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Doctoral Thesis
DOI
https://doi.org/10.11606/T.42.2021.tde-12082022-174356
Document
Author
Full name
Natiely Silva Sales
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2021
Supervisor
Committee
Ferreira, Luis Carlos de Souza (President)
Cavalcante, Rafael Ciro Marques
Herbster, Suellen da Silva Gomes
Maldonado, Gabriel Padilla
Title in Portuguese
Controle de tumores induzidos por HPV por imunoterapia baseada na associação de anticorpos monoclonais de bloqueio de vias imunossupressoras a uma vacina terapêutica capaz de ativar linfócitos T CD8+ citotóxico.
Keywords in Portuguese
anti-CTLA-4 mAbs
anti-PD-1
anti-PD-L1
aptâmeros
Câncer cervical
imunoterapia
vacinas de DNA
Abstract in Portuguese
O câncer cervical é um grave problema de saúde pública e representa o quarto tipo de câncer mais frequente em mulheres. As pacientes diagnosticadas com câncer cervical podem ser tratadas com cirurgia, radio e/ou quimioterapia, que apresentam eficiência reduzida em casos mais avançados da doença e, além disto, estão associados à indução de efeitos adversos severos. Estudos buscam desenvolver novas terapias contra câncer associado à infecção por HPV, como a combinação de estratégias quimioterápicas e imunoterapêuticas que atuam em diferentes mecanismos (morte celular, imunossupressão, indução de resposta antígeno-específica). Nesse sentido, nosso grupo desenvolveu uma vacina de DNA contra tumores induzidos por HPV baseada na expressão de uma proteína híbrida resultado da fusão gênica da glicoproteína D (gD) do HSV-1 à oncoproteína E7 do HPV-16 (pgDE7h). O objetivo desse trabalho foi avaliar a eficácia antitumoral de estratégias imunoterapêuticas baseadas na combinação da vacina pgDE7h e anticorpos monoclonais (mAb) de bloqueio de checkpoint (anti-PD-1, anti-PD-L1 e anti-CTLA-4), ou a combinação da vacina pgDE7h com aptâmeros antagonistas das moléculas PD-1 e PD-L1 (aptPD-1 e aptPD-L1), frente ao modelo experimental baseado no implante de células da linhagem TC-1, capaz de expressar as oncoproteínas E6 e E7 do HPV-16. A associação de pgDE7h com os mAbs anti-PD-1 ou com anti-PD-L1 foi capaz de promover resposta terapêutica parcial. No entanto, ao combinarmos ambos os mAbs anti-PD-1 e anti-PD-L1 com a vacina pgDE7h não observamos aumento adicional da resposta antitumoral. Por outro lado, a associação da vacina pgDE7h com o mAb anti-CTLA-4 foi capaz de promover um aumento da resposta terapêutica antitumoral e sobrevivência dos animais observados em relação aos animais que receberam apenas um dos tratamentos. Em relação à combinação de pgDE7h e o aptPD-L1, observamos resposta terapêutica antitumoral prejudicada, porém, quando associamos a vacina ao aptPD-1, notamos um aumento discreto da resposta antitumoral. Em resumo, esses dados obtidos durante a presente tese demonstram que a associação de pgDE7h e o mAb anti-CTLA-4 mostra-se como uma estratégia terapêutica promissora contra tumores induzidos por HPV.
Title in English
Control of HPV-induced tumours by immunotherapy based on the association of monoclonal antibodies blocking immunosuppressive pathways and a therapeutic vaccine capable of activating cytotoxic CD8+ T lymphocytes.
Keywords in English
anti-PD-1 and anti-CTLA-4 mAb
anti-PD-L1
aptamers
Cervical cancer
DNA vaccines
immunotherapy
Abstract in English
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.
 
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Release Date
2024-08-11
Publishing Date
2022-12-09
 
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