Active immunization combined with cisplatin confers enhanced therapeutic protection and prevents relapses of HPV-induced tumors at different anatomical sites |
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Authors: | Bruna Felí cio Milazzotto Maldonado Porchia,Luana Raposo de Melo Moraes Aps,Ana Carolina Ramos Moreno,Jamile Ramos da Silva,Mariâ ngela de Oliveira Silva,Natiely Silva Sales,Rubens Prince dos Santos Alves,Clarissa Ribeiro Reily Rocha,Matheus Molina Silva,Karine Bitencourt Rodrigues,Tá cita Borges Barros,Roberta Liberato Pagni,Patrí cia da Cruz Souza,Mariana de Oliveira Diniz,Luí s Carlos de Souza Ferreira |
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Affiliation: | 1.Vaccine Development Laboratory, Department of Microbiology, Biomedical Sciences Institute, University of Sao Paulo, Sao Paulo, SP, Brazil;2.ImunoTera Soluções Terapêuticas Ltda;3.DNA Repair Laboratory, Department of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil;Porchia, BFMM and Aps, LRMM contributed equally to this work. |
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Abstract: | The active immunotherapy concept relies on the use of vaccines that are capable of inducing antitumor immunity, reversion of the suppressive immunological environment, and long-term memory responses. Previously, antitumor vaccines based on a recombinant plasmid (pgDE7h) or a purified protein (gDE7) led to regression of early-established human papillomavirus (HPV)-associated tumors in a preclinical model. In this work, the anticancer vaccines were combined with cisplatin to treat HPV-induced tumors at advanced growth stages. The antitumor effects were evaluated in terms of tumor regression, induction of specific CD8+ T cells, and immune modulation of the tumor microenvironment. Acute toxicity induced by the treatment was measured by weight loss and histological alterations in the liver and kidneys. Our results revealed that the combination of cisplatin with either one of the tested immunotherapies (pgDE7h or gDE7) led to complete tumor regression in mice. Also, the combined treatment resulted in synergistic effects, particularly among mice immunized with gDE7, including activation of systemic and tumor-infiltrating E7-specific CD8+ T cells, tumor infiltration of macrophages and dendritic cells, and prevention of tumor relapses at different anatomical sites. Furthermore, the protocol allowed the reduction of cisplatin dosage and its intrinsic toxic effects, without reducing antitumor outcomes. These results expand our knowledge of active immunotherapy protocols and open perspectives for alternative treatments of HPV-associated tumors. |
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Keywords: | Cancer HPV vaccine gDE7 immunotherapy |
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