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| Author(s): |
Natiely Silva Sales
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) |
| Defense date: | 2021-10-04 |
| Examining board members: |
Luis Carlos de Souza Ferreira;
Rafael Ciro Marques Cavalcante;
Suellen da Silva Gomes Herbster;
Gabriel Padilla Maldonado
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| Advisor: | Luis Carlos de Souza Ferreira |
| Abstract | |
Cervical cancer is a serious public health problem and represents the fourth most common type of cancer in women. Patients diagnosed with cervical cancer may be treated with surgery, radio and/or chemotherapy, which have reduced efficiency in more advanced cases of the disease and, in addition, are associated with the induction of severe adverse effects. Studies seek to develop new therapies against cancer associated with HPV infection, such as the combination of chemotherapy and immunotherapeutic strategies that act on different mechanisms (cell death, immunosuppression, induction of an antigen-specific response). In this sense, our group developed a DNA vaccine against HPV-induced tumours based on the expression of a hybrid protein resulting from the fusion of genes encoding the glycoprotein D (gD) of HSV-1 and the oncoprotein E7 of HPV-16 (pgDE7h). The aim of this work was to evaluate the antitumor efficacy of the immunotherapeutic strategies based on the combination of the pgDE7h vaccine and checkpoint blocking monoclonal antibodies (mAb) (anti-PD-1, anti-PD-L1 and anti-CTLA-4), or the combination of the pgDE7h vaccine with antagonist aptamers of the PD-1 and PD-L1 molecules (aptPD-1 and aptPD-L1), using the experimental model based on the implantation of TC-1 cell lineage, capable of expressing the E6 and E7 oncoproteins of the HPV-16. The association of pgDE7h with anti-PD-1 or anti-PD-L1 mAbs was capable to promote a partial therapeutic protective response. However, when we combined both anti-PD-1 and anti-PD-L1 mAbs with the pgDE7h vaccine, we did not observe further increase in the antitumor responses. On the other hand, the association of the pgDE7h vaccine with the anti-CTLA-4 mAb promoted an increase in the antitumor therapeutic response and survival of the animals in relation to animals that received only one of the treatments. Regarding the combination of pgDE7h and aptPD-L1, we observed an impaired antitumor therapeutic response, however, when we combined the vaccine with aptPD-1, we noticed a slight increase in the antitumor response. In summary, these data obtained during the present thesis demonstrate that the association of pgDE7h and the anti-CTLA-4 mAb shows itself as a promising therapeutic strategy against HPV-induced tumours. (AU) | |
| FAPESP's process: | 16/14344-1 - Control tumors induced by HPV -based immunotherapy in combination monoclonal antibodies blocking immunosuppressive pathways a therapeutic vaccine capable of activating CD8 + cytotoxic T lymphocytes |
| Grantee: | Natiely Silva Sales |
| Support Opportunities: | Scholarships in Brazil - Doctorate |