Inhibition of tumor growth by cancer vaccine combined with metronomic chemotherapy and anti-PD-1 in a pre-clinical setting
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Annacarmen Petrizzo1, Angela Mauriello1, Antonio Luciano2, Domenica Rea2, Antonio Barbieri2, Claudio Arra2, Piera Maiolino3, Marialina Tornesello1, Vincenzo Gigantino4, Gerardo Botti4, Gennaro Ciliberto5, Franco M. Buonaguro1, Maria Tagliamonte1 and Luigi Buonaguro1
1Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
2Animal Facility, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
3Pharmacy Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
4Unit of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy
5Scientific Directorate, Regina Elena National Cancer Institute, Rome, Italy
Maria Tagliamonte, email: [email protected]
Luigi Buonaguro, email: [email protected]
Keywords: cancer vaccine; mutated epitopes; metronomic chemotherapy; anti PD-1; combinatorial strategy
Received: August 31, 2017 Accepted: October 25, 2017 Published: December 08, 2017
Tumor microenvironment (TME) is characterized by multiple immune suppressive mechanisms able to suppress anti-tumor effector cell immunity. Combinatorial strategies, including vaccine and immunomodulatory drugs, need to be developed for improved immunotherapy efficacy.
A novel combinatorial approach was assessed in C57BL/6 mice injected with mouse melanoma B16F10 cells. A multi-peptide vaccine (PEPT) was combined with a low dose metronomic chemotherapy (MCT) and an anti-PD-1 checkpoint inhibitor (CI). Statistical analysis were performed with the unpaired two-sided Student’s t-test and ANOVA.
Animals treated with the multi-peptide vaccine combined with MCT or CI showed remarkable delay in tumor growth and prolonged survival as compared to control groups. The multi-pronged combination including PEPT+MCT+CI was able to prolong survival in all mice and inhibit tumor growth in 66.6% of mice. All animals which did not show tumor growth were re-challenged with the same melanoma cells and one of them showed complete tumor growth inhibition. The anti-tumor effect was associated with strong T cell immune response to vaccine mutated peptides and significant reduction of regulatory T cells.
The combination of a vaccine with MCT and CI was highly efficient in potentiating the vaccine’s anti-tumor effects. The approach is highly promising to be moved into clinical trial.
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