1. Stereotactic Body Radiation and Interleukin-12 Combination Therapy Eradicates Pancreatic Tumors by Repolarizing the Immune Microenvironment.
- Author
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Mills BN, Connolly KA, Ye J, Murphy JD, Uccello TP, Han BJ, Zhao T, Drage MG, Murthy A, Qiu H, Patel A, Figueroa NM, Johnston CJ, Prieto PA, Egilmez NK, Belt BA, Lord EM, Linehan DC, and Gerber SA
- Subjects
- Animals, CD8-Positive T-Lymphocytes immunology, Cell Line, Tumor, Cellular Reprogramming, Humans, Immunity, Interferon-gamma metabolism, Lymphocyte Activation immunology, Mice, Inbred C57BL, Microspheres, Models, Biological, Myeloid Cells pathology, Survival Analysis, Tumor Burden, Interleukin-12 therapeutic use, Pancreatic Neoplasms immunology, Pancreatic Neoplasms therapy, Radiosurgery, Tumor Microenvironment immunology
- Abstract
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., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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