Therapeutic vaccination using minimal HPV16 epitopes in a novel MHC-humanized murine HPV tumor model

Abstract

Therapeutic vaccination as a treatment option for HPV-induced cancers is actively pursued because the two HPV proteins E6 and E7 represent ideal targets for immunotherapy, as they are non-self and expressed in all tumor stages. MHC-humanized mice are valuable tools for the study of therapeutic cancer vaccinesgiven the availability of a suitable tumor model. Here, we present for the first time an HPV16 tumor model suitable for fully MHC-humanized A2.DR1 mice, PAP-A2 cells, which in contrast to existing HPV16 tumor models allows the exclusive study of HLA-A2-and DR1-mediated immune responses, without any interfering murine MHC-presented epitopes. We used several HPV16 epitopes that were shown to be presented on human cervical cancer cells by mass spectrometry for therapeutic anti-tumor vaccination in the new tumor model. All epitopes were immunogenic when rendered amphiphilic by incorporation into a molecule containing stearic acids. Prophylactic and therapeutic vaccination experiments with the epitope E7/11-19 demonstrated that effective immune responses could be induced with these vaccination approaches in A2.DR1 mice. Interestingly, the combination of E7/11-19 with other immunogenic HPV16 E6/E7 epitopes caused a reduction of vaccine efficacy, although all tested combinations resulted in a survival benefit. In summary, we present the first HPV16 tumor model for exclusive studies of HLA-A2-mediated anti-HPV tumor immune responses and show anti-tumor efficacy of minimal epitope vaccines. ARTICLE HISTORY

Papillomavirus Immune Evasion Strategies Target the Infected Cell and the Local Immune System

“…Moreover, these mouse models limit the choice of immune epitopes, and therefore might not be used to test those epitopes found exclusively in human patients. Recently, MHC-humanized mouse HPV tumor models have been developed (218), which could potentially be used as new vaccine testing platforms in the future. Nevertheless, the limitation of these humanized mouse models still exists as they are not able to mimic the entire human immune system.…”

Performance Evaluation of MHC Class-I Binding Prediction Tools Based on an Experimentally Validated MHC–Peptide Binding Data Set

“…We previously identified immunogenic epitopes among our data set of HLA-A2 binding peptides through IFNg responses of peripheral blood mononucleated cells from healthy donors (62). Four selected epitopes were validated in vivo in an MHC-humanized mouse model (64). This demonstrates that MHC class-I binding prediction, applying the commonly used strong and intermediate binding affinity thresholds, provides high prediction specificity.…”

Robust Anti‐Tumor T Cell Response with Efficient Intratumoral Infiltration by Nanodisc Cancer Immunotherapy

“…[6] To address the safety issues and regulatory challenges associated with live vectors, peptide-based subunit vaccines with HPV16 E6/E7 antigens have been studied extensively. [7,41,42] However, peptide-based subunit vaccines generally suffer from limited anti-tumor efficacy due to inefficient antigen delivery to lymphoid tissues and the lack of appropriate innate immune stimulation. [4,12] In our previous work, we have shown that the nanodisc vaccine technology administered s.c. can efficiently drain to LNs and generate potent antigenspecific T cell responses.…”