Intracellular delivery of a novel multiepitope peptide vaccine by an amphipathic peptide carrier enhances cytotoxic T‐cell responses in HLA‐A*201 mice

Abstract

Cytotoxic T lymphocytes (CTL) are key players in the neutralization of viruses and killing of tumor cells. However, for generating an optimal CTL response by vaccination, the antigen has to be delivered directly into the cytoplasm for presentation by the conventional MHC class I pathway. To mimic the presentation of multiple epitopes by a tumor or virus infected cell, we have designed a multiepitope peptide vaccine incorporating thee CTL epitopes in tandem with double arginine spacers to facilitate efficient cleavage of the individual epitopes. To deliver the multiepitope peptide vaccine into the cytoplasm of mature dendritic cells for presentation by the MHC class I pathway we made use of an amphipathic peptide carrier. Direct injection of a non-covalent complex of the multiepitope peptide vaccine and amphipathic peptide carrier in an aqueous formulation into HLA-A*0201 (HHD) transgenic mice enhanced the cytotoxic T-cell responses by two to sixfold compared with multiepitope peptide vaccination alone. This novel antigen delivery strategy may find general application in the development of more effective vaccines for the treatment of cancer and infectious disease.

A paradigm shift: Cancer therapy with peptide-based B-cell epitopes and peptide immunotherapeutics targeting multiple solid tumor types: Emerging concepts and validation of combination immunotherapy

“…We have developed novel HER-2 vaccines that have the potential to act as highly effective immunotherapies against a wide variety of tumor types. 25,43,48,112 First generation HER-2 vaccine I identified by using antigenicity algorithms (reviewed by Kaumaya and co-workers) several B-cell epitopes of HER-2 ECD using computer-aided analysis. 43,48 These peptide B-cell sequences were assembled by solid phase peptide synthesis together with a measles virus fusion protein (MVF, amino acid sequence 288-302) "promiscuous" T cell epitope.…”

An Anti-Nucleic Acid Antibody Delivers Antigen to the Cross-Presentation Pathway in Dendritic Cells and Potentiates Therapeutic Antitumor Effects

“…This finding can be explained by the strong CTL response to OVA elicited by injection of 3D8-OVA 250-264 . Accumulating evidence shows the efficacy of prophylactic tumor vaccines incorporating Hsp70 (39), CPPs (27,40), and a2M* (41); however, little evidence exists for the efficacy of therapeutic vaccines. Moreover, CPPs require adjuvant to generate an effective antitumor response.…”

B Cell Epitope-Based Vaccination Therapy

“…Miller et al developed B cell-based EGFR (Her1) and Her2 vaccines [70][71][72][73][74][75][76]. Her2 is a well-known antigen that is highly expressed on breast cancer cells in ~20% of patients.…”