Abstract
Pancreatic cancer is the 5th leading cause of cancer deaths, and there are no effective treatments. We developed a poxvirus platform vaccine with improved immunogenicity and inserted the mesothelin gene to create an anti-mesothelin cancer vaccine. Mesothelin expression is mostly restricted to tumors in adult mammals and thus may be a good target for cancer treatment. We show here that the modified vaccinia virus Ankara (MVA) virus expressing mesothelin and the enhanced MVA virus missing the immunosuppressive A35 gene and expressing mesothelin were both safe in mice and were able to induce IFN-gamma secreting T cells in response to mesothelin expressing tumor cells. In addition, the MVA virus has oncolytic properties in vitro as it can replicate in and kill Panc02 pancreatic adenocarcinoma cell line tumor cells, even though it is unable to replicate in most mammalian cells. Deletion of the A35 gene in MVA improved T cell responses as expected. However, we were unable to demonstrate inhibition of Panc02 tumor growth in immunocompetent mice with pre-vaccination of mice, boosts, or even intratumoral injections of the recombinant viruses. Vaccine efficacy may be limited by shedding of mesothelin from tumor cells thus creating a protective screen from the immune system.
Highlights
Pancreatic cancer is the 5th leading cause of cancer deaths in the United States [1] and has the lowest 5-year survival rate (7%) for solid tumors [2] largely owing to the fact that radiation, surgery, and current chemotherapy options are ineffective
Mesothelin protein was strongly expressed in both modified vaccinia virus Ankara (MVA) mesothelin virus-infected Baby hamster kidney (BHK) cells, with monomers and apparent dimers (~100 kDa), but not in cells infected with MVA parental wild type virus or uninfected BHK cells (Fig 1)
We have shown that murine mesothelin can be expressed from the MVA virus genome and detected as a ~50 kDa monomer protein on SDS-PAGE immunoblot, and a ~100 kDa presumed dimer
Summary
Pancreatic cancer is the 5th leading cause of cancer deaths in the United States [1] and has the lowest 5-year survival rate (7%) for solid tumors [2] largely owing to the fact that radiation, surgery, and current chemotherapy options are ineffective. Human mesothelin is normally expressed only in mesothelial cells of the pleura, peritoneum, and pericardium. Mesothelin is overexpressed in a high percentage of ovarian cancers, pancreatic cancers, non–small lung cancers, and mesotheliomas, making it a potential target for anti-cancer treatments [3,4,5,6,7]. Human and mouse mesothelin share sequence similarity, expression patterns, and biochemical characteristics, [7], and the homeostatic function of mesothelin in mammals is unknown: the gene can be deleted without apparent effect in mice.
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