Abstract 3635: Enhanced intra-tumoral immune cell infiltration following tumor targeted delivery of chemotherapy using theranostic nanoparticles in an orthotopic mouse pancreatic model
Authors: Bozeman Erica N. , Gao Ning , Qian Weiping , Wang Andrew , Yang Lily 
Published: May 2015

Abstract
Development of novel therapeutics that have the dual capacity to de-bulk a tumor mass as well as induce tumor-specific immunological responses are critical to potent, effective and sustainable clinical responses against cancer. Such an integrated therapeutic approach has the potential to significantly improve the survival of cancer patients. 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 the conjugation of ligands that will bind specifically to tumor cells, tumor associated cells as well as the tumor stroma such as the urokinase plasminogen activator receptor (uPAR). uPAR expression is also associated with increased invasiveness and patients with uPAR gene amplification are considered a clinically high risk population which further makes this protein an ideal target. In an orthotopic mouse pancreatic cancer model in C57BL/6 mice (PANC02), we found that intraperitoneal delivery of 5 mg/kg cisplatin equivalent of uPAR-targeted IONP-cisplatin twice per week for four injections led to a reduced orthotopic tumor burden of ∼40% relative to untreated mice. We observed increased accumulation of the IONPs in the tumor center following uPAR-targeted delivery of the IONP-cisplatin by Prussian Blue staining relative to non-targeted IONP-cisplatin delivery. Importantly, we found increased infiltration of CD4+ and CD8+ T cells as well as CD20+ B cells into pancreatic tumors compared to tumors obtained from the mice treated with conventional cisplatin or non-targeted IONP-cisplatin. Although we observed an increase in clusters of CD20+ B cells in the tumor, we did not detect tumor-specific antibody responses in serum samples obtained from those mice suggesting the presence of immune suppressive mechanisms in the tumor that inhibited tumor-specific immune responses. However, the presence of higher levels of T and B lymphocytes in the center of the tumors suggest the opportunity to activate cytotoxic T cell responses and tumor-specific antibody production by the addition of immune-modulatory factors to the theranostic nanoparticles which is under current investigation in our laboratory. Taken together, these findings indicate that receptor-targeted delivery of chemotherapeutic drugs using IONPs has the potential to simultaneously induce direct anti-tumor activity and enhance the intratumoral infiltration of immune cells thus providing an optimal environment for further tumor-specific immune activation.
Citation Format: Erica N. Bozeman, Ning Gao, Weiping Qian, Andrew Wang, Lily Yang. Enhanced intra-tumoral immune cell infiltration following tumor targeted delivery of chemotherapy using theranostic nanoparticles in an orthotopic mouse pancreatic model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3635. doi:10.1158/1538-7445.AM2014-3635