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Induction of ErbB-2/neu-specific protective and therapeutic antitumor immunity using genetically modified dendritic cells: enhanced efficacy by cotransduction of gene encoding IL-12

Gene Therapy volume 8, pages 316–323 (2001)Cite this article

Abstract

Overexpression of ErbB-2/neu occurs in 20–30% of patients with breast cancer and indicates a poor prognosis. The presence of a detectable immune response to ErbB-2/neu in some patients suggests that this oncogene may be a useful target for vaccine therapy. We evaluated whether genetic immunization using dendritic cells (DC) transduced ex vivo with an adenovirus expressing the ErbB-2/neu gene (AdNeuTK) could induce protective and therapeutic immunity against a breast tumor cell line overexpressing ErbB-2/neu. Subcutaneous (s.c.) immunization with the DC vaccine elicited protective immunity in an average of 60% of animals. CTL analysis demonstrated specific cytotoxic activity against breast tumor cells, as well as syngeneic fibroblasts transduced with AdNeuTK. In vivo depletion studies demonstrated both CD4+ and CD8+ T cells were required. In a therapeutic setting, immunization with the DC vaccines could cure mice with pre-established tumors and efficacy was further enhanced by cotransducing DCs with a vector expressing murine IL-12 (AdmIL-12). These studies support DC vaccines as a therapeutic strategy for human breast cancer, while emphasizing the importance of optimizing an immune response by combining tumor antigen presentation with immunostimulatory cytokines.

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References

  1. Alroy I, Yarden Y . The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions FEBS Lett 1997 410: 83–86

    Article  CAS  PubMed  Google Scholar 

  2. Graus-Porta D, Beerli RR, Daly JM, Hynes NE . ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling EMBO J 1997 16: 1647–1655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Slamon DJ et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene Science 1987 235: 177–182

    Article  CAS  PubMed  Google Scholar 

  4. Guy CT et al. Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease Proc Natl Acad Sci USA 1992 89: 10578–10582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Paterson MC et al. Correlation between c-erbB-2 amplification and risk of recurrent disease in node-negative breast cancer Cancer Res 1991 51: 556–567

    CAS  PubMed  Google Scholar 

  6. Andrulis IL et al. neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group J Clin Oncol 1998 16: 1340–1349

    Article  CAS  PubMed  Google Scholar 

  7. Disis ML, Cheever M . Oncogenic proteins as tumor antigens Curr Opin Immunol 1996 8: 637–642

    Article  CAS  PubMed  Google Scholar 

  8. Bei R et al. Immune responses to all ErbB family receptors detectable in serum of cancer patients Oncogene 1999 18: 1267–1275

    Article  CAS  PubMed  Google Scholar 

  9. Disis ML, Grabstein KH, Sleath PR, Cheever MA . Generation of immunity to the HER-2/neu oncogenic protein in patients with breast and ovarian cancer using a peptide-based vaccine Clin Cancer Res 1999 5: 1289–1297

    CAS  PubMed  Google Scholar 

  10. Zaks TZ, Rosenberg SA . Immunization with a peptide epitope (p369–377) from HER-2/neu leads to peptide-specific cytotoxic T lymphocytes that fail to recognize HER-2/neu+tumors Cancer Res 1998 58: 4902–4908

    CAS  PubMed  Google Scholar 

  11. Nagata Y et al. Peptides derived from a wild-type murine proto-oncogene c-erbB-2/HER2/neu can induce CTL and tumor suppression in syngeneic hosts J Immunol 1997 159: 1336–1343

    CAS  PubMed  Google Scholar 

  12. Chen Y et al. DNA vaccines encoding full-length or truncated Neu induce protective immunity against Neu-expressing mammary tumors Cancer Res 1998 58: 1965–1971

    CAS  PubMed  Google Scholar 

  13. Wei WZ et al. Protection against mammary tumor growth by vaccination with full-length, modified human ErbB-2 DNA Int J Cancer 1999 81: 748–754

    Article  CAS  PubMed  Google Scholar 

  14. Amici A, Venanzi FM, Concetti A . Genetic immunization against neu/erbB2 transgenic breast cancer Cancer Immunol Immunother 1998 47: 183–190

    Article  CAS  PubMed  Google Scholar 

  15. Gabrilovich DI et al. Decreased antigen presentation by dendritic cells in patients with breast cancer Clin Cancer Res 1997 3: 483–490

    CAS  PubMed  Google Scholar 

  16. Troy AJ et al. Minimal recruitment and activation of dendritic cells within renal cell carcinoma Clin Cancer Res 1998 4: 585–593

    CAS  PubMed  Google Scholar 

  17. Gabrilovich DI, Ciernik IF, Carbone DP . Dendritic cells in antitumor immune responses. I. Defective antigen presentation in tumor-bearing hosts Cell Immunol 1996 170: 101–110

    Article  CAS  PubMed  Google Scholar 

  18. Chaux P, Favre N, Martin M, Martin F . Tumor-infiltrating dendritic cells are defective in their antigen-presenting function and inducible B7 expression in rats Int J Cancer 1997 72: 619–624

    Article  CAS  PubMed  Google Scholar 

  19. Nestle FO et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells Nature Med 1998 4: 328–332

    Article  CAS  PubMed  Google Scholar 

  20. Dhodapkar MV et al. Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells J Clin Invest 1999 104: 173–180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wan Y et al. Dendritic cells transduced with an adenoviral vector encoding a model tumor-associated antigen for tumor vaccination Hum Gene Ther 1997 8: 1355–1363

    Article  CAS  PubMed  Google Scholar 

  22. Zhong L, Granelli-Piperno A, Choi Y, Steinman RM . Recombinant adenovirus is an efficient and non-perturbing genetic vector for human dendritic cells Eur J Immunol 1999 29: 964–972

    Article  CAS  PubMed  Google Scholar 

  23. Song W et al. Dendritic cells genetically modified with an adenovirus vector encoding the cDNA for a model antigen induce protective and therapeutic antitumor immunity J Exp Med 1997 186: 1247–1256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ribas A et al. Genetic immunization for the melanoma antigen MART-1/Melan-A using recombinant adenovirus-transduced murine dendritic cells Cancer Res 1997 57: 2865–2869

    CAS  PubMed  Google Scholar 

  25. Kaplan JM et al. Induction of antitumor immunity with dendritic cells transduced with adenovirus vector-encoding endogenous tumor-associated antigens J Immunol 1999 163: 699–707

    CAS  PubMed  Google Scholar 

  26. Kataoka TN et al. Concanamycin A, a powerful tool for characterization and estimation of contribution of perforin- and Fas-based lytic pathways in cell-mediated cytotoxicity J Immunol 1996 156: 3678–3686

    CAS  PubMed  Google Scholar 

  27. Zajac AJ, Quinn DG, Cohen PL, Frelinger JA . Fas-dependent CD4+ cytotoxic T-cell-mediated pathogenesis during virus infection Proc Natl Acad Sci USA 1996 93: 14730–14735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shesta S et al. How do cytotoxic lymphocytes kill their targets? Curr Opin Immunol 1998 10: 581–587

    Article  Google Scholar 

  29. Wan Y et al. Enhanced immune response to the melanoma antigen gp100 using recombinant adenovirus-transduced dendritic cells Cell Immunol 1999 198: 131–138

    Article  CAS  PubMed  Google Scholar 

  30. Yang S et al. Murine dendritic cells transfected with human GP100 elicit both antigen-specific CD8(+) and CD4(+) T-cell responses and are more effective than DNA vaccines at generating anti-tumor immunity Int J Cancer 1999 83: 532–540

    Article  CAS  PubMed  Google Scholar 

  31. Cao X et al. Lymphotactin gene-modified bone marrow dendritic cells act as more potent adjuvants for peptide delivery to induce specific antitumor immunity J Immunol 1998 161: 6238–6244

    CAS  PubMed  Google Scholar 

  32. Hsieh CS et al. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages Science 1993 260: 547–549

    Article  CAS  PubMed  Google Scholar 

  33. Bianchi R et al. Autocrine IL-12 is involved in dendritic cell modulation via CD40 ligation J Immunol 1999 163: 2517–2521

    CAS  PubMed  Google Scholar 

  34. Wan Y et al. Murine dendritic cells transduced with an adenoviral vector expressing a defined tumor antigen can overcome anti-adenovirus neutralizing immunity and induce effective tumor regression Int J Oncol 1999 14: 771–776

    CAS  PubMed  Google Scholar 

  35. Ben-Levy R, Paterson HF, Marshall CJ, Yarden Y . A single autophosphorylation site confers oncogenicity to the Neu/ErbB-2 receptor and enables coupling to the MAP kinase pathway EMBO J 1994 13: 3302–3311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Toes RE, Ossendorp F, Offringa R, Melief CJ . CD4 T cells and their role in antitumor immune responses J Exp Med 1999 189: 753–756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ahuja SS et al. Dendritic cell (DC)-based anti-infective strategies: DCs engineered to secrete IL-12 are a potent vaccine in a murine model of an intracellular infection J Immunol 1999 163: 3890–3897

    CAS  PubMed  Google Scholar 

  38. Zitvogel L et al. IL-12-engineered dendritic cells serve as effective tumor vaccine adjuvants in vivo Ann NY Acad Sci 1996 795: 284–293

    Article  CAS  PubMed  Google Scholar 

  39. Siegel PM, Dankort DL, Hardy WR, Muller WJ . Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors Mol Cell Biol 1994 14: 7068–7077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bramson J et al. Construction of a double recombinant adenovirus vector expressing a heterodimeric cytokine: in vitro and in vivo production of biologically active interleukin-12 Hum Gene Ther 1996 7: 333–342

    Article  CAS  PubMed  Google Scholar 

  41. Bett AJ, Haddara W, Prevec L, Graham FL . An efficient and flexible system for construction of adenovirus vectors with insertions or deletions in early regions 1 and 3 Proc Natl Acad Sci USA 1994 91: 8802–8806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Duncan Chong, Xueya Feng and Chunyan Li for their expert technical assistance, and Dr Jonathan Bramson for critical reading of the manuscript. This work was supported in part by funds from the Breast Cancer Society of Canada, the Medical Research Council of Canada (MRC), the Hamilton Health Science Corporation and the St Joseph's Hospital.

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  1. Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada

    Y Chen, P Emtage, Q Zhu, R Foley, W Muller, M Hitt, J Gauldie & Y Wan

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Chen, Y., Emtage, P., Zhu, Q. et al. Induction of ErbB-2/neu-specific protective and therapeutic antitumor immunity using genetically modified dendritic cells: enhanced efficacy by cotransduction of gene encoding IL-12. Gene Ther 8, 316–323 (2001). https://doi.org/10.1038/sj.gt.3301396

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