become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED.The broad objective of this proposal is to identify antigens expressed by human pancreaticadenocarcinomas and validate these antigens as predictors of immune response. These antigens canultimately be used in targeted cancer vaccine strategies. We have been developing an allogeneic granulocytemacrophagecolony-stimulating factor (GM-CSF) secreting pancreatic tumor vaccine approach for thetreatment of patients with pancreatic cancer. Recently completed phase I and II studies demonstrated thebioactivity of this vaccine as measured by elevated post-vaccination serum levels of GM-CSF, post-vaccinationeosinophilia that is associated with systemic vaccine related rashes and vaccine recall reactions, and postvaccinationdelayed type hypersensitivity (DTH) reactions to autologous tumor. These responses are mostoften observed in patients demonstrating prolonged disease-free survival. Analysis of post-vaccination immuneresponses identified mesothelin and prostate stem cell antigen (PSCA) as two candidate new targets againstwhich both T cell responses were directed in patients who remain disease-free. With a recently completedphase II study in resected patients, and a new currently enrolling phase II combinatorial vaccine study, we arepoised to extend our immune target discovery program and to validate identified genes as immune relevanttargets of the immune response.
In Aim 1, we will screen a panel of genes that are turned on early and late inpancreatic cancer progression using immunized leukopheresed lymphocytes from patients treated in ouradjuvant phase II study.
In aim 2, we will validate the panel of genes evaluated in aim 1 using patientlymphocytes from two vaccine studies for their relevance as post-vaccination immune targets.
In aim 3, we willevaluate the function of T cells specific for new antigenic targets identified in aims 1 and 2. We will focus onthree functional parameters: expression of lytic function, induction of memory T cells, and induction of higheravidity T cells.We will utilize tissues from clinical trials and Core 2 to translate expressed marker antigens found inproposed Project 3C (formerly 2A) to clinical trial monitoring and new trials, to prioritize candidate antigens forbasic studies in proposed Project 1B, and to apply measures of host immune responses in proposed Project 2B.
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|Shumar, Stephanie A; Kerr, Evan W; Geldenhuys, Werner J et al. (2018) Nudt19 is a renal CoA diphosphohydrolase with biochemical and regulatory properties that are distinct from the hepatic Nudt7 isoform. J Biol Chem 293:4134-4148|
|Li, Yuguo; Qiao, Yuan; Chen, Hanwei et al. (2018) Characterization of tumor vascular permeability using natural dextrans and CEST MRI. Magn Reson Med 79:1001-1009|
|Saung, May Tun; Muth, Stephen; Ding, Ding et al. (2018) Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer. J Immunother Cancer 6:118|
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