The broad objective of this proposal is to identify antigens expressed by human pancreatic adenocarcinomas and validate these antigens as predictors of immune response. These antigens can ultimately be used in targeted cancer vaccine strategies. We have been developing an allogeneic granulocytemacrophage colony-stimulating factor (GM-CSF) secreting pancreatic tumor vaccine approach for the treatment of patients with pancreatic cancer. Recently completed phase I and II studies demonstrated the bioactivity of this vaccine as measured by elevated post-vaccination serum levels of GM-CSF, post-vaccination eosinophilia that is associated with systemic vaccine related rashes and vaccine recall reactions, and postvaccination delayed type hypersensitivity (DTH) reactions to autologous tumor. These responses are most often observed in patients demonstrating prolonged disease-free survival. Analysis of post-vaccination immune responses identified mesothelin and prostate stem cell antigen (PSCA) as two candidate new targets against which both T cell responses were directed in patients who remain disease-free. With a recently completed phase II study in resected patients, and a new currently enrolling phase II combinatorial vaccine study, we are poised to extend our immune target discovery program and to validate identified genes as immune relevant targets of the immune response.
In Aim 1, we will screen a panel of genes that are turned on early and late in pancreatic cancer progression using immunized leukopheresed lymphocytes from patients treated in our adjuvant phase II study.
In aim 2, we will validate the panel of genes evaluated in aim 1 using patient lymphocytes from two vaccine studies for their relevance as post-vaccination immune targets.
In aim 3, we will evaluate the function of T cells specific for new antigenic targets identified in aims 1 and 2. We will focus on three functional parameters: expression of lytic function, induction of memory T cells, and induction of higher avidity T cells. We will utilize tissues from clinical trials and Core 2 to translate expressed marker antigens found in proposed Project 3C (formerly 2A) to clinical trial monitoring and new trials, to prioritize candidate antigens for basic studies in proposed Project 1B, and to apply measures of host immune responses in proposed Project 2B.
Showing the most recent 10 out of 883 publications
