Insights into Peptide-Based Vaccine Design for Cancer Immunotherapy

Abstract

The presentation of peptides derived from tumor associated proteins (TAAs) by the major histocompatibility complex (MHC) to T cell receptor (TcR) initiates a cascade of events that constitute the immune response. Eliciting an effective immune response, however, requires the coordinated regulation of both the cellular and humoral arms of the immune system. The design of effective peptide-based vaccines for cancer immunotherapeutic applications, therefore, requires intimate knowledge and understanding of peptide-MHC (pMHC) as well as TcR-pMHC interactions. Despite the wealth of information available to date from X-ray crystallographic and biological studies, the task of rationally designing peptide-based vaccines that can effectively prevent and/or treat cancer cell proliferation remains challenging. The complexity of interactions involved are not readily predictable and are further complicated by the involvement of surrounding molecules in vivo, which can lead to reduced biological activity and/or unwanted side effects. Furthermore, the delivery of peptide-based vaccines into the cell, for further processing and presentation to effector cell, represents an additional challenge which needs to be addressed. The incorporation of appropriate chemical entities into peptide-based vaccines can improve cellular uptake thereby enhancing biological activity. Finally, the susceptibility of peptide-based vaccines to enzymatic degradation warrants the need for the incorporation of non-natural amino acids, retro-inversion and/or cyclization to improve bioavailability essentially reducing the required dosage with minimum side effects.

Heat shock protein 110 improves the anti-tumor effects of the cytotoxic T lymphocyte epitope E7 in mice

“…Faliang Ren, 1 Yunsheng Xu, 10,14 Unfortunately these attributes minimize immunogenicity and led to unsatisfactory therapeutic efficacy. Thus, epitope-based vaccines still require development of improved strategies to maximize their immunogenic potential.…”

“…5,6 To date, there have been many strategies developed for therapeutic vaccines targeting HPV 16 E6/E7 proteins, including recombinant protein/peptide vaccines, DNA vaccines, dendritic cell (DC)-based vaccines, and viral and bacterial vector-based vaccines. [7][8][9][10][11] However, completely effective therapeutic vaccines have not yet been established. 3,12,13 Among these vaccine types, the polypeptide vaccine appears to be the most promising and effective.…”

“…3,12,13 Among these vaccine types, the polypeptide vaccine appears to be the most promising and effective. 7,10,11,14 To our knowledge, the cellular immune response plays a key role in tumor immunity where T-cells recognize the epitope peptide in the context of MHC molecules, rather than the intact protein antigen. 15,16 Therefore, peptide vaccine designs based on the epitope will elicit antigen-specific cytotoxic T lymphocyte responses.…”

“…15,16 Therefore, peptide vaccine designs based on the epitope will elicit antigen-specific cytotoxic T lymphocyte responses. 10,14 Besides specificity, other advantages of epitope-based vaccines include good clinical safety, quality control, chemical synthesis, several strategies have been used to enhance the vaccine-induced immunity of peptide vaccines and effective therapeutic benefits, including the utilization of heat shock proteins (hsp), especially the hsp70 family. hsp110 exhibits a higher binding affinity with protein and is capable of enhancing the immunogenicity of protein antigens; however, whether hsp110 can also increase the efficiency of peptide vaccine remains unclear.…”

MHC and MHC‑like molecules: Structural perspectives on the design of molecular vaccines

“…1). [7][8][9][10][11][12] A long groove between the helices constitutes the binding site for processed peptides. 6 The side chains of peptides, i.e., anchor residues, fit into specificity pockets that extend along the floor of the groove.…”