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Therapeutic vaccination against HPV-positive tumors in a MHC-humanized mouse model

Kruse, Sebastian

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Abstract

Human papillomaviruses (HPV) are responsible for 5 % of all annual cancer cases worldwide and thus present a major health problem. HPVs can cause oropharyngeal and anogenital cancers. More than 60 % of the HPV-induced cancers are caused by HPV16. Therapeutic anti-tumor vaccination against the two HPV oncoproteins E6 and E7 represents an attractive treatment option because these proteins are expressed in all tumor stages and are indispensable for tumor initiation and survival. Therapeutic vaccination could combine long-term immunity with reduced treatment side effects compared to conventional therapies such as surgery and chemotherapy. Preclinical studies for the development of a therapeutic HPV vaccine have yielded promising results. However, most clinical studies could not reproduce these findings. One obstacle to achieving better translatability of preclinical findings is the absence of a mouse model that allows the exclusive study of human HPV epitopes. A2.DR1 mice express two of the most common major histocompatibility complex (MHC) molecules, HLA-A2 and HLA-DR1, without the expression of any interfering murine MHCs. The aim of this PhD project was to develop a HPV16 tumor model for these mice, and to test various formulations of epitope-specific therapeutic anti-HPV16 vaccines. This work shows that the newly established PAP-A2 tumor cells express HPV16 E6/E7 and present four epitopes on HLA-A2 that can also be found on HPV16-transformed human tumor cells. The immunogenicity of all four epitopes in A2.DR1 mice was shown by the induction of CD8+ T cell responses after vaccination with these epitopes. Comparing emulsion-based, mRNA-based and different amphiphilic peptide-based vaccines, it was observed that amphiphilic peptides induced the highest frequencies of E7/11-19-specific CD8+ T cells. Furthermore, it could be demonstrated that therapeutic vaccination with an amphiphilic version of the minimal epitope E7/11-19 induces complete PAP-A2 tumor rejection in 50 % of animals. Interestingly, upon vaccination with the other three epitopes or combination vaccination with the four different epitopes we observed decreased anti-tumor responses compared to single E7/11-19 vaccination. In summary, this study presents the first HPV16 E6/E7-positive tumor model that allows the exclusive analysis of HPV16 epitopes in fully MHC-humanized mice and shows pronounced anti-tumor effects by minimal epitope vaccination. These results emphasize the need for the careful selection and combination of minimal epitope vaccines and could improve the efficacy of future therapeutic HPV vaccines.

Item Type: Dissertation
Supervisor: Müller, Prof. Dr. Martin
Date of thesis defense: 14 January 2019
Date Deposited: 05 Mar 2019 15:19
Date: 2019
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
610 Medical sciences Medicine
Uncontrolled Keywords: Cancer immunotherapy, therapeutic vaccination, HLA-humanized mice, human papillomavirus (HPV), A2.DR1, PAP-A2
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