Canine model of melanoma immunotherapy using adenoviral vectors carrying p14Arf and interferon-beta cDNAs

Author(s)

Otavio Augusto Rodrigues

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD)
• Defense date: 2023-11-13

Examining board members

Bryan Eric Strauss; Roger Chammas; Fábio Luís Forti; Tiago da Silva Medina

• Advisor: Bryan Eric Strauss

Abstract

Melanoma is an aggressive kind of cancer, difficult to treat in advanced cases in both human and veterinary medicine. Despite the considerable progress in therapeutic proposals, mortality rates are still high, making it necessary to develop new therapeutic approaches. Melanomas often present a dysfunctional p53 pathway, although it frequently retains the wild type protein. In previous studies, our group has used adenoviral vectors for the transfer of p14ARF (tumour suppressor protein) in order to reactivate the p53 pathway in murine and human cells, both in vitro and vivo. Co-transduction with IFN (immunomodulatory cytokine) induced especially high levels of cell killing along with the release of immunogenic cell death markers in vitro, significant reduction of tumour progression and stimulation of a strong immune responses in vivo. Before moving to human tests, we wish to verify these outcomes in animal models that more closely represent the complexity of human cases of melanoma, including the capability to form spontaneous tumours and metastases. Therefore, this work aimed to develop adenoviral vectors encoding the canine p14ARF and IFN genes in order to validate our approach in a model utilizing canine oral melanoma cell lines previously established in our laboratory. Consistent with our previous studies in mouse and human cell lines, we observed that this combination of vectors induced cell death accompanied by the release of immunogenic factors, such as ATP and HMGB1 in the canine cell lines GAB-F6 and BAN-C10. In a xenograft model of in situ gene therapy, we demonstrated the inhibition of tumour progression in vivo, and delay of tumour development and extended survival. These results support testing this therapeutic approach in veterinary patients, an important step in the development of our melanoma gene therapy (AU)

• FAPESP's process: 17/25284-2 - Construction and characterization of adenoviral vectors encoding the canine cDNAs for p14Arf and IFN-beta
• Grantee: Otavio Augusto Rodrigues
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)