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Chimeric rat/human HER2 efficiently circumvents HER2 tolerance in cancer patients.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2014 Jun 01; Vol. 20 (11), pp. 2910-21. Date of Electronic Publication: 2014 Mar 25. - Publication Year :
- 2014
-
Abstract
- Purpose: Despite the great success of HER2 vaccine strategies in animal models, effective clinical results have not yet been obtained. We studied the feasibility of using DNA coding for chimeric rat/human HER2 as a tool to break the unresponsiveness of T cells from patients with HER2-overexpressing tumors (HER2-CP).<br />Experimental Design: Dendritic cells (DCs) generated from patients with HER2-overexpressing breast (n = 28) and pancreatic (n = 16) cancer were transfected with DNA plasmids that express human HER2 or heterologous rat sequences in separate plasmids or as chimeric constructs encoding rat/human HER2 fusion proteins and used to activate autologous T cells. Activation was evaluated by IFN-γ ELISPOT assay, perforin expression, and ability to halt HER2+ tumor growth in vivo.<br />Results: Specific sustained proliferation and IFN-γ production by CD4 and CD8 T cells from HER2-CP was observed after stimulation with autologous DCs transfected with chimeric rat/human HER2 plasmids. Instead, T cells from healthy donors (n = 22) could be easily stimulated with autologous DCs transfected with any human, rat, or chimeric rat/human HER2 plasmid. Chimeric HER2-transfected DCs from HER2-CP were also able to induce a sustained T-cell response that significantly hindered the in vivo growth of HER2(+) tumors. The efficacy of chimeric plasmids in overcoming tumor-induced T-cell dysfunction relies on their ability to circumvent suppressor effects exerted by regulatory T cells (Treg) and/or interleukin (IL)-10 and TGF-β1.<br />Conclusions: These results provide the proof of concept that chimeric rat/human HER2 plasmids can be used as effective vaccines for any HER2-CP with the advantage of being not limited to specific MHC. Clin Cancer Res; 20(11); 2910-21. ©2014 AACR.<br /> (©2014 American Association for Cancer Research.)
- Subjects :
- Animals
Cancer Vaccines pharmacology
Dendritic Cells immunology
Enzyme-Linked Immunosorbent Assay
Female
Flow Cytometry
Humans
Immune Tolerance immunology
Immunohistochemistry
Mice
Mice, Inbred NOD
Mice, SCID
Plasmids
Rats
Recombinant Fusion Proteins immunology
Recombinant Fusion Proteins pharmacology
Transfection
Transplantation Chimera
Vaccines, DNA pharmacology
Xenograft Model Antitumor Assays
Breast Neoplasms immunology
Cancer Vaccines immunology
Pancreatic Neoplasms immunology
Receptor, ErbB-2 immunology
Vaccines, DNA immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 20
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 24668647
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-13-2663