Nanoparticle Conjugation of Human Papillomavirus 16 E7-long Peptides Enhances Therapeutic Vaccine Efficacy against Solid Tumors in Mice

Abstract

Treatment of patients bearing human papillomavirus (HPV)-related cancers with synthetic long peptide (SLP) therapeutic vaccines has shown promising results in clinical trials against premalignant lesions, whereas responses against later stage carcinomas have remained elusive. We show that conjugation of a well-documented HPV-E7 SLP to ultra-small polymeric nanoparticles (NPs) enhances the antitumor efficacy of therapeutic vaccination in different mouse models of HPV + cancers. Immunization of TC-1 tumor-bearing mice with a single dose of NPconjugated E7LP (NP-E7LP) generated a larger pool of E7-specific CD8 + T cells with increased effector functions than unconjugated free E7LP. At the tumor site, NP-E7LP prompted a robust infiltration of CD8 + T cells that was not accompanied by concomitant accumulation of regulatory T cells (Tregs), resulting in a higher CD8 + T cell to Treg ratio. Consequently, the amplified immune response elicited by the NP-E7LP formulation led to increased regression of large, well-established tumors, resulting in a significant percentage of complete responses that were not achievable by immunizing with the non-NP-conjugated long-peptide. The partial responses were characterized by distinct phases of regression, stable disease, and relapse to progressive growth, establishing a platform to investigate adaptive resistance mechanisms. The efficacy of NP-E7LP could be further improved by therapeutic activation of the costimulatory receptor 4-1BB. This NP-E7LP formulation illustrates a 'solid-phase' antigen delivery strategy that is more effective than a conventional freepeptide ('liquid') vaccine, further highlighting the potential of using such formulations for therapeutic vaccination against solid tumors.

Polyacrylate–Peptide Antigen Conjugate as a Single-Dose Oral Vaccine against Group A Streptococcus

“…These systems, especially polyelectrolytes, have also been examined for oral vaccine delivery, as they can protect antigens from enzymatic degradation and often have mucosal adhesive and adjuvanting properties [50]. Polymers have rarely been directly conjugated to antigens to form self-adjuvanting, self-assembled nanoparticles [51][52][53][54]. Moreover, to our knowledge, such amphiphilic conjugates have never been used for the oral delivery of a vaccine.…”

Development of HPV16,18,31,45 E5 and E7 peptides-based vaccines predicted by immunoinformatics tools

“…Other study showed that the conjugation of HPV16 E7 long peptide (E7 43-77 : GQAEPDRAHY-NIVTFCCKCDSTLRLCVQSTHVDIR) to ultrasmall polymeric nanoparticles could enhance the antitumor effects in different mouse models of HPV ? cancers (Galliverti et al 2018). Van der Burg et al reported the immunogenic epitopes of HPV16 E7 41-62 including a CTL epitope (QAEPDRAHY) (van der Burg et al 2001;Jabbar et al 2018).…”

Nanoparticles to Improve the Efficacy of Peptide-Based Cancer Vaccines

“…Gold nanoparticles (AuNPs) are biocompatible, not immunogenic and manufactured in diverse sizes and shapes [30]. AuNPs can be easily prepared from gold salt (H[AuCl4]) in water and their particle sizes are controllable (ranging from 1-100 nm diameter) [54,55].…”