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Principal Investigator: Elias Sayour
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2020
Award: $158,188
Funding agency: National Cancer Institute
Abstract:
I am now in my first faculty position as an Assistant Professor of Neurosurgery and Pediatrics at the University
of Florida. I completed a T32 NIH fellowship at Duke University in Cancer Biology and Developmental
Therapeutics before accepting a junior faculty position at the University of Florida where I moved with my
mentor, Dr. Duane Mitchell. Dr. Mitchell and I have selected an advisory committee to ensure accrual of my
intellectual and professional growth. The non-overlapping expertise of our advisory committee will be an
avenue for me to develop new knowledge in tumor immunology, molecular biology, nanotechnology and
translational oncology. This proposal will leverage much of this experience as it outlines a career development
plan for me to become an independent investigator exploring novel RNA-nanoparticle vaccines that can re-
direct the immune system against malignant brain tumors.
Background: Glioblastoma (GBM) remains almost uniformly lethal with a median survival of less than 15
months thus necessitating the development of more efficacious and targeted therapeutics. While we have
shown in a randomized/blinded trial that RNA-pulsed dendritic cell (DC) vaccines elicit significant survival
benefits in GBM patients, these therapies remain encumbered by cost and complexity. Alternatively, RNA-
nanoparticles (RNA-NPs) can deliver total tumor RNA (TTRNA), extracted and amplified from as few as 500
biopsied tumor cells, to endogenous antigen presenting cells (APCs) inducing potent, nontoxic anti-tumor
immunity. Since these nanoliposomes have been used with limited toxicity in clinical-grade medicine, are
stable for several hours in solution, protect nucleic acids from degradation, and can be engineered to modulate
immune responses, we have explored the use of TTRNA-loaded NPs as an attractive, “off-the-shelf”
therapeutic platform to re-direct host-immunity against intracranial tumors. While we have demonstrated that
intravenous delivery of RNA-NPs mediate antigen specific T cell responses against intracranial malignancies
comparable to DC vaccines, these formulations were shown to induce differential phenotypes on APCs in the
spleen and liver.
Hypothesis: RNA-NPs transfect distinct APCs in the spleen and liver inducing differential immune responses
that can be modulated in favor of enhanced effector functions.
Specific Aims:
1) Determine critical APC subsets and evaluate their role in RNA-NP mediated immune responses.
2) Identify regulatory pathways involved in RNA-NP mediated immunity and investigate capacity to target
these pathways through incorporation of immunomodulatory RNAs into vaccine formulations.
3) Evaluate the safety and efficacy of the most promising RNA-NP formulation in a malignant murine glioma
model.
Research Design: We propose to identify critical APCs involved in RNA-NP mediated immunity, target
regulatory pathways identified after vaccination, and evaluate the safety and efficacy of RNA-NPs in an
invasive preclinical murine malignant glioma model. Since this platform can deliver combinatorial therapies
using a single delivery platform, we will investigate if RNA-NP co-delivery of RNAs (i.e. small interfering RNAs
or RNAs encoding for monoclonal antibodies) targeting regulatory pathways (i.e. programmed death-ligand 1)
can potentiate our vaccine’s already promising anti-tumor immunity.
Innovation: Since RNA-NPs bypass the complexity of cellular therapeutics, are amenable to central
distribution, and can be made within days of tumor resection, these formulations supplant DC vaccines
providing near immediate immune induction against inciting malignancies. By employing liposomal RNA-NPs
encoding for both tumor RNAs and immunomodulatory molecules, as an innovative and versatile platform for
delivering combinatorial therapeutics via a single treatment modality, we can rapidly screen strategies to
enhance the efficacy of our vaccine platform.
Potential Impact: Despite aggressive and highly toxic multi-modal therapy, GBM remains invariably recalcitrant.
RNA-NP vaccines can provide a more effective and specific therapy critical in improving clinical outcomes for
patients affected by GBMs without adding further toxicity to existing treatments. This novel therapeutic platform
has potential to better understand the immunologic potential of RNA-NPs and contains a wide range of clinical
application for all malignancies that can be targeting using TTRNA obtained from surgical resection of solid
tumors.
Terms: <Abscission><Advisory Committees><Affect><Antigen-Presenting Cells><Antigens><Area><Autologous Dendritic Cells><B7-H1><B7H1><Biopsy><Blinded><Brain Cancer><Bypass><CD274><Cancer Biology><Cancers><Cations><Cell Body><Cells><Cellular immunotherapy><Clinical><Clinical Treatment Moab><Collection><Combined Modality Therapy><DNA Molecular Biology><Dendritic Cell Vaccine><Dendritic Cells><Development><Development Plans><Developmental Therapeutics><Developmental Therapeutics Program><Developmental Therapy><Disease Progression><Drug Delivery><Drug Delivery Systems><Encapsulated><Engineering><Ensure><Excision><Extirpation><Faculty><Fellowship><Florida><Formulation><Freund's Adjuvant><Freund's Complete Adjuvant><Generalized Growth><Generations><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Global Change><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Growth><Hepatic><Hour><Human><Immune><Immune Cell Activation><Immune response><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunomodulation><Immunotherapeutic agent><Intracranial Central Nervous System Neoplasms><Intracranial Central Nervous System Tumors><Intracranial Neoplasms><Intracranial Tumor><Intravenous><Investigators><Knowledge><Lipids><Liposomal><Liposomes><Liver><Malignant><Malignant - descriptor><Malignant Glial Neoplasm><Malignant Glial Tumor><Malignant Glioma><Malignant Neoplasms><Malignant Neuroglial Neoplasm><Malignant Neuroglial Tumor><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Marketing><Mediating><Medicine><Mentors><Messenger RNA><Mice><Mice Mammals><Modality><Modeling><Modern Man><Molecular Biology><Monoclonal Antibodies><Multimodal Therapy><Multimodal Treatment><Murine><Mus><NIH><Nanotechnology><National Institutes of Health><Nature><Neuroglial Neoplasm><Neuroglial Tumor><Non-Polyadenylated RNA><Nucleic Acids><Oncology><Oncology Cancer><Operative Procedures><Operative Surgical Procedures><Organ><PD 1><PD-1><PD-L1><PD1><PDL-1><PDL1><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pediatrics><Peptide Vaccines><Peripheral><Phenotype><Physiologic><Physiologic pulse><Physiological><Position><Positioning Attribute><Preparation><Production><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Pulse><RNA><RNA Gene Products><RNA delivery><Randomized><Refractory><Regulatory Pathway><Removal><Research Design><Research Personnel><Researchers><Ribonucleic Acid><Role><Route><Safety><Short interfering RNA><Small Interfering RNA><Solid Neoplasm><Solid Tumor><Spleen><Spleen Reticuloendothelial System><Study Type><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><T cell response><T-Cell Activation><T-Cells><T-Lymphocyte><Task Forces><Technology><Testing><Therapeutic><Time><Tissue Growth><Toxic effect><Toxicities><Transfection><Translations><Treatment outcome><Tumor Cell><Tumor Immunity><Tumor-Derived><United States National Institutes of Health><Universities><Up-Regulation><Upregulation><Vaccination><Vaccines><Veiled Cells><accessory cell><advisory team><allergic/immunologic body system><allergic/immunologic organ system><anti-cancer immunotherapy><anti-tumor immunity><anticancer immunotherapy><antigen-specific T cells><antitumor immunity><cancer immunity><cancer immunology><cancer immunotherapy><career development><cell-based immunotherapy><chemo-/radio-therapy><chemo-radio-therapy><chemo-radiotherapy><chemoradiation><chemoradiotherapy><clinical applicability><clinical application><clinically translatable><combination therapy><combinatorial><combined modality treatment><combined treatment><commercialization><cost><cytokine><develop a vaccine><development of a vaccine><developmental><effective therapy><effective treatment><experience><glial-derived tumor><glioblastoma multiforme><hepatic body system><hepatic organ system><host response><immune activation><immune cell therapy><immune drugs><immune modulation><immune regulation><immune regulator><immune-based cancer therapies><immune-based therapeutics><immunogen><immunologic preparation><immunologic reactivity control><immunologic therapeutics><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunotherapeutics><immunotherapy agent><immunotherapy for cancer><immunotherapy of cancer><improved><innovate><innovation><innovative><mAbs><mRNA><malignancy><multi-modal therapy><multi-modal treatment><nano liposome><nano particle><nano tech><nano technology><nano-sized particle><nano-technological><nanoliposomal><nanoliposome><nanoparticle><nanosized particle><nanotech><nanotechnological><neoplasm immunology><neoplasm/cancer><neoplastic cell><neuroglia neoplasm><neuroglia tumor><neurosurgery><new drug target><new drug treatments><new druggable target><new drugs><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><ontogeny><pathway><pre-clinical><preclinical><professor><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><radio-chemo-therapy><radio-chemotherapy><radiochemotherapy><randomisation><randomization><randomly assigned><resection><siRNA><sle2><social role><spongioblastoma multiforme><study design><surgery><systemic lupus erythematosus susceptibility 2><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic RNA><thymus derived lymphocyte><tumor><tumor immunology><uptake><vaccine development><vaccine formulation>