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Intratumoral DNA electroporation induces anti-tumor immunity and tumor regression

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Abstract

In situ expression of a foreign antigen and an immune-modulating cytokine by intratumoral DNA electroporation was tested as a cancer therapy regimen. Transgene expression in the tumors was sustained for 2–3 weeks after intratumoral electroporation with mammalian expression plasmid containing firefly luciferase cDNA. Electroporation with cDNA encoding tetanus toxin fragment C (TetC) induced tetanus toxin-binding antibody, demonstrating immune recognition of the transgene product. Intratumoral electroporation with TetC and IL-12 cDNA after mice were treated with CD25 mAb to remove regulatory T cells induced IFN-γ producing T-cell response to tumor-associated antigen, heavy inflammatory infiltration, regression of established tumors and immune memory to protect mice from repeated tumor challenge. Intratumoral expression of immune-modulating molecules may be most suitable in the neoadjuvant setting to enhance the therapeutic efficacy and provide long-term protection.

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References

  1. Allen J, Jahanzeb M (2008) Neoadjuvant chemotherapy in stage III NSCLC. J Natl Compr Canc Netw 6:285–293

    CAS  PubMed  Google Scholar 

  2. Boggio K, Nicoletti G, Di CE et al (1998) Interleukin 12-mediated prevention of spontaneous mammary adenocarcinomas in two lines of Her-2/neu transgenic mice. J Exp Med 188:589–596

    Article  CAS  PubMed  Google Scholar 

  3. Buchan S, Gronevik E, Mathiesen I et al (2005) Electroporation as a “prime/boost” strategy for naked DNA vaccination against a tumor antigen. J Immunol 174:6292–6298

    CAS  PubMed  Google Scholar 

  4. Collins CG, Tangney M, Larkin JO et al (2006) Local gene therapy of solid tumors with GM-CSF and B7-1 eradicates both treated and distal tumors. Cancer Gene Ther 13:1061–1071

    Article  CAS  PubMed  Google Scholar 

  5. Fushimi T, Kojima A, Moore MA et al (2000) Macrophage inflammatory protein 3alpha transgene attracts dendritic cells to established murine tumors and suppresses tumor growth. J Clin Invest 105:1383–1393

    Article  CAS  PubMed  Google Scholar 

  6. Galili U, Wigglesworth K, Abdel-Motal UM (2007) Intratumoral injection of alpha-gal glycolipids induces xenograft-like destruction and conversion of lesions into endogenous vaccines. J Immunol 178:4676–4687

    CAS  PubMed  Google Scholar 

  7. Glover DJ, Lipps HJ, Jans DA (2005) Towards safe, non-viral therapeutic gene expression in humans. Nat Rev Genet 6:299–310

    Article  CAS  PubMed  Google Scholar 

  8. Grossman HB, Natale RB, Tangen CM et al (2003) Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859–866

    Article  CAS  PubMed  Google Scholar 

  9. Gruenberger B, Scheithauer W, Punzengruber R et al (2008) Importance of response to neoadjuvant chemotherapy in potentially curable colorectal cancer liver metastases. BMC Cancer 8:120

    Article  PubMed  Google Scholar 

  10. Helting TB, Zwister O (1977) Structure of tetanus toxin, breakdown of the toxin molecule and discrimination between polypeptide fragments. J Biol Chem 252:187–93

    Google Scholar 

  11. Jacob J, Radkevich O, Forni G et al (2006) Activity of DNA vaccines encoding self or heterologous Her-2/neu in Her-2 or neu transgenic mice. Cell Immunol 240:96–106

    Article  CAS  PubMed  Google Scholar 

  12. Jacob JB, Kong YM, Nalbantoglu I et al (2009) Tumor regression following DNA vaccination and regulatory T-cell depletion in neu transgenic mice leads to an increased risk for autoimmunity. J Immunol 182:5873–5881

    Article  CAS  PubMed  Google Scholar 

  13. Jacob JB, Kong YM, Meroueh C et al (2007) Control of Her-2 tumor immunity and thyroid autoimmunity by MHC and regulatory T cells. Cancer Res 67:7020–7027

    Article  CAS  PubMed  Google Scholar 

  14. Kaufman HL, Disis ML (2004) Immune system versus tumor: shifting the balance in favor of DCs and effective immunity. J Clin Invest 113:664–667

    CAS  PubMed  Google Scholar 

  15. Knutson KL, Schiffman K, Disis ML (2001) Immunization with a HER-2/neu helper peptide vaccine generates HER-2/neu CD8 T-cell immunity in cancer patients. J Clin Invest 107:477–484

    Article  CAS  PubMed  Google Scholar 

  16. Lin KY, Guarnieri FG, Staveley-O’Carroll KF et al (1996) Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Res 56:21–26

    CAS  PubMed  Google Scholar 

  17. Liu A, Guardino A, Chinsangaram L et al (2007) Therapeutic vaccination against murine lymphoma by intratumoral injection of recombinant fowlpox virus encoding CD40 ligand. Cancer Res 67:7037–7044

    Article  CAS  PubMed  Google Scholar 

  18. Lu X, Kallinteris NL, Li J et al (2003) Tumor immunotherapy by converting tumor cells to MHC class II-positive, Ii protein-negative phenotype. Cancer Immunol Immunother 52:592–598

    Article  CAS  PubMed  Google Scholar 

  19. Lucas ML, Heller L, Coppola D et al (2002) IL-12 plasmid delivery by in vivo electroporation for the successful treatment of established subcutaneous B16.F10 melanoma. Mol Ther 5:668–675

    Article  CAS  PubMed  Google Scholar 

  20. Mahoney KH, Miller BE, Heppner GH (1985) FACS quantitation of leucine aminopeptidase and acid phosphatase on tumor-associated macrophages from metastatic and nonmetastatic mouse mammary tumors. J Leukoc Biol 38:573–585

    CAS  PubMed  Google Scholar 

  21. Mathew J, Asgeirsson KS, Cheung KL et al (2008) Neoadjuvant chemotherapy for locally advanced breast cancer: a review of the literature and future directions. Eur J Surg Oncol 35:113–122

    PubMed  Google Scholar 

  22. Muller AJ, Scherle PA (2006) Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors. Nat Rev Cancer 6:613–625

    Article  CAS  PubMed  Google Scholar 

  23. Panina-Bordignon P, Tan A, Termijtelen A et al (1989) Universally immunogenic T-cell epitopes: promiscuous binding to human MHC class II and promiscuous recognition by T cells. Eur J Immunol 19:2237–2242

    Article  CAS  PubMed  Google Scholar 

  24. Piechocki MP, Pilon SA, Wei WZ (2001) Complementary antitumor immunity induced by plasmid DNA encoding secreted and cytoplasmic human ErbB-2. J Immunol 167:3367–3374

    CAS  PubMed  Google Scholar 

  25. Prud’homme GJ, Glinka Y, Khan AS et al (2006) Electroporation-enhanced nonviral gene transfer for the prevention or treatment of immunological, endocrine and neoplastic diseases. Curr Gene Ther 6:243–273

    Article  PubMed  Google Scholar 

  26. Rabinovich GA, Gabrilovich D, Sotomayor EM (2007) Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25:267–296

    Article  CAS  PubMed  Google Scholar 

  27. Radkevich-Brown O, Jacob J, Kershaw M et al (2009) Genetic regulation of the response to Her-2 DNA vaccination in human Her-2 transgenic mice. Cancer Res 69:212–218

    Article  CAS  PubMed  Google Scholar 

  28. Rovero S, Amici A, Carlo ED et al (2000) DNA vaccination against rat her-2/Neu p185 more effectively inhibits carcinogenesis than transplantable carcinomas in transgenic BALB/c mice. J Immunol 165:5133–5142

    CAS  PubMed  Google Scholar 

  29. Sharma S, Dominguez AL, Manrique SZ et al (2008) Systemic targeting of CpG-ODN to the tumor microenvironment with anti-neu-CpG hybrid molecule and T regulatory cell depletion induces memory responses in BALB-neuT tolerant mice. Cancer Res 68:7530–7540

    Article  CAS  PubMed  Google Scholar 

  30. Stevenson FK, Rice J, Ottensmeier CH et al (2004) DNA fusion gene vaccines against cancer: from the laboratory to the clinic. Immunol Rev 199:156–180

    Article  CAS  PubMed  Google Scholar 

  31. Stratford R, Douce G, Zhang-Barber L et al (2000) Influence of codon usage on the immunogenicity of a DNA vaccine against tetanus. Vaccine 19:810–815

    Article  CAS  PubMed  Google Scholar 

  32. Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3:133–146

    Article  CAS  PubMed  Google Scholar 

  33. Wei WZ, Jacob JB, Zielinski JF et al (2005) Concurrent induction of antitumor immunity and autoimmune thyroiditis in CD4+ CD25+ regulatory T cell-depleted mice. Cancer Res 65:8471–8478

    Article  CAS  PubMed  Google Scholar 

  34. Wei WZ, Shi WP, Galy A et al (1999) Protection against mammary tumor growth by vaccination with full-length, modified human ErbB-2 DNA. Int J Cancer 81:748–754

    Article  CAS  PubMed  Google Scholar 

  35. Wolmark N, Wang J, Mamounas E et al (2001) Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr 9:6–102

    Google Scholar 

  36. Yu P, Lee Y, Wang Y et al (2007) Targeting the primary tumor to generate CTL for the effective eradication of spontaneous metastases. J Immunol 179:1960–1968

    CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by NIH CA76340 and CA125680 (WZW).

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Authors and Affiliations

  1. Karmanos Cancer Institute, Wayne State University, 110 E. Warren Ave., Detroit, MI, 48201, USA

    Olga Radkevich-Brown, Marie P. Piechocki, Jessica B. Back, Amy M. Weise, Shari Pilon-Thomas & Wei-Zen Wei

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  1. Olga Radkevich-Brown
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  2. Marie P. Piechocki
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  3. Jessica B. Back
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  4. Amy M. Weise
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  5. Shari Pilon-Thomas
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  6. Wei-Zen Wei
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Correspondence to Wei-Zen Wei.

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Radkevich-Brown, O., Piechocki, M.P., Back, J.B. et al. Intratumoral DNA electroporation induces anti-tumor immunity and tumor regression. Cancer Immunol Immunother 59, 409–417 (2010). https://doi.org/10.1007/s00262-009-0760-1

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  • DOI: https://doi.org/10.1007/s00262-009-0760-1

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