Mills et al. demonstrated that the combination of stereotactic body radiation therapy and intratumoral injection of microspheres encapsulating IL-12 led to reduced tumor burden and increased survival in three mouse models of pancreatic ductal adenocarcinoma. Combination treatment led to increased intratumoral production of IFNγ (by T effectors and myeloid cells), repolarization of the intratumoral myeloid and lymphoid populations toward an antitumor state, an increase in activated intratumoral CD8+ T cells (crucial for antitumor efficacy), generation of immunological memory, and elimination of metastases. A phase I clinical trial is in the works.
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 (IFNgamma) 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.
Author Info: (1) Department of Surgery, University of Rochester Medical Center, Rochester, NY 14620, USA. (2) Department of Microbiology and Immunology, University of Rochester Medical Center,
Author Info: (1) Department of Surgery, University of Rochester Medical Center, Rochester, NY 14620, USA. (2) Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14620, USA. (3) Department of Surgery, University of Rochester Medical Center, Rochester, NY 14620, USA. (4) Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14620, USA. (5) Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14620, USA. (6) Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14620, USA. (7) Department of Surgery, University of Rochester Medical Center, Rochester, NY 14620, USA. (8) Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14620, USA. (9) Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14620, USA. (10) Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY 14620, USA. (11) Department of Surgery, University of Rochester Medical Center, Rochester, NY 14620, USA. (12) Department of Surgery, University of Rochester Medical Center, Rochester, NY 14620, USA. (13) Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY 14620, USA. (14) Department of Surgery, University of Rochester Medical Center, Rochester, NY 14620, USA. (15) Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40202, USA. (16) Department of Surgery, University of Rochester Medical Center, Rochester, NY 14620, USA. (17) Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14620, USA. (18) Department of Surgery, University of Rochester Medical Center, Rochester, NY 14620, USA. (19) Department of Surgery, University of Rochester Medical Center, Rochester, NY 14620, USA; Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14620, USA; Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY 14620, USA. Electronic address: scott_gerber@urmc.rochester.edu.
