T cell activity after dendritic cell vaccination is dependent on both the type of antigen and the mode of delivery.
Previous work in both human and animal models has shown that CTL responses can be generated against proteins derived from tumors using either peptide-pulsed dendritic cells (DCs) or nucleic acids from the tumor transfected into autologous DCs. Despite the efficacy of this approach for vaccine therapy, many questions remain regarding whether the route of administration, the frequency of administration, or the type of Ag is critical to generating T cell responses to these Ags. We have investigated methods to enhance CTL responses to a peptide derived from the human proto-oncogene HER-2/neu using mice containing a chimeric HLA A2 and H2Kb allele. Changes in amino acids in the anchor positions of the peptide enhanced the binding of the peptide to HLA-A2 in vitro, but did not enhance the immunogenicity of the peptide in vivo. In contrast, when autologous DCs presented peptides, significant CTL activity was induced with the altered, but not the wild-type, peptide. We found that the route of administration affected the anatomic site and the time to onset of CTL activity, but did not impact on the magnitude of the response. To our surprise, we observed that weekly administration of peptide-pulsed DCs led to diminishing CTL activity after 6 wk of treatment. This was not found in animals injected with DCs every 3 wk for six treatments or in animals initially given DCs weekly and then injected weekly with peptide-pulsed C1R-A2 transfectants.
Serody
J S
JS
Department of Medicine, University of North Carolina School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599, USA. jonathan_serody@med.unc.edu
Collins
E J
EJ
Tisch
R M
RM
Kuhns
J J
JJ
Frelinger
J A
JA
D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage* / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D004306:Dose-Response Relationship, Immunologic; D006183:H-2 Antigens / Q000235:genetics; D015789:HLA-A2 Antigen / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007271:Injections, Intradermal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D051379:Mice; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D011489:Protein Denaturation; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000008:administration & dosage / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013696:Temperature
D000951:Antigens, Neoplasm; D006183:H-2 Antigens; D015789:HLA-A2 Antigen; D009842:Oligopeptides; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; C032876:H-2Kb protein, mouse; C000715470:MAS1 protein, human