cellular Immunity><Checkpoint inhibitor><Chemokine, CC Motif, Ligand 2><Chemotherapy and Radiation><Chemotherapy and/or radiation><Chronic><Clinical><Clinical Trials><Clinical Trials Design><Data><Dendritic Cells><Development><Dogs><Dogs Mammals><Dose><Evaluation><Excision><Extirpation><Formulation><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><H3 K27M mutant><H3 K27M mutation><H3K27M mutant><H3K27M mutation><Hemato-Encephalic Barrier><Heterogeneity><Hour><Human><IACUC><IFIH1><IFN><IFN Alpha><IFN α><IFN-α><IFNAR><IFNAR1><IFNAR1 gene><IFNa><IFNα><Immune><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immune checkpoint inhibitor><Immune mediated therapy><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunocompetent><Immunologic><Immunological><Immunologically><Immunologically Directed Therapy><Immunologics><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapeutic agent><Immunotherapy><Induction Therapy><Institutional Animal Care and Use Committee><Interferon Alfa-n3><Interferon Induced With Helicase C Domain 1><Interferon alpha><Interferon-α><Interferons><Intracellular Communication and Signaling><KO mice><Knock-out Mice><Knockout Mice><Leukocyte Interferon><Lipids><Long-Term Survivors><Luciferase Immunologic><Luciferases><Lymphoblast Interferon><Lymphoblastoid Interferon><MCAF><MCP-1><MCP1><MDA 5><Mediating><Memory><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Murine><Mus><NEOADJ><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Neuroglial Neoplasm><Neuroglial Tumor><Non-Polyadenylated RNA><Null Mouse><Operative Procedures><Operative Surgical Procedures><Pathway interactions><Patients><RNA><RNA Gene Products><Randomized><Receptor Protein><Recurrence><Recurrent><Removal><Resistance><Ribonucleic Acid><SCYA2><Safety><Serum><Signal Transduction><Signal Transduction Systems><Signaling><Small Inducible Cytokine A2><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><T memory cell><T-Cell Activation><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TLR protein><Technology><Toll-Like Receptor Family Gene><Toll-like receptors><Toxic effect><Toxicities><Translations><Tumor-Derived><Vaccines><Veiled Cells><Viral><Viremia><activate T cells><adaptive immunity><arm><biologic><biological signal transduction><blood-brain barrier crossing><bloodbrain barrier><bloodbrain barrier crossing><cancer microenvironment><canine><cell type><chemo/radiation therapy><chemotherapy and radiotherapy><clinical relevance><clinically relevant><cohort><cytokine><developmental><domestic dog><effective therapy><effective treatment><experiment><experimental research><experimental study><experiments><first in man><first-in-human><gene signatures><genetic signature><glial-derived tumor><glioblastoma multiforme><immune check point inhibitor><immune competent><immune drugs><immune microenvironment><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunogenic><immunogenicity><immunologic reactivity control><immunologic therapeutics><immunomodulatory><immunomodulatory biologics><immunoregulation><immunoregulatory><immunosuppressive activity><immunosuppressive function><immunosuppressive microenvironment><immunosuppressive response><immunosuppressive tumor microenvironment><immunotherapeutics><immunotherapy agent><improved><induction therapies><interest><intravenous administration><knock-out animal><knockout animal><longterm survivors><mRNA><manufacture><melanoma differentiation associated gene 5><melanoma differentiation associated protein 5><memory T lymphocyte><model of animal><nano><nano particle><nano-sized particle><nanoparticle><nanosized particle><neuroglia neoplasm><neuroglia tumor><new drug treatments><new drugs><new pharmacological therapeutic><new technology><new therapeutics><new therapy><new vaccines><next generation therapeutics><next generation vaccines><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel technologies><novel therapeutics><novel therapy><novel vaccines><particle><pathogen><pathway><phase 1 designs><phase I designs><programs><radiation or chemotherapy><randomisation><randomization><randomly assigned><receptor><resection><resistant><response><spongioblastoma multiforme><surgery><survival outcome><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thymus derived lymphocyte><trafficking><translation><trial design><tumor><tumor immune microenvironment><tumor microenvironment><tumor-immune system interactions><vaccine for immunotherapy><vaccine immunotherapy><vaccine response><vaccine responsiveness><vaccine-based immunotherapy><vaccine-induced response><viraemia><viral sepsis><virusemia>