Overcoming metastatic spread of osteosarcoma with RNA loaded nanoparticles

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Principal Investigator: Elias  Sayour
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2023
Award: $531,320
Funding agency: National Cancer Institute

Project Summary
Immunotherapy has shown profound benefit for adult patients but has yet to be fully unlocked for pediatric solid
tumors such as osteosarcoma (OSA) where a significant percentage of children/adolescents succumb due to
the presence of lung metastasis. OSA, like many poorly tumor immunogenic tumors, is defined by a lack of tumor
specific targets and a regulatory tumor microenvironment (TME). Unleashing immunotherapy against poorly
immunogenic cancers requires new technologies that activate the TME, while concomitantly engaging both
innate and adaptive arms of the immune system to generate sustained cellular immunity.
 We have developed a novel (FDA approved) RNA-nanoparticle (RNA-NP) vaccine that simultaneously
penetrates/reprograms the TME while inducing an OSA specific T cell response. This vaccine utilizes a novel
engineering design that layers tumor derived mRNA into a lipid-nanoparticle (NP) “onion-like” package. We have
shown that systemic administration of RNA-NPs safely mimics viremia, activating the quiescent immune system
in only a few hours for induction of potent anti-tumor efficacy in several poorly immunogenic murine tumors
resistant to immune checkpoint inhibitors. These RNA-NPs activate dendritic cells (DCs) that supplant regulatory
intratumoral myeloid populations inducing antigen-recall response with long-term survivor benefits in murine
metastatic pulmonary OSA models. We have established safety of RNA-NPs in acute/chronic murine toxicity
studies, and launched a large animal canine OSA trial which demonstrated that RNA-NP administration is
feasible, safe and immunologically active. While RNA-NPs mediate substantial anti-tumor activity, some animals
suffer tumor outgrowth that warrant exploration of resistance mechanisms in our non-survivors. We have shown
that RNA-NPs can be enriched for tumor specific antigens or configured with siRNAs to target pertinent
regulatory axes (i.e. PD-L1), which can be studied in our murine/canine OSA models. The scientific premise for
this work is that osteosarcoma is encased by a regulatory myeloid microenvironment that actively subverts
adaptive immunity. We hypothesize that myeloid reprogramming of metastatic OSA will lead to safe eradication
of disease. Our SPECIFIC AIMS are:
1. Establish mechanisms of OSA treatment resistance that can be overcome with adaptable RNA-NPs.
2. Identify correlates for vaccine response and escape in a comparative oncology canine OSA model.
3. Conduct a multi-institutional phase I/II study evaluating the safety and activity of the most promising
RNA-NP formulation in recurrent OSA patients.
Successful completion of this study will lead to a novel OSA therapy and a mechanistic understanding of its
therapeutic effects that will be co-opted as biologic response correlates in a human clinical trial.
.

Terms: <0-11 years old><21+ years old><Acute><Adolescent><Adolescent Youth><Adult><Adult Human><Allium cepa><Animals><Antigens><B7-H1><B7H1><Biological><Biology><Biopsy><Blood><Blood Reticuloendothelial System><Blood Serum><Bone Sarcoma><CD274><Cancers><Canine Species><Canis familiaris><Cell Body><Cell Mediated Immunology><Cell-Mediated Immunity><Cells><Cellular Immunity><Checkpoint inhibitor><Child><Child Youth><Childhood Solid Neoplasm><Childhood Solid Tumor><Children (0-21)><Chronic><Client><Clinical Trials><Data><Dendritic Cells><Diagnosis><Disease><Disease-Free Survival><Disorder><Dogs><Dogs Mammals><Dose><Event-Free Survival><FDA approved><Formulation><Genetic Alteration><Genetic Change><Genetic defect><Hour><Human><IFN><Immune checkpoint inhibitor><Immune mediated therapy><Immune system><Immunochemical Immunologic><Immunocompetent><Immunologic><Immunological><Immunologically><Immunologically Directed Therapy><Immunologics><Immunomodulation><Immunotherapeutic agent><Immunotherapy><Institution><Interferons><Long-Term Survivors><Lung><Lung Respiratory System><Macrophage><Malignant Neoplasms><Malignant Tumor><Mediating><Messenger RNA><Metastasis to the Lung><Metastatic Neoplasm to the Lung><Metastatic Osteogenic Sarcoma><Metastatic Osteosarcoma><Metastatic Tumor to the Lung><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Mutation><Myelogenous><Myeloid><Myeloid Cells><Mφ><Non-Polyadenylated RNA><Oncology><Oncology Cancer><Onions><Osseous Sarcoma><Osteogenic Sarcoma><Outcome Measure><PD-L1><PDL-1><PDL1><Pathway interactions><Patients><Pediatric Solid Tumor><Penetration><Phase><Population><Production><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><RNA><RNA Gene Products><Recurrence><Recurrent><Research Design><Resistance><Ribonucleic Acid><Safety><Serum><Short interfering RNA><Skeletal Sarcoma><Small Interfering RNA><Study Type><T cell response><Testing><Therapeutic Effect><Toxic effect><Toxicities><Tumor Antigens><Tumor-Associated Antigen><Tumor-Derived><VAC-TX><Vaccine Therapy><Vaccines><Veiled Cells><Viremia><Work><adaptive immune response><adaptive immunity><adulthood><arm><biologic><blood-based biomarker><blood-based marker><cancer antigens><cancer microenvironment><canine><canine animal model><canine model><cohort><comparative><design><designing><dog model><domestic dog><engineering design><exome><exomes><genome mutation><immune check point inhibitor><immune competent><immune drugs><immune modulation><immune regulation><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><immunogen><immunogenic><immunologic reactivity control><immunologic therapeutics><immunomodulatory><immunoregulation><immunoregulatory><immunotherapeutics><immunotherapy agent><juvenile><juvenile human><kids><lipid based nanoparticle><lipid nanoparticle><longterm survivors><lung metastasis><mRNA><malignancy><measurable outcome><metastasize to the lung><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><new technology><novel><novel technologies><osteochondrosarcoma><osteoid sarcoma><osteosarcoma><outcome measurement><pathway><programmed cell death ligand 1><programmed cell death protein ligand 1><programs><protein death-ligand 1><pulmonary><pulmonary metastasis><resistance mechanism><resistance to therapy><resistant><resistant mechanism><resistant to therapy><response><response biomarker><response markers><siRNA><siRNA delivery><single cell sequencing><study design><therapeutic resistance><therapeutic vaccination><therapy resistant><treatment resistance><tumor><tumor microenvironment><tumor-specific antigen><vaccine response><vaccine responsiveness><vaccine-induced response><viraemia><viral sepsis><virusemia><youngster>