New treatments are urgently needed for pancreatic cancer, which usually resists traditional radiotherapy, chemotherapy, and even modern targeted therapies. An alternative treatment, an active therapeutic cancer vaccine, has been actively studied for pancreatic and other cancers. However, cancer vaccines have been largely unsuccessful to date, perhaps because (1) the vaccines did not induce sufficiently robust cytotoxic T cells (CTLs); (2) the tumor antigens chosen as cancer vaccines may not have been vital for cancer cell survival, so even when robust CTLs are induced, cancer cells may downregulate these antigens to escape immune control; and (3) the cancer cells downregulate the expression of the major histocompatibility complex (MHC) that is required for CTL recognition, an aspect not addressed by most cancer vaccines. The goal of this proposal is to develop an effective cancer vaccine program as a treatment for pancreatic cancer. My hypotheses are that (1) survivin, a protein inhibitor of apoptosis overexpressed in more than 80% of pancreatic cancers, is a good cancer vaccine target that can induce specific CTL responses in patients with pancreatic cancer; and (2) IFN-a can overcome the immunologic escape of cancer cells by upregulating MHC expression in the tumor microenvironment, which could enhance immune recognition by CTLs. I will test these hypotheses with the following specific aims: (1) to identify novel survivin peptides as cancer vaccines that induce the strongest CTL responses by screening blood samples from patients with pancreatic cancer against a 15-mer overlapping survivin peptide library; (2) to determine CTL responses to survivin peptide vaccines and test if concurrent IFN-a treatment enhances these responses in patients with pancreatic cancer in a randomized two-arm phase I clinical trial of survivin peptides with and without IFN-a as a preoperative treatment in patients with resectable pancreatic cancer; and (3) to determine whether IFN-a increases MHC expression in the tumor microenvironment by immunohistochemical staining of surgical specimens from the phase I trial. Accomplishing these aims will establish survivin epitopes as cancer vaccine targets and IFN-a as a cancer vaccine adjuvant, leading to development of an active cancer vaccine as a treatment for patients with pancreatic cancer. This work will also provide me with the experience, knowledge, and skills necessary to launch an independent research career as a translational tumor immunologist in pancreatic cancer. The results of this project will position me to submit a competitive NIH R01 application during the fourth year of the proposed award period. ? ? ?
| Chang, David Z; Ma, Ying; Ji, Baoan et al. (2012) Increased CDC20 expression is associated with pancreatic ductal adenocarcinoma differentiation and progression. J Hematol Oncol 5:15 |
| Chang, David Z; Ma, Ying; Ji, Baoan et al. (2011) Mast cells in tumor microenvironment promotes the in vivo growth of pancreatic ductal adenocarcinoma. Clin Cancer Res 17:7015-23 |
