5.2　Polypeptide Vaccine

Tumor polypeptide vaccine has become a new method of tumor immunotherapy due to its simple manufacturing process, low cost, stable chemical properties and no carcinogenicity.The ideal peptide vaccine is highly immunogenic and can activate antigen-specific CTL and HTL responses,effectively killing tumor cells and not toxic to normal cells.However, the common polypeptide resistance causes a weak immunogenicity due to its single epitope, small molecular weight and easy degradation, and can only stimulate low levels of CTL response.Therefore, in the process of designing the peptide vaccine, it is necessary to focus on solving the problem of improving immunogenicity.

The most common vaccination strategies used to activate CD8+ T cells have been based on MHC class I restricted peptide epitopes on TAAs.These have been delivered in a variety of adjuvant formulations (including cytokines and toll-like receptor (TLR) ligands) to promote in vivo presentation by endogenous APCs.Peptide based vaccines take advantage of the ability of computer algorithms to screen protein amino acid sequences for candidate MHC class I restricted peptide epitopes derived from TAAs.Candidate epitopes are then tested experimentally for those that bind commonly expressed HLA molecules, are naturally proceed and presented by tumor cells,and are immunogenic (capable of activating CD8+ cells).Many have also been tested in mouse models, and were found to have the therapeutic properties of a tumor rejection antigen.(https://www.daowen.com)

One of the most common approaches for cancer vaccination is the delivery of MHC class I restricted peptide epitopes derived from shared TAAs with the aim of activating rare specific CD8+T cell clones that react against self-antigen.Data from animal models support the potential for such vaccines to have a substantial therapeutic effect.Adjuvants such as GM-CSF and interferon γ, or TLR agonists, have shown clinical benefit in small- and large-scale clinical trials.

Research have tested whether a synthetic CpG 7909 ODN (deoxycytidyl-deoxyguanosin oligodeoxynucleotides) mixed with NY-ESO-1 peptide p157-165 and incomplete Freund’s adjuvants(Montanide(R) ISA-51) led to enhanced NY-ESO-1 antigen-specific CD8+ immune responses in patients with NY-ESO-1 or LAGE-1 expressing tumors.Postvaccine T-cell clones were shown to induction of NY-ESO-1specific immune responses and clinical outcome compared to Montanide ISA-51 alone [15].The combination of poly-ICLC, the agonist for TLR-3, in Montanide ISA-51 for a NY-ESO-1 vaccine with long overlapping peptides was shown in another study to enhance Th1 CD4+Tcell responses, which is in turn important for a robust CTL response [16].Induction of tumor-specific Treg cells was also observed in a MAGE-A3 peptide vaccine using a peptide epitope capable of inducing both CD4+T cell and CD8+T cell responses [17].Vaccination using a full-length recombinant MAGE-A3 protein with an immunostimulant adjuvant (GSK), in contrast, showed superior induction of humoral and cellular responses in patients with resectednon-small cell lung cancer (NSCLC) and possibly clinical activity in patients with metastatic melanoma in phase 2 studies [18].However, the phase 3 MAGRIT trial of MAGE-A3 peptide vaccine for NSCLC patients with MAGE-3+ and resected tumor failed to show an increase in the primary endpoint of disease-free survival compared with controls and was terminated in 2014, once again highlighting the clinical challenges of cancer vaccines [19].One personalized approach utilizes the high peptide binding properties of the gp96 family of heat-shock proteins, which can be purified from patient tumors and employed as an autologous vaccine [20].Gp96-peptide complexes can be internalized by antigen-presenting cells and processed to bind MHC class I molecules for presentation, thereby stimulating potent CTL responses.However, Vitespen did not improve overall survival of stage IV melanoma patients in a randomized phase 3 trial.