Murine metastatic embryonal rhabdomyosarcoma survival and immune response with a total tumor RNA lipid particle aggregate vaccine.

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e14646 Background: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma (STS) requiring intense multiagent chemotherapy in conjunction with surgical resection and radiation therapy for cure rates of only 70%. Patients with metastatic and recurrent disease experience dismal chances of long-term survival ( < 20%). STSs are considered immunologically cold tumors, and immunotherapeutic innovation is desperately needed. Our lab developed a novel multilamellar lipid particle aggregate mRNA (RNA-LPA) vaccine currently being studied in early phase human clinical trials for glioblastoma, osteosarcoma, and melanoma using total tumor RNA (ttRNA). Our platform loads and delivers large quantities of full-length mRNA to antigen presenting cells leading to robust innate and adaptive immune responses as we have demonstrated in mice, dogs, cats, and humans. Dendritic cell vaccines have demonstrated promise for RMS, but scaling this therapy can be challenging. Comparably, lipid particle vaccines are simple and relatively inexpensive. Herein we describe our RMS models and treatment outcomes using ttRNA-LPA vaccination. Methods: We established that a dose of 25,000 M3-9-M cells given by tail vein injection to C57BL/6 mice reliably developed pulmonary tumors that resemble human ERMS 100% of the time. Starting day 1 after tumor implantation, 6 ttRNA-LPA vaccines were administered which were manufactured using our standard protocol – 3 doses in the first week followed by 3 weekly doses. Controls included untreated and non-specific RNA-LPA vaccines. Survival data was reported via Kaplan-Meier curves; hypothesis testing performed via t-tests. Serum was collected 6 hours after vaccine administration to assess the cytokine response and immune trafficking. An ex vivo assay using tumor spheroids was developed to demonstrate adaptive immunity via co-culture with splenocytes or isolated T cells from euthanized mice. Spheroid diameter was charted over time. Results: Results of the survival study are ongoing. At the time of submission, all untreated mice died. Mice treated with ttRNA-LPA vaccination have experienced a significant survival benefit compared to untreated mice (p = 0.002). Mice treated with a non-specific RNA-LPA vaccine also experienced a survival benefit over untreated mice (p = 0.0084) without long-term immunity. Immune response was robust as expected. Spheroids co-cultured with vaccinated immune cells demonstrated decreasing diameter over time. Conclusions: An immunogenic murine model of RMS with pulmonary metastases experienced a survival benefit with our ttRNA-LPA vaccine. Non-specific RNA provided some benefit likely owing to the robust innate immune response and may support development of a non-personalized vaccine for STS. These data directly support translation to human clinical trial for STS. Veterinary clinical trials for STS will be pursued.

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