Control tumors induced by HPV -based immunotherapy in combination monoclonal antibodies blocking immunosuppressive pathways a therapeutic vaccine capable of activating CD8 + cytotoxic T lymphocytes

Abstract

Cervical cancer associated with persistent infections by human papilloma virus ( HPV) infection is a public health problem and is the third most frequent type of cancer in women. Patients diagnosed with HPV -induced tumors are treated with surgery, radiotherapy and chemotherapy , which have a lower rate of efficiency to more advanced stages of the disease and inducing severe adverse effects. Several studies seek to develop new therapies against cancer associated with HPV infection as the combination of chemotherapy and immunotherapeutic strategies that work in different mechanisms ( cell death , immunosuppression, specific antigen response induction). The establishment of an immunotherapy treatment capable of activating immune cells to act specifically on tumor cells may significantly influence the success of conventional therapies and improve the quality of life of patients. In Vaccine Development Laboratory (LDV) a DNA vaccine against tumors induced by HPV has been developed based on the expression of a hybrid protein result of gene fusion glycoprotein D (gD) of HSV-1 E7 oncoprotein of HPV-16 (pgDE7h ). In animal models, this vaccine has proved effective in inducing specific cytotoxic cellular response and control tumors expressing E6 and HPV-16 E7 (TC-1 cells). However, the clinical translation of the vaccine requires an increase in its power, mainly for the control of more advanced tumors. In the present work, we propose the development of a new immunotherapy based on the lock pool of monoclonal antibodies of "checkpoints" immune (anti-CTLA-4, anti-PD-1 and anti-PDL-1), and pgDE7h vaccine, aiming evaluate the antitumor activity in mice implanted with TC-1 cells subcutaneously or mucosal (oral or intravaginal).After the establishment of the immunization protocol , treatment will be associated with cisplatin chemotherapy , in order to verify a possible synergistic effect with standard therapy . the ability of different therapeutic protocols to activate antigen-specific immune responses and control the immunosuppressive response triggered by the tumor will be assessed . From the research proposal we hope to obtain data which contribute to the establishment of a novel therapy based on a combination of active immunotherapy ( DNA vaccines ) and passive ( monoclonal antibodies) that can be rapidly validated in clinical conditions .