Enhanced presentation of MHC class Ia, Ib and class II-restricted peptides encapsulated in biodegradable nanoparticles: a promising strategy for tumor immunotherapy

Wenxue Ma,Boris Minev,Ewa Carrier,Vladimir Bogin,Cengiz Ozkan,Trevor Smith,Davorka Messmer,Vipin Kumar,Yu Zhang,Melanie Hayden,Mihri Ozkan,Stephanie Schroter

doi:10.1186/1479-5876-9-34

Abstract

BackgroundMany peptide-based cancer vaccines have been tested in clinical trials with a limited success, mostly due to difficulties associated with peptide stability and delivery, resulting in inefficient antigen presentation. Therefore, the development of suitable and efficient vaccine carrier systems remains a major challenge.MethodsTo address this issue, we have engineered polylactic-co-glycolic acid (PLGA) nanoparticles incorporating: (i) two MHC class I-restricted clinically-relevant peptides, (ii) a MHC class II-binding peptide, and (iii) a non-classical MHC class I-binding peptide. We formulated the nanoparticles utilizing a double emulsion-solvent evaporation technique and characterized their surface morphology, size, zeta potential and peptide content. We also loaded human and murine dendritic cells (DC) with the peptide-containing nanoparticles and determined their ability to present the encapsulated peptide antigens and to induce tumor-specific cytotoxic T lymphocytes (CTL) in vitro.ResultsWe confirmed that the nanoparticles are not toxic to either mouse or human dendritic cells, and do not have any effect on the DC maturation. We also demonstrated a significantly enhanced presentation of the encapsulated peptides upon internalization of the nanoparticles by DC, and confirmed that the improved peptide presentation is actually associated with more efficient generation of peptide-specific CTL and T helper cell responses.ConclusionEncapsulating antigens in PLGA nanoparticles offers unique advantages such as higher efficiency of antigen loading, prolonged presentation of the antigens, prevention of peptide degradation, specific targeting of antigens to antigen presenting cells, improved shelf life of the antigens, and easy scale up for pharmaceutical production. Therefore, these findings are highly significant to the development of synthetic vaccines, and the induction of CTL for adoptive immunotherapy.

Highlights

Many peptide-based cancer vaccines have been tested in clinical trials with a limited success, mostly due to difficulties associated with peptide stability and delivery, resulting in inefficient antigen presentation
We found that the cytotoxic T lymphocytes (CTL) induced with the melanoma peptide MART-127-35 encapsulated into our nanoparticles were able to recognize and kill the peptide-pulsed T2 cells, and the HLAA2-positive melanoma cells 624
DC were co-cultured for 20 hours with TIL1235 or TIL1520 cells, and the antigen presentation was evaluated in an IFN-g ELISPOT assay. (C) Cytotoxic activity of CTL induced in vitro with peptide-pulsed or NP-loaded dendritic cells: Dendritic cells were pulsed with the peptide MART-127-35 or with MART-127-35-containing NP and used as antigen-presenting cells (APC) to induce MART-127-35-specific CTL

Summary

Introduction

Many peptide-based cancer vaccines have been tested in clinical trials with a limited success, mostly due to difficulties associated with peptide stability and delivery, resulting in inefficient antigen presentation. Peptides derived from tumor-associated antigens (TAA) have been identified for a variety of human cancers [1]. Effective peptide vaccination of patients with cancer has been limited to very few trials [2]. The lack of efficient and long-lasting antigen presentation by DC in vivo has been a major difficulty in the development of effective vaccines. These obstacles could be circumvented through the development of nanoparticles, which can efficiently deliver the antigenic peptides into the APC

Methods

Discussion

Conclusion