Abstract A60: Synergistic effect of targeted chemotherapy delivery using theranostic nanoparticles and PD-L1 blockade in an orthotopic mouse pancreatic cancer model
Authors: Bozeman Erica N. , Gao Ning , Qian Weiping , Wang Andrew , Yang Lily 
Published: October 2015

Abstract
Pancreatic cancer is the fourth deadliest form of cancer with a dismal 5-year survival rate of less than 5%. As a result there is an urgent need for the development of more efficacious therapies for pancreatic cancer. In order to overcome the immune suppression that is prevalent in this disease, the use of immune checkpoint blockades, CTLA-4 and PD-L1, have been investigated. However, published reports have indicated that pancreatic cancer is generally non-responsive to these immunotherapies. Because it has been shown that combinatorial therapies consisting of immunotherapy and chemotherapy can act synergistically, we sought to investigate the efficacy of targeted delivery of the chemotherapeutic cisplatin using nanoparticle carriers along with PD-L1 blockade in a highly aggressive orthotopic model of pancreatic cancer derived from the PANC02 mouse cell line. Our lab has developed a receptor targeted magnetic iron oxide nanoparticle (IONP) platform for targeted tumor imaging and drug delivery and demonstrated its effect on tumor growth inhibition in breast, ovarian, and pancreatic cancer mouse models. Active targeting of IONPs requires conjugation of the recombinant amino terminal fragment (ATF) of the urokinase plasminogen activator (uPA) that will bind specifically to tumor cells and tumor associated stromal cells that express a high level of its receptor (uPAR). uPAR expression is associated with increased invasiveness and a poorer prognosis, which further makes this protein an ideal target. In the orthotopic PANC02 model, we found that intraperitoneal delivery of 100µg of PD-L1 blockade alone (clone 10F.9G2) twice per week for four injections reduced orthotopic tumor burden by ~30% relative to untreated mice. Whereas, the combination therapy with uPAR-targeted IONP-cisplatin (10mg/kg drug equivalent) decreased tumor burden by ~65%. Enhanced inhibition of ascites fluid accumulation was also observed following combinatorial therapy, 81% versus 55.6%, respectively. We observed that a high level of uPAR-targeted IONP-cisplatin accumulated in the orthotopic pancreatic tumor following intraperitoneal delivery by Prussian blue staining indicating the effective delivery of the chemotherapeutic drug to the tumor site which could mediate tumor growth inhibition. Additionally, this therapeutic synergy is likely due, in part, to the enhanced intratumoral infiltration of T cells following targeted IONP-drug treatment. Taken together, these findings indicate that the minimal therapeutic efficacy of immune checkpoint blockades such as PD-L1 in pancreatic cancer can be enhanced by the tumor-targeted delivery of chemotherapeutic drugs using theranostic nanoparticles and this combinatorial therapeutic regime warrants further investigation.
Citation Format: Erica N. Bozeman, Ning Gao, Weiping Qian, Andrew Wang, Lily Yang. Synergistic effect of targeted chemotherapy delivery using theranostic nanoparticles and PD-L1 blockade in an orthotopic mouse pancreatic cancer model. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A60.