Abstract IA16: Tipping the balance from a procarcinogenic to an antitumor microenvironment in pancreatic cancers

Until recently, barriers to immunotherapy clinical successes for pancreatic cancer have been due to a lack of understanding of the immune pathways within the pancreatic tumor microenvironment that hinder successful immune responses. Recent advances have identified new targets for developing cancer specific vaccines and new targets for modulating the tumor microenvironment to allow more potent activation and improved access of vaccine induced immune responses. We are just learning that non-neoplastic cells, including cancer-associated myofibroblasts, regulatory T cells, dendritic cells, myeloid-derived suppressor cells, and tumor-associated macrophages, are hijacked by pre-invasive and invasive cancer cells to create a tolerogenic tumor microenvironment. Current research is focused on elucidating the mechanisms of this tolerogenic polarization within the tumor microenvironment with the goal of tipping the balance in favor of an anticancer immune response. With the recent advances in molecular technologies and the development of relevant pancreatic cancer mouse models, it is now within our reach to dissect the inhibitory pathways within the pancreatic tumor microenvironment. This will in turn, lead to new therapeutic opportunities that will eliminate these barriers and convert this deadly cancer into a treatable disease. Building on our extensive experience developing immunotherapies for pancreatic cancer, we are now developing combinatorial immunotherapies that combine T cell inducing agents with agents that modulate T cell down regulatory signals within the tumor microenvironment. These studies have shown for the first time that traditionally “non-immunogenic” cancers that do not respond to single agent immune modulating agents, can be converted into tumors susceptible to these agents if a T cell inducing vaccine is given together with these immune modulating agents. Results from both pre-clinical and clinical studies will be discussed. References: 1. Le, DT et al. Evaluation of Ipilimumab in Combination With Allogeneic Pancreatic Tumor Cells Transfected With a GM-CSF Gene in Previously Treated Pancreatic Cancer. Journal of Immunotherapy 2013; 36 (7): 382-389. 2. Keenan et al. A Listeria vaccine and depletion of Tregs activate immunity against early pancreatic intraepithelial neoplasms and prolong the survival of mice. Gastronterology 2014;146:1784-1994. 3. Lutz et al. Immunotherapy converts nonimmunogenic pancreatic tumors into foci of immune regulation. Cancer Immunology Research 2014; 2(7):616-631. 4. Le DT, Wang-Gillam A, Picozzi V, Greten TF, Crocenzi T, Springett G, Morse M, Zeh H, Cohen D, Fine RL, Onners B, Uram JN, Laheru DA, Lutz ER, Solt S, Murphy AL, Skoble J, Lemmens E, Grous J, Dubensky T, Jr., Brockstedt DG, Jaffee EM. Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes-Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer. J Clin Oncol. 2015; 33 (12): 1325-33. PMCID: PMC4397277. 5. Kouo T, Huang L, Pucsek AB, Cao M, Solt S, Armstrong T, Jaffee E. Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells. Cancer immunology research. 2015; 3 (4): 412-23. PMCID: PMC4390508. 6. Chu NJ, Armstrong TD, Jaffee EM. Nonviral Oncogenic Antigens and the Inflammatory Signals Driving Early Cancer Development as Targets for Cancer Immunoprevention. Clin Cancer Res. 2015; 21 (7): 1549-57. PMCID: PMC4383709. Supported by grants from the National Cancer Institute, National Institutes of Health (P50CA062924, R01CA122081, and U19CA113341 to E.M.J.), Stand Up to Cancer-Lustgarten Foundation Pancreatic Cancer Convergence Dream, and supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer. Citation Format: Elizabeth M. Jaffee. Tipping the balance from a procarcinogenic to an antitumor microenvironment in pancreatic cancers. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA16.