Development of a New Strategy to Treat Locally Advanced Pancreatic Cancer
Bradley N. Mills1, Kelli A. Connolly1, Jian Ye1, Tony Zhao1, Nejat K. Egilmez2, David C. Linehan1 and Scott A. Gerber1 1University of Rochester, Rochester, NY; 2University of Louisville, Louisville, KY
Pancreatic cancer (PC) is the third leading cause of cancer deaths in the United States due to disease aggressiveness and lack of effective therapeutics. Currently, the only curative treatment for PC is surgical resection, however, most patients (>80%) are diagnosed with non-resectable late stage disease. While standard therapies are rarely capable of downsizing locally advanced lesions to surgical candidacy, the recent emergence of stereotactic body radiation therapy (SBRT) has shown promise. This targeted approach minimizes toxicity to surrounding tissues, thereby affording the delivery of higher dose fractions. Our laboratory previously demonstrated that immune cells play an essential role in the efficacy of radiotherapy; therefore, we hypothesized that an adjuvant immunotherapy would enhance the antitumor potency of SBRT in advanced pancreatic malignancies. To accomplish this, we developed a syngeneic mouse model of PC for treatment with clinically relevant SBRT and immunotherapy regimens. Mouse pancreas tumor cells stably expressing luciferase were orthotopically implanted prior to SBRT treatment on a Small Animal Radiation Research Platform (SARRP) and intratumoral injection of biodegradable polymer microspheres (MS) containing the pleiotropic cytokine interleukin 12 (IL12). Remarkably, combined SBRT and IL12 MS treatments demonstrated major reductions in tumor size and cures in both radioresistant and radiosensitive pancreatic tumor cell line models. Flow cytometry analysis revealed increased CD8+ T cell occupancy in tumors, and cytokine immunoassays using the Luminex multi-analyte profiling platform demonstrated significant increases in plasma interferon gamma (IFNG) levels. To assess the dependence of SBRT/IL12 MS antitumor activity on IFNG expression, we repeated orthotopic modeling in IFNG-/- mice and confirmed therapeutic dependence on the proinflammatory cytokine. In summary, we have developed a clinically relevant model of PC that was used to successfully identify a potent combinatory therapy. Although our investigation of tandem SBRT and IL12 MS intervention remains preliminary, it clearly shows promise as a prospective therapy for locally advanced PC.
Credits: None available.
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