# Overcoming metastatic spread of osteosarcoma with RNA loaded nanoparticles

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2023 · $531,320

## Abstract

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.
.

## Key facts

- **NIH application ID:** 10691495
- **Project number:** 5R01CA266857-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Elias Sayour
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $531,320
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10691495

## Citation

> US National Institutes of Health, RePORTER application 10691495, Overcoming metastatic spread of osteosarcoma with RNA loaded nanoparticles (5R01CA266857-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10691495. Licensed CC0.

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