Our goal is to target novel immune-modulating agents directly to the pancreatic tumor site using a tumorspecificMUC1 antibody as a carrier. This will be administered in combination with the MUC1/KRAS peptidevaccine and low-dose gemcitabine. MUC1 and Kras are over expressed in 90% of pancreatic ductaladenocarcinomas (PDA) and have long been targets for therapeutic interventions. Thus far, cancer vaccineshave not been clinically as successful as one had hoped for. Vaccines have failed to generate long-termimmune memory against the tumor antigens because tumors have adopted ways to escape immunerecognition and killing. Several new agents that can reverse immune evasion have been tested with modestclinical responses probably because the agents were administered systemically and may have neverreached the tumor site. We hypothesize that by directly delivering the immune modulating agents to thepancreatic tumor site and combining this with a multi-peptide MUC1/Kras vaccine, we can generate a robustanti-tumor response with a strong memory response. The treatment will affect both localized anddisseminated tumors, and strong memory responses will prevent recurrence. We will test the hypothesis inan appropriate mouse model of spontaneous PDA that clearly resembles the human disease.
Our specificaims are: 1) To optimize a MUC1/Kras-based vaccine in the PDA X MUCLTg mice by immobilizing fourimmune modulating agents directly to the tumor site by chemically conjugating the agents to a tumor-specificMUC1 monoclonal antibody. This antibody will home not only to the primary pancreas tumor but also to themetastatic tumor sites that over express MUC1; 2) To assess immune status and naturally occurring MUC1 -specific cellular and humoral immune responses in pancreatic cancer patients.
This aim will provide a soliddatabase as to the roles of tumor-associated tolerizing factors and anti-MUCI responses in tumorprogression, metastasis, survival, and prognosis and 3) A Phase I trial for the treatment of pancreas cancer.This trial utilizes a MUC1-pep1ide based vaccine, celecoxib, gemcitabine, and external beam radiation inpatients with locally advanced pancreatic cancer. We will monitor the immune tolerance mechanisms, andthe immune responses before, during, and after treatment. Future: This study could lead to development of anew combination modality for the treatment of localized and disseminated pancreas tumors.
Showing the most recent 10 out of 336 publications
