We propose to evaluate the potential anti-tumor effects of current conventional therapies (chemo/radiation) combined with targeted immunotherapy and specific COX-2 inhibition in a clinically relevant mouse model of spontaneous pancreatic cancer. We will investigate the synergistic and antagonistic mechanisms of action of these therapies alone and in various combinations. Multiple mechanisms including tumor cell proliferation, apoptosis, angiogenesis, invasion, immunosuppression, and cell cycle arrest will be determined. The mouse studies will be validated by studies of human primary pancreatic cancer cells in a xenograft model. Rationale: Immunotherapy by itself can elicit tumor-specific cytotoxic T lymphocytes (CTLs), which become non-functional within the pancreas tumor microenvironment allowing the tumor to grow. Thus, altering the tumor microenvironment by targeting distinct but interdependent aspects of pancreatic cancer signaling pathways may be essential for effective treatment. COX-2 inhibitors target multiple pathways of tumorigenesis including proliferation, apoptosis, angiogenesis, invasion and immune suppression. Hypothesis: Inhibiting tumor-induced COX-2 and activating anti-tumor immunity combined with standard adjuvant chemo/radiotherapy will exert maximal anti-tumor effect in the treatment of spontaneous pancreatic cancer. We propose to utilize autologous dendritic cells fed with pancreatic tumor lysate as the vaccine source, celecoxib as the COX-2 inhibitor, and gemcitabine as the chemotherapeutic agent.
Specific Aims are 1) to determine the most potent dose, schedule and toxicity of the vaccine, COX-2 inhibitor and chemo/radiation alone and in combination in the mouse model. We will also evaluate the anti-tumor activity and survival benefit in response to combinatorial treatment; 2) to evaluate the anti- tumor immune responses and dissect the potential mechanisms of interaction between COX-2 inhibition, immunotherapy and chemo/radiotherapy with regards to tumor cell growth, tumor cell death (apoptosis), tumor cell motility (metastasis) and immune-suppression and 3) to extend the mouse studies to a human xenograft model of pancreatic cancer. We expect that our proposal will lead towards development of novel combination modalities that target known molecules in new ways. Long-term trajectory is to evaluate toxicity of the most effective combinatorial treatment strategy and immunological endpoints in a Phase 1/11clinical trial.
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