Stereotactic Body Radiation and Interleukin-12 Combination Therapy Eradicates Pancreatic Tumors by Repolarizing the Immune Microenvironment

• Published in: Cell reports (Cambridge) 2019-10, Vol.29 (2), p.406-421.e5
• Main Authors: Mills, Bradley N., Connolly, Kelli A., Ye, Jian, Murphy, Joseph D., Uccello, Taylor P., Han, Booyeon J., Zhao, Tony, Drage, Michael G., Murthy, Aditi, Qiu, Haoming, Patel, Ankit, Figueroa, Nathania M., Johnston, Carl J., Prieto, Peter A., Egilmez, Nejat K., Belt, Brian A., Lord, Edith M., Linehan, David C., Gerber, Scott A.
• Format: Article
• Language: English
• Subjects: abscopal effect; Animals; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Cellular Reprogramming; combination immunotherapy; Humans; IFNg; IL-12; Immunity; in situ tumor vaccine; interferon gamma; Interferon-gamma - metabolism; interleukin-12; Interleukin-12 - therapeutic use; Lymphocyte Activation - immunology; Mice, Inbred C57BL; Microspheres; Models, Biological; Myeloid Cells - pathology; myeloid reprogramming; pancreatic ductal adenocarcinoma; Pancreatic Neoplasms; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - therapy; PDA; Radiosurgery; SBRT; stereotactic body radiation therapy; Survival Analysis; Tumor Burden; Tumor Microenvironment - immunology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.08.095

Over 80% of pancreatic ductal adenocarcinoma (PDA) patients are diagnosed with non-resectable late-stage disease that lacks effective neoadjuvant therapies. Stereotactic body radiation therapy (SBRT) has shown promise as an emerging neoadjuvant approach for treating PDA, and here, we report that its combination with local interleukin-12 (IL-12) microsphere (MS) immunotherapy results in marked tumor reduction and cures in multiple preclinical mouse models of PDA. Our findings demonstrate an increase of intratumoral interferon gamma (IFNγ) production following SBRT/IL-12 MS administration that initiates suppressor cell reprogramming and a subsequent increase in CD8 T cell activation. Furthermore, SBRT/IL-12 MS therapy results in the generation of systemic tumor immunity that is capable of eliminating established liver metastases, providing a rationale for follow-up studies in advanced metastatic disease. [Display omitted] •SBRT/IL-12 MS combination immunotherapy eradicates murine orthotopic PDA tumors•IFNγ produced following SBRT/IL-12 MS repolarizes intratumoral myeloid suppressors•Robust CD8 T cell activation and memory formation is initiated by SBRT/IL-12 MS•SBRT/IL-12 MS treatment elicits an abscopal effect, eliminating hepatic metastases Mills et al. demonstrate a marked antitumor response following radiotherapy and IL-12 microsphere combination treatment (SBRT/IL-12 MS) of murine pancreatic cancer. The IFNγ-dependent mechanism repolarized myeloid suppressors and promoted robust T cell activation. SBRT/IL-12 MS elicited in situ tumor “vaccination” and an abscopal effect capable of eliminating hepatic metastases.