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 cancer genetics and 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 down regulatory 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. These successes also open the door for developing immunotherapy approaches that target the earliest genetic changes that occur in the normal tissue as it begins undergo transformation to malignancy.

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 both pre-invasive and invasive cancer cells to create a procarcinogenic tumor microenvironment. Current research is focused on elucidating the mechanisms of this tolerogenic polarization within the early tissue at the time of the earliest genetic changes that drive transformation from normal to malignant tissue. 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 progressive inhibitory pathways that develop within the premalignant microenvironment and to develop ways to alter these signals in favor of an anticancer response. Understanding the earliest inflammatory changes that are associated with the earliest genetic changes should allow the development of approaches that can prevent cancer development even in individuals who are risk for cancer and may have already expressed the earliest driver genes.

This presentation will highlight the recent advances and future expectations for immunotherapy as prevention 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 granulocyte-macrophage 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

7. Le DT, Lutz E, Uram JN, Sugar E, Onners B, Solt S, Zheng L, Diaz Jr LA, Donehower R, Jaffee EM, Laheru D. 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.

Citation Format: Elizabeth Jaffee. Tipping the balance from a procarcinogenic to an anticancer response to prevent pancreatic cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr CN01-02.

©2013 American Association for Cancer Research.
2013