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Customized Viral Immunotherapy for HPV-Associated Cancer.
- Source :
-
Cancer immunology research [Cancer Immunol Res] 2017 Oct; Vol. 5 (10), pp. 847-859. Date of Electronic Publication: 2017 Sep 14. - Publication Year :
- 2017
-
Abstract
- The viral-transforming proteins E6 and E7 make human papillomavirus-positive (HPV <superscript>+</superscript> ) malignancies an attractive target for cancer immunotherapy. However, therapeutic vaccination exerts limited efficacy in the setting of advanced disease. We designed a strategy to induce substantial specific immune responses against multiple epitopes of E6 and E7 proteins based on an attenuated transgene from HPV serotypes 16 and 18 that is incorporated into MG1-Maraba virotherapy (MG1-E6E7). Mutations introduced to the transgene abrogate the ability of E6 and E7 to perturb p53 and retinoblastoma, respectively, while maintaining the ability to invoke tumor-specific, multifunctional CD8 <superscript>+</superscript> T-cell responses. Boosting with MG1-E6E7 significantly increased the magnitude of T-cell responses compared with mice treated with a priming vaccine alone (greater than 50 × 10 <superscript>6</superscript> E7-specific CD8 <superscript>+</superscript> T cells per mouse was observed, representing a 39-fold mean increase in boosted animals). MG1-E6E7 vaccination in the HPV <superscript>+</superscript> murine model TC1 clears large tumors in a CD8 <superscript>+</superscript> -dependent manner and results in durable immunologic memory. MG1-Maraba can acutely alter the tumor microenvironment in vivo and exploit molecular hallmarks of HPV <superscript>+</superscript> cancer, as demonstrated by marked infection of HPV <superscript>+</superscript> patient tumor biopsies and is, therefore, ideally suited as an oncolytic treatment against clinical HPV <superscript>+</superscript> cancer. This approach has the potential to be directly translatable to human clinical oncology to tackle a variety of HPV-associated neoplasms that cause significant morbidity and mortality globally. Cancer Immunol Res; 5(10); 847-59. ©2017 AACR .<br /> (©2017 American Association for Cancer Research.)
- Subjects :
- Adenoviruses, Human genetics
Animals
Cancer Vaccines immunology
Cell Line, Tumor
Cytokines metabolism
Cytotoxicity, Immunologic
Disease Models, Animal
Epitopes, T-Lymphocyte immunology
Female
Genetic Vectors genetics
Humans
Mice
Mutation
Neoplasms metabolism
Neoplasms therapy
Oncogene Proteins, Viral genetics
Oncogene Proteins, Viral immunology
Oncolytic Virotherapy
Papillomavirus E7 Proteins genetics
Papillomavirus E7 Proteins immunology
Proteolysis
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins immunology
Repressor Proteins genetics
Repressor Proteins immunology
T-Lymphocyte Subsets immunology
T-Lymphocyte Subsets metabolism
Transgenes
Tumor Burden immunology
Tumor Suppressor Protein p53 metabolism
Xenograft Model Antitumor Assays
Immunotherapy methods
Neoplasms etiology
Neoplasms pathology
Papillomaviridae
Papillomavirus Infections complications
Papillomavirus Infections virology
Subjects
Details
- Language :
- English
- ISSN :
- 2326-6074
- Volume :
- 5
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cancer immunology research
- Publication Type :
- Academic Journal
- Accession number :
- 28912369
- Full Text :
- https://doi.org/10.1158/2326-6066.CIR-17-0102