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Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
Development of improved therapeutic mesothelin-based vaccines for pancreatic cancer
Michael White1, Andrew Freistaedter2, Gwendolyn J B Jones2
1Department of Surgery, Brody School of Medicine, East Carolina University, Greenville, NC, United States of America.
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.
Insights
A novel poxvirus vaccine targeting mesothelin shows safety and induces T cell responses in mice. However, it did not inhibit pancreatic tumor growth, possibly due to mesothelin shedding.
Area of Science:
- Oncology
- Immunology
- Virology
Background:
- Pancreatic cancer is a leading cause of cancer mortality with limited treatment options.
- Mesothelin is a tumor-associated antigen, making it a potential target for cancer therapy.
- Modified vaccinia virus Ankara (MVA) is a poxvirus platform with potential for vaccine development.
Purpose of the Study:
- To develop and evaluate an anti-mesothelin cancer vaccine using an enhanced MVA platform.
- To assess the safety, immunogenicity, and anti-tumor efficacy of the MVA-based vaccine in preclinical models.
Main Methods:
- Engineered MVA to express mesothelin, including a variant lacking the immunosuppressive A35 gene.
- Evaluated vaccine safety and induction of IFN-gamma secreting T cells in mice.
- Assessed in vitro oncolytic activity against Panc02 pancreatic cancer cells.
- Tested in vivo anti-tumor efficacy in immunocompetent mice with Panc02 tumors.
Main Results:
- Both MVA-mesothelin vaccines were safe in mice and induced mesothelin-specific T cell responses.
- The MVA virus demonstrated in vitro oncolytic activity against Panc02 cells.
- Deletion of the A35 gene enhanced T cell responses.
- No significant inhibition of Panc02 tumor growth was observed in vivo.
Conclusions:
- MVA-based vaccines targeting mesothelin are safe and immunogenic but lack efficacy in a preclinical pancreatic cancer model.
- Mesothelin shedding from tumor cells may represent a mechanism of immune evasion, limiting vaccine effectiveness.
- Further strategies are needed to overcome immune suppression and enhance therapeutic outcomes for pancreatic cancer.
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