Int J Biol Sci 2022; 18(1):15-29. doi:10.7150/ijbs.56644 This issue

Research Paper

Active immunization combined with cisplatin confers enhanced therapeutic protection and prevents relapses of HPV-induced tumors at different anatomical sites

Bruna Felício Milazzotto Maldonado Porchia1,2,*, Luana Raposo de Melo Moraes Aps1,2, Ana Carolina Ramos Moreno1, Jamile Ramos da Silva1, Mariângela de Oliveira Silva1, Natiely Silva Sales1, Rubens Prince dos Santos Alves1, Clarissa Ribeiro Reily Rocha3, Matheus Molina Silva3, Karine Bitencourt Rodrigues1, Tácita Borges Barros1, Roberta Liberato Pagni1, Patrícia da Cruz Souza1, Mariana de Oliveira Diniz1,2,#, Luís Carlos de Souza Ferreira1✉

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.
* Present address: Laboratory of Tumor Immunology, Department of Immunology, Biomedical Sciences Institute, University of Sao Paulo, Sao Paulo, SP, Brazil
# Present address: Division of Infection and Immunity, University College London, 5 University St, Bloomsbury WC1E 6JF, London

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Porchia BFMM, Aps LRdMM, Moreno ACR, da Silva JR, Silva MdO, Sales NS, Alves RPdS, Rocha CRR, Silva MM, Rodrigues KB, Barros TB, Pagni RL, Souza PdC, Diniz MdO, Ferreira LCdS. Active immunization combined with cisplatin confers enhanced therapeutic protection and prevents relapses of HPV-induced tumors at different anatomical sites. Int J Biol Sci 2022; 18(1):15-29. doi:10.7150/ijbs.56644. Available from https://www.ijbs.com/v18p0015.htm

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Abstract

Graphic 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.

Keywords: Cancer, HPV, vaccine, gDE7, immunotherapy