Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion.
Overexpression of HER-2/neu (c-erbB2) is associated with increased risk of recurrent disease in ductal carcinoma in situ (DCIS) and a poorer prognosis in node-positive breast cancer. We therefore examined the early immunotherapeutic targeting of HER-2/neu in DCIS. Before surgical resection, HER-2/neu(pos) DCIS patients (n = 13) received 4 weekly vaccinations of dendritic cells pulsed with HER-2/neu HLA class I and II peptides. The vaccine dendritic cells were activated in vitro with IFN-gamma and bacterial lipopolysaccharide to become highly polarized DC1-type dendritic cells that secrete high levels of interleukin-12p70 (IL-12p70). Intranodal delivery of dendritic cells supplied both antigenic stimulation and a synchronized preconditioned burst of IL-12p70 production directly to the anatomic site of T-cell sensitization. Before vaccination, many subjects possessed HER-2/neu-HLA-A2 tetramer-staining CD8(pos) T cells that expressed low levels of CD28 and high levels of the inhibitory B7 ligand CTLA-4, but this ratio inverted after vaccination. The vaccinated subjects also showed high rates of peptide-specific sensitization for both IFN-gamma-secreting CD4(pos) (85%) and CD8(pos) (80%) T cells, with recognition of antigenically relevant breast cancer lines, accumulation of T and B lymphocytes in the breast, and induction of complement-dependent, tumor-lytic antibodies. Seven of 11 evaluable patients also showed markedly decreased HER-2/neu expression in surgical tumor specimens, often with measurable decreases in residual DCIS, suggesting an active process of "immunoediting" for HER-2/neu-expressing tumor cells following vaccination. DC1 vaccination strategies may therefore have potential for both the prevention and the treatment of early breast cancer.
Czerniecki
Brian J
BJ
Department of Surgery, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA. brian.czerniecki@uphs.upenn.edu
Koski
Gary K
GK
Koldovsky
Ursula
U
Xu
Shuwen
S
Cohen
Peter A
PA
Mick
Rosemarie
R
Nisenbaum
Harvey
H
Pasha
Terry
T
Xu
Min
M
Fox
Kevin R
KR
Weinstein
Susan
S
Orel
Susan G
SG
Vonderheide
Robert
R
Coukos
George
G
DeMichele
Angela
A
Araujo
Louis
L
Spitz
Francis R
FR
Rosen
Mark
M
Levine
Bruce L
BL
June
Carl
C
Zhang
Paul J
PJ
D000920:Antibody-Dependent Cell Cytotoxicity; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000276:immunology / Q000628:therapy*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D018664:Interleukin-12 / Q000276:immunology* / Q000378:metabolism; D007937:Leukapheresis; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D019496:Cancer Vaccines; D007371:Interferon-gamma; D018664:Interleukin-12; D008070:Lipopolysaccharides; D018719:Erb-b2 Receptor Tyrosine Kinases