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.

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.