Novel Poxvirus-based Mesothelin Pancreatic Cancer Vaccine Grant uri icon

abstract

  • Pancreatic cancer and its late presentation are increasing disproportionately in Eastern North Carolina due to the high incidence of confounding risk factors and barriers to the health care system that characterize the demographics of our region. The majority of patients are inoperable at presentation and, only 20% of patients who undergo potentially curative surgery enjoy long term survival. Traditional cytotoxic chemotherapy is used primarily in a palliative capacity and novel strategies such as immunotherapy have been proposed as an alternative method to achieve improved survival. Clinical trials employing immunotherapy have shown promise, but none has progressed beyond the investigative phase, primarily due to the inability to identify a universally expressed antigen or an effective mechanism for antigen presentation. Recently, mesothelin has emerged as a near universally expressed antigen in human pancreatic tumors but not normal pancreas and may serve as a useful target for future immunotherapy trials. In fact, a number of investigators have identified reactivity to mesothelin as an independent predictor of favorable response to other vaccine strategies. We have identified high levels of mesothelin expression in the murine pancreatic cancer cell line Panc02. This cell line is highly resistant to cytotoxic chemotherapy, much like its human counterpart and grows in a predictably lethal fashion when injected heterotopically in mice. Poxviruses have been commonly used to develop vaccines in humans but their efficacy is limited by virally encoded virulence genes, some of which are immunosuppressive. Our group has identified a virulence gene in the poxvirus (A35R) that, when deleted, results in a much attenuated virus and increased immune responses. This vector has been shown to enhance antibody, IL-2, IFN? and cytotoxic T lymphocyte killing compared to wild type. In this preclinical trial, we propose to create a mesothelin transduced A35 deficient poxvirus to treat immunocompetent mice bearing syngeneic pancreatic tumors. Immune responses, tumor progression and survival will be monitored to determine efficacy. The impact of such research, if successful, would allow for a more immunogenic specific pancreatic cancer vaccine, which could be used alone, or in combination with other regimens to treat this deadly cancer.

date/time interval

  • April 2009 - March 2011