Pilot study of an HLA-A2 peptide vaccine using flt3 ligand as a systemic vaccine adjuvant.
A pilot vaccine study was conducted to test the safety and immunological efficacy of four monthly immunizations of an MHC class I peptide vaccine, the E75 HLA-A2 epitope from HER-2/neu, using flt3 ligand as a systemic vaccine adjuvant. Twenty HLA-A2-expressing subjects with advanced stage prostate cancer were randomly assigned to one of four immunization or treatment schedules: (a) Flt3 ligand (20 microg/kg per day) administered subcutaneously daily for 14 days on a 28-day cycle, monthly for four months; (b) flt3 ligand course as above with the E75 peptide vaccine administered on day 7 of each flt3 ligand cycle; (c) flt3 ligand course as above with the E75 peptide vaccine administered on day 14 of each flt3 ligand cycle; or (d) E75 peptide admixed with granulocyte-macrophage colony-stimulating factor and administered intradermally once every 28 days, as has previously been reported. The primary endpoints of the study were the determination of safety and immunological efficacy in generating E75-specific T cells as determined by peptide-specific interferon-gamma ELIspot. Adverse events included one grade 3 skin reaction and the development of grade 2 autoimmune hypothyroidism in two subjects with preexisting subclinical autoimmune hypothyroidism. Dendritic cells were markedly increased in the peripheral blood of subjects receiving flt3 ligand with each repetitive cycle, but augmentation of antigen-presenting cells within the dermis was not observed. Apart from a single subject, no significant peptide-specific T-cell responses were detected by ELIspot, whereas delayed-type hypersensitivity responses were detectable in control subjects and in subjects receiving peptide vaccine early in the course of flt3 ligand administration. The absence of robust peripheral immune responses in the current study may be attributable to the small numbers of subjects or differences in the subject population. In addition, the inability of fit3 ligand to augment the number of peripheral skin antigen-presenting cells may have contributed to the absence of robust peptide-specific immunity detectable in the peripheral blood of immunized subjects treated with flt3 ligand.
McNeel
Douglas G
DG
Department of Medicine, Section of Medical Oncology, University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792, USA. dm3@medicine.wisc.edu
Knutson
Keith L
KL
Schiffman
Kathy
K
Davis
Donna R
DR
Caron
Dania
D
Disis
Mary L
ML
D000230:Adenocarcinoma / Q000188:drug therapy; D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000009:adverse effects; D006801:Humans; D007801:Langerhans Cells / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000627:therapeutic use*; D010455:Peptides / Q000009:adverse effects / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy; D022223:Vaccines, Subunit / Q000009:adverse effects
D000276:Adjuvants, Immunologic; D015789:HLA-A2 Antigen; D008565:Membrane Proteins; D010455:Peptides; D022223:Vaccines, Subunit; C084881:flt3 ligand protein