Abstract PL04-03: Fatal Attraction: A new story featuring the immune system and pancreatic cancer

Pancreatic cancer remains a “death sentence,” with the poorest survival rates reported for solid tumors. Escalating this problem is the fact that pancreatic cancer is among the most resistant cancers to traditional forms of therapy. But in this new era of targeted therapies, there is reason to hope that significant progress will be made in the development of new treatments in the near future. In fact, we have entered into a new era of cancer therapies and are witnessing the rapid approval of antibodies and small molecule agents that inhibit cancer associated pathways. In the past year we have also witnessed the approval of the first cancer vaccine (Provenge) for the treatment of prostate cancer. Soon after, the first immune check point inhibitor (Yervoy, ipilimumab) that blocks the downregulatory signal, CTLA-4 on T cells, was approved for the treatment of malignant melanoma. These groundbreaking examples have opened the floodgates for a whole new class of anticancer agents. 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 in our understanding of its immunobiology has 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 preinvasive 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. This presentation will provide historical prospective on the field, and highlight the recent advances and future expectations for the immunotherapy of pancreatic cancer. References: 1. Thomas AM, Santarsiero LM, Armstrong TD, Chen Y-C, Huang L-Q, Laheru DA, Goggins M, Hruban RH, Jaffee EM. Mesothelin Specific CD8+ T Cell Responses Provide Human Evidence of In Vivo Cross-Priming by Antigen Presenting Cells in Vaccinated Pancreatic Cancer Patients. J Exp Med., 200(3):297–306, 2004. 2. Laheru D, Jaffee EM. Immunotherapy of pancreatic cancer - science driving clinical progress. Nat Rev Cancer 2005; 5(6):459–67. PMID: 15905855 3. Laheru D, Lutz E, Burke J, Biedrzycki B, Solt S, Onners B, Tartakovsky I, Nemunaitis J, Le D, Sugar E, Hege K, Jaffee EM. Allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Cancer Therapy: Clin Can Res 2008 Mar l:14(5):1455–1463. PMID: 18316569 NIHMSID # 105519 4. Lutz E, Yeo CJ, Lillemoe KD, Biedrzycki B, Kobrin B, Herman J, Sugar E, Piantadosi S, Cameron JL, Solt S, Onners B, Tartakovsky I, Choi M, Sharma R, Illei PB, Hruban RH, Abrams RA, Le D, Jaffee E, Laheru D. A lethally irradiated allogeneic granulocytemacrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation. Ann Surg. 2011;253(2):328-35. PMCID: 3085934. 5. Le DT, Brockstedt DG, Nir-Paz R, Hampl J, Mathur S, Nemunaitis J, Sterman DH, Hassan R, Lutz E, Moyer B, Giedlin M, Louis JL, Sugar EA, Pons A, Cox AL, Levine J, Murphy AL, Illei P, Dubensky TW, Jr., Eiden JE, Jaffee EM, Laheru DA. A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase i studies of safety and immune induction. Clinical cancer research: an official journal of the American Association for Cancer Research. 2012;18(3):858–68. PMCID: 3289408. 6. Blankenstein T, Coulie PG, Gilboa E, Jaffee EM. The determinants of tumour immunogenicity. Nat Rev Cancer 2010; 12(4):307–13. PMID: 22378190. Citation Format: Elizabeth M. Jaffee. Fatal attraction: A new story featuring the immune system and pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr IA17.