Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion

Brian J. Czerniecki, Gary K. Koski, Ursula Koldovsky, Shuwen Xu, Peter A Cohen, Rosemarie Mick, Harvey Nisenbaum, Terry Pasha, Min Xu, Kevin R. Fox, Susan Weinstein, Susan G. Orel, Robert Vonderheide, George Coukos, Angela DeMichele, Louis Araujo, Francis R. Spitz, Mark Rosen, Bruce L. Levine, Carl JunePaul J. Zhang

Research output: Contribution to journalArticle

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Abstract

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 posDCIS 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-γ 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-γ-secreting CD4pos (85%) and CD8pos (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.

Original languageEnglish (US)
Pages (from-to)1842-1852
Number of pages11
JournalCancer Research
Volume67
Issue number4
DOIs
StatePublished - Feb 15 2007
Externally publishedYes

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Interleukin-12
Dendritic Cells
Vaccination
Carcinoma, Intraductal, Noninfiltrating
Breast Neoplasms
T-Lymphocytes
Interleukins
Neoplasm Antibodies
HLA-A2 Antigen
Peptides
Lipopolysaccharides
Neoplasms
Breast
B-Lymphocytes
Vaccines
Staining and Labeling
Ligands
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion. / Czerniecki, Brian J.; Koski, Gary K.; Koldovsky, Ursula; Xu, Shuwen; Cohen, Peter A; Mick, Rosemarie; Nisenbaum, Harvey; Pasha, Terry; Xu, Min; Fox, Kevin R.; Weinstein, Susan; Orel, Susan G.; Vonderheide, Robert; Coukos, George; DeMichele, Angela; Araujo, Louis; Spitz, Francis R.; Rosen, Mark; Levine, Bruce L.; June, Carl; Zhang, Paul J.

In: Cancer Research, Vol. 67, No. 4, 15.02.2007, p. 1842-1852.

Research output: Contribution to journalArticle

Czerniecki, BJ, Koski, GK, Koldovsky, U, Xu, S, Cohen, PA, Mick, R, Nisenbaum, H, Pasha, T, Xu, M, Fox, KR, Weinstein, S, Orel, SG, Vonderheide, R, Coukos, G, DeMichele, A, Araujo, L, Spitz, FR, Rosen, M, Levine, BL, June, C & Zhang, PJ 2007, 'Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion', Cancer Research, vol. 67, no. 4, pp. 1842-1852. https://doi.org/10.1158/0008-5472.CAN-06-4038
Czerniecki, Brian J. ; Koski, Gary K. ; Koldovsky, Ursula ; Xu, Shuwen ; Cohen, Peter A ; Mick, Rosemarie ; Nisenbaum, Harvey ; Pasha, Terry ; Xu, Min ; Fox, Kevin R. ; Weinstein, Susan ; Orel, Susan G. ; Vonderheide, Robert ; Coukos, George ; DeMichele, Angela ; Araujo, Louis ; Spitz, Francis R. ; Rosen, Mark ; Levine, Bruce L. ; June, Carl ; Zhang, Paul J. / Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion. In: Cancer Research. 2007 ; Vol. 67, No. 4. pp. 1842-1852.
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abstract = "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 posDCIS 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-γ 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-γ-secreting CD4pos (85{\%}) and CD8pos (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.",
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AU - Mick, Rosemarie

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N2 - 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 posDCIS 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-γ 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-γ-secreting CD4pos (85%) and CD8pos (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.

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