Development of a CTL vaccine for Her-2/neu using peptide-microspheres and adjuvants

• Published in: Vaccine 2005-05, Vol.23 (27), p.3545-3554
• Main Authors: Mossman, S.P., Evans, L.S., Fang, H., Staas, J., Tice, T., Raychaudhuri, S., Grabstein, K.H., Cheever, M.A., Johnson, M.E.
• Format: Article
• Language: English
• Subjects: Adjuvants; Adjuvants, Immunologic - administration & dosage; Animals; Antigens; Applied microbiology; Aqueous solutions; Biological and medical sciences; Cancer; Cancer Vaccines - administration & dosage; Cancer Vaccines - chemical synthesis; Cancer Vaccines - immunology; Cells, Cultured; Clinical trials; CTL; Cytotoxicity, Immunologic; Female; Fundamental and applied biological sciences. Psychology; Her-2/neu; Humans; Immune system; Immunization; Ligands; Lymphocytes; Mice; Mice, Transgenic; Microbiology; Microspheres; Molecular weight; Peptide Fragments - administration & dosage; Peptide Fragments - immunology; Peptides; Polyglactin 910 - administration & dosage; Receptor, ErbB-2 - administration & dosage; Receptor, ErbB-2 - immunology; Spleen - cytology; Spleen - immunology; T-Lymphocytes, Cytotoxic - immunology; Vaccine; Vaccines; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects)
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2005.01.149

With the ultimate goal of developing a therapeutic cancer vaccine, we encapsulated the Her-2/neu peptide p369–377 in poly(lactide-co-glycolide) microspheres. This formulation was found to effectively elicit CD8+ cytotoxic T cell (CTL) responses in an HLA-A*0201 transgenic mouse model. In contrast, immunization with either peptide alone or peptide formulated in incomplete Freund's adjuvant (IFA) failed to elicit such CTL responses. Responses induced by the peptide-microsphere formulation were found to peak at approximately 6 weeks post-immunization, and were enhanced by delivering increased doses of peptide and with repeated administrations over time. Co-administration of the peptide-microspheres with adjuvants, including granulocyte–macrophage colony stimulating factor, MPL ® adjuvant and select synthetic Toll-Like Receptor 4 ligands, the aminoalkyl glucosaminide-4 phosphates, significantly augmented CTL responses. These studies provide important guidance for the design of human clinical trials of microsphere vaccines in terms of optimal peptide-microsphere formulation, vaccination regimen, vaccine dose, and adjuvant selection.