Development of a CTL vaccine for Her-2/neu using peptide-microspheres and adjuvants.
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.
Mossman
S P
SP
Corixa Corporation, Suite 1100, 1900 9th Avenue, Seattle, WA 98101, USA. sally.mossman@corixa.com
Evans
L S
LS
Fang
H
H
Staas
J
J
Tice
T
T
Raychaudhuri
S
S
Grabstein
K H
KH
Cheever
M A
MA
Johnson
M E
ME
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000276:immunology*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008863:Microspheres; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D011098:Polyglactin 910 / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000008:administration & dosage / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D010446:Peptide Fragments; D011098:Polyglactin 910; D018719:Erb-b2 Receptor Tyrosine Kinases