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Combination of cytokine-enhanced vaccine and chemo-gene therapy as surgery adjuvant treatments for spontaneous canine melanoma

Abstract

After 6 years of follow-up treating 364 canine melanoma patients, we present here results about the proof-of-concept, safety, and efficacy of a new surgery adjuvant combined gene therapy. The adjuvant treatment (AT) group was divided in three arms as follows: (i) complete surgery plus vaccine (CS-V), (ii) complete surgery plus combined treatment (CS-CT), and (iii) partial surgery plus combined treatment (PS-CT). Besides the genetic vaccines composed by tumor extracts and lipoplexes carrying human interleukin-2 and granulocyte-macrophage colony-stimulating factor genes, the patients were subjected to combined treatment received in the post-surgical bed injections of lipid-complexed thymidine kinase suicide gene plus ganciclovir and canine interferon-β gene plus bleomycin. As compared with surgery-only treated controls (So), CS-CT and CS-V treatments significantly increased the fraction of local disease-free (from 20 to 89 and 74%) and distant metastases-free patients (M0: from 45 to 87 and 84%). Although less effective than CS arms, PS-CT arm demonstrated a significantly improved control of metastatic disease (M0: 80%) compared with So (M0: 44%). In addition, AT produced a significant 9.3- (CS-CT), 6.5- (CS-V), and 5.4-fold (PS-CT) increase of overall survival as compared with their respective So controls. In general terms, the AT changed a lethal disease into a chronic disease where 70% of CS-CT, 51% of CS-V, and 14% of PS-CT patients died of melanoma unrelated causes. These surgery adjuvant treatments delayed or prevented post-surgical recurrence and distant metastasis, and improved disease-free and overall survival while maintaining quality of life. These successful outcomes encourage assaying a similar scheme for human melanoma.

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Acknowledgements

We are grateful to our patients and their owners for their cooperation and participation in this study. We recognize the technical assistance and advice of MSc. Doris Riveros, Ms. Graciela Zenobi, and MSc. Juan Cardini. We thank all VMDs involved in this study for patients’ treatment and care, especially Drs. Fernando Calcagno, José L. Suárez, Pablo Meyer, Julián Piñeyra, Jorge Blomberg, Soledad Ramírez, Agustina Spector, Alexis Jalikias, Marie Maminska, Lorena Peteta, Martín Aureggi, and Alejandro Goldman. This work was partially supported by grants from ANPCYT/FONCYT (PICT2012-1738 and PICT2014-1652) and CONICET (PIP 11220110100627 and PIP 11220150100885). L.M.E.F. and G.C.G. are investigators of the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET, Argentina), and C.F. and L.A. are research fellows of the CONICET.

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The authors declare no conflicts of interest.

Correspondence to Liliana M. E. Finocchiaro.

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