*3.4. Pancreatic Cancer*

Pancreatic cancer is resistant to many forms of treatment, highlighting the urgent need to develop novel therapies to fight this neoplastic disease.

Mesothelin (MSLN), a glycoprotein membrane whose expression is limited to mesothelial cells, is overexpressed in most pancreatic cancers and is involved in tumor adhesion and dissemination, making it a robust therapeutic target [95,96]. By presenting the human (h) MSLN on simian-human immunodeficiency VLP (SHIV), a pancreatic VLP-hMSLN vaccine was created [30]. The efficacy of VLP-hMSLN was tested in Panc02 cells implanted orthotopically in mice, showing significantly lower tumor progression and reduction in tumor mass and the survival of 60% of vaccinated mice. Protection was due to the induction of high concentrations of specific anti-hMSLN antibodies and the release of IFN-γ, accompanied by a strong and specific CTL response and a reduction in regulatory T cells (Treg; CD4+FOXP3+ICOS−) [30]. The hMSLN was a xenogenic antigen in mice, even if human and mouse MSLN has 60% homology. To verify whether the mouse (m)MSLN can break self-tolerance, mMSLN was displayed in the SHIV VLP (VLP-mMSLN). Immunization with this murine VLP version efficiently induced CD8<sup>+</sup> T cell activation, reduced tumor volume, and survival of tumor-bearing mice [30].

Another pancreatic vaccine candidate was previously developed using SIV expressing mTrop2 (mTrop2 VLP) [31]. Trop2 is a surface glycoprotein overexpressed in pancreatic cancer and is associated with poor patient survival [97]. The efficacy of mTrop2 VLP vaccination was tested in the syngeneic pancreatic cancer murine model. The immunization was able to break tolerance and generate a cellular and humoral response overcoming some of the suppressive tumor microenvironment agents. The results showed a reduction in tumor growth, activation and infiltration of CD4+, CD8<sup>+</sup> T cells, and NK cells. VLP vaccination, in combination with gemcitabine, increased the survival of tumor-bearing mice, suggesting that mTrop2 VLP might be the right approach for pancreatic cancer treatment [31].
