Local Delivery of SBRT and IL12 by mRNA Technology Overcomes Immunosuppressive Barriers to Eliminate Pancreatic Cancer

Hughson, A. L.; Hannon, G.; Salama, N. A.; Vrooman, T. G.; Stockwell, C. A.; Mills, B. N.; Garrett-Larsen, J.; Qui, H.; Katerji, R.; Benoodt, L.; Johnston, C. J.; Murphy, J. D.; Kruger, E.; Ye, J.; Gavras, N. W.; Keeley, D. C.; Qin, S. S.; Lesch, M. L.; Muhitch, J. B.; Love, T. M. T.; Calvi, L. M.; Lord, E. M.; Luheshi, N.; Elyes, J.; Linehan, D.; Gerber, S. A.

doi:10.1101/2023.10.30.564833

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bioRxiv · 10.1101/2023.10.30.564833

Local Delivery of SBRT and IL12 by mRNA Technology Overcomes Immunosuppressive Barriers to Eliminate Pancreatic Cancer

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Abstract

The immunosuppressive milieu in pancreatic cancer (PC) is a significant hurdle to treatments, resulting in survival statistics that have barely changed in 5 decades. Here we present a combination treatment consisting of stereotactic body radiation therapy (SBRT) and IL-12 mRNA lipid nanoparticles delivered directly to pancreatic murine tumors. This treatment was effective against primary and metastatic models, achieving cures in both settings. IL-12 protein concentrations were transient and localized primarily to the tumor. Depleting CD4 and CD8 T cells abrogated treatment efficacy, confirming they were essential to treatment response. Single cell RNA sequencing from SBRT/IL-12 mRNA treated tumors demonstrated not only a complete loss of T cell exhaustion, but also an abundance of highly proliferative and effector T cell subtypes. SBRT elicited T cell receptor clonal expansion, whereas IL-12 licensed these cells with effector function. This is the first report demonstrating the utility of SBRT and IL-12 mRNA in PC. Statement of significanceThis study demonstrates the use of a novel combination treatment consisting of radiation and immunotherapy in murine pancreatic tumors. This treatment could effectively treat local and metastatic disease, suggesting it may have the potential to treat a cancer that has not seen a meaningful increase in survival in 5 decades.

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Hughson, A. L., Hannon, G., Salama, N. A., Vrooman, T. G., Stockwell, C. A., Mills, B. N., Garrett-Larsen, J., Qui, H., Katerji, R., Benoodt, L., Johnston, C. J., Murphy, J. D., Kruger, E., Ye, J., Gavras, N. W., Keeley, D. C., Qin, S. S., Lesch, M. L., Muhitch, J. B., Love, T. M. T., Calvi, L. M., Lord, E. M., Luheshi, N., Elyes, J., Linehan, D., Gerber, S. A.. 2023-11-02. Local Delivery of SBRT and IL12 by mRNA Technology Overcomes Immunosuppressive Barriers to Eliminate Pancreatic Cancer. https://doi.org/10.1101/2023.10.30.564833

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