Abstract A30: AR20.5-based novel immunotherapy for pancreatic cancer
Authors: Mehla Kamiya , Grunkemeyer James A. , O'Connell Kelly A. , Steele Maria M. , Caffrey Thomas , Madiyalakan Ragupathy , Nicodemus Christopher F. , Hollingsworth Michael A. 
Published: March 2017

Abstract
Pancreatic cancer is a fourth leading cause of cancer death in United States. Recent advances in tumor immunology have provided evidence for immune surveillance against pancreatic cancer. Previous studies have documented the presence of specific antibodies and cytotoxic T cell activities to Mucin 1 (MUC1), an antigen that is expressed in most pancreatic cancers. Hence, MUC1 remains a candidate for immunotherapeutic strategies for pancreatic cancer. Numerous attempts have been made to target this mucin glycoprotein; however, these efforts have shown only moderate success in part due to the complexity of the pancreatic tumor microenvironment. Previously, administration of murine monoclonal antibody BrevaRexAb-AR20.5 alone produced MUC1 specific immune response in a phase I study of advanced cancer patients, including increased human anti-MUC1 antibody levels and MUC1 specific T cell response in few patients. Though this was a phase I study, modest changes in tumor marker (CA15.3) but no anecdotal anti-tumor activity was observed in this small group of patients. Moving forward it is obvious that future immunization strategies should include other immune-modulators to amplify MUC1 specific immune responses of mAbAR20.5 and enhance other factors that contribute to tumor rejection. To that end, we investigated the anti-tumor effect of mAbAR20.5 in combination with anti-PD-L1 and poly (I:C) in murine models of pancreatic adenocarcinoma using human MUC1 expressing transgenic (hMUC1.Tg) mice, which are immunologically tolerant to MUC1. The therapeutic combination of mAb-AR20.5+anti-PD-L1+Poly (I:C) induced rejection or significant inhibition of tumor growth for two different MUC1 expressing pancreatic tumor cell lines, which was accompanied by persistent MUC1 specific memory immune response, which could be adoptively transferred to other mice and shown to protect against subsequent tumor challenge. We show that the anti-tumor response was effected by CD8 T cells, as their abrogation attenuated the anti-tumor response. Flow cytometric analysis of immunized mice demonstrated progressive increases in activated CD8 T cells in the peripheral circulation of combination treated mice. Together, these data support the hypothesis that targeting checkpoint induced immunosuppression (anti-PD-L1) together with the use of toll-like receptor 3 agonist as an adjuvant (poly (I:C) ) enhances the capacity of mAbAR20.5 to induce specific cell mediated immune responses to MUC1, which in turn provide long lasting anti-tumor response against pancreatic tumors. Our study supports the rapid translation of this strategy into clinical trials for pancreatic cancer patients.
Citation Format: Kamiya Mehla, James A. Grunkemeyer, Kelly A. O'Connell, Maria M. Steele, Thomas Caffrey, Ragupathy Madiyalakan, Christopher F. Nicodemus, Michael A. Hollingsworth. AR20.5-based novel immunotherapy for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A30.