Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Phase-I clinical trial of IL-12 plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer

Gene Therapy volume 17, pages 360–369 (2010)Cite this article

Abstract

A phase-I trial to assess the safety and tolerability of human interleukin-12 (IL-12) plasmid (phIL-12) formulated with a synthetic lipopolymer, polyethyleneglycol–polyethyleneimine–cholesterol (PPC), was conducted on women with chemotherapy-resistant recurrent ovarian cancer. A total of 13 patients were enrolled in four dose-escalating cohorts and treated with 0.6, 3, 12 or 24 mg m−2 of the formulated plasmid once every week for 4 weeks. Administration of phIL-12/PPC was generally safe and well-tolerated. Common side effects included low-grade fever and abdominal pain. Stable disease and reduction in serum CA-125 levels were clinically observed in some patients. Measurable levels of IL-12 plasmid were detectable in PF samples collected throughout the course of phIL-12/PPC treatment. In comparison, serum samples either did not contain detectable amounts of plasmid DNA or contained <1% of the amount found in the corresponding PF samples. Treatment-related increases in IFN-γ levels were observed in PF but not in serum. These data demonstrate that IL-12 gene delivery with a synthetic delivery system is feasible for ovarian cancer patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. American Cancer Society (2007). Cancer Facts and Figures 2007. American Cancer Society: Atlanta, 2007.

  2. Chobanian N, Dietrich CS . Ovarian cancer. Surg Clin North Am 2008; 88: 285–299.

    Article  PubMed  Google Scholar 

  3. Bhoola S, Alvarez R . Novel therapies for recurrent ovarian cancer management. Expert Rev Anticancer Ther 2004; 4: 437–448.

    Article  CAS  PubMed  Google Scholar 

  4. Oei L, Sweep FC, Thomas CM, Boerman OC, Massuger LF . The use of monoclonal antibodies for the treatment of epithelial ovarian cancer. Int J Oncol 2008; 32: 1145–1157.

    Article  CAS  PubMed  Google Scholar 

  5. Chu CS, Kim SH, June CH, Coukos G . Immunotherapy opportunities in ovarian cancer. Expert Rev Anticancer Ther 2008; 8: 243–257.

    Article  CAS  PubMed  Google Scholar 

  6. Hogberg T, Glimelius B, Nygree P . A systematic overview of chemotherapy effects in ovarian cancer. Acta Oncol 2001; 40: 340–360.

    Article  CAS  PubMed  Google Scholar 

  7. Robertson MJ, Ritz J . Interleukin-12: basic biology and potential applications in cancer treatment. Oncologist 1996; 1: 88–97.

    CAS  PubMed  Google Scholar 

  8. Manetti R, Parronchi P, Giudizi MG, Piccinni MP, Maggi E, Trinchieri G et al. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing The cells. J Exp Med 1993; 177: 1199–1204.

    Article  CAS  PubMed  Google Scholar 

  9. Colombo MP, Trinchieri G . Interleukin-12 in antitumor immunity and immunotherapy. Cytokine Growth Factor Rev 2002; 13: 155–168.

    Article  CAS  PubMed  Google Scholar 

  10. Trinchieri G, Gerosa F . Immunoregulation by interleukin-12. J Leuk Biol 1996; 59: 505–511.

    Article  CAS  Google Scholar 

  11. Manetti R, Gerosa F, Giudizi MG, Biagiotti R, Parronchi P, Piccinni MP et al. Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones. J Exp Med 1994; 179: 1273–1283.

    Article  CAS  PubMed  Google Scholar 

  12. Wigginton JM, Gruys E, Geiselhart L, Subleski K, Komschlies KL, Park JW et al. IFN-gamma and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy. J Clin Invest 2001; 108: 51–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Murphy WJ, Welniak L, Back T, Hixon J, Subleski J, Seki N et al. Synergistic anti-tumor responses after administration of agonistic antibodies to CD40 and IL-2: coordination of dendritic and CD8+ cell responses. J Immunol 2003; 170: 2727–2733.

    Article  CAS  PubMed  Google Scholar 

  14. Wigginton JM, Lee JK, Wiltrout TA, Alvord WG, Hixon JA, Subleski J et al. Synergistic engagement of an ineffective endogenous anti-tumor immune response and induction of IFN-gamma and Fas-ligand-dependent tumor eradication by combined administration of IL-18 and IL-2. J Immunol 2002; 169: 4467–4474.

    Article  CAS  PubMed  Google Scholar 

  15. Strieter RM, Polverini PJ, Arenberg DA, Kunkel SL . The role of Cxc chemokines as regulators of angiogenesis. Shock 1995; 4: 155–160.

    Article  CAS  PubMed  Google Scholar 

  16. Sgadari C, Angiolillo A, Tosato G . Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10. Blood 1996; 87: 3877–3882.

    CAS  PubMed  Google Scholar 

  17. Yu WG, Yamamoto N, Takenaka H, Mu J, Tai XG, Zou JP et al. Molecular mechanisms underlying IFN-g mediated tumor growth inhibition induced during tumor immunotherapy with rIL-12. Int Immunol 1996; 8: 855–865.

    Article  CAS  PubMed  Google Scholar 

  18. Guckek B, Meyer GC, Rudy W, Batrla R, Meuer SC, Bastert G et al. Interleukin-12 requires initial CD80-mediated T-cell activation to support immune responses toward human breast and ovarian carcinoma. Cancer Gene Ther 1999; 6: 228–237.

    Article  Google Scholar 

  19. Ogawa M, Yu WG, Umehara K, Iwasaki M, Wijesuriya R, Tsujimura T et al. Multiple role of interferon-gamma in the mediation of interleukin 12-induced tumor regression. Cancer Res 1998; 58: 2426–2432.

    CAS  PubMed  Google Scholar 

  20. Silver DF, Hempling RE, Piver MS, Repasky EA . Effects of IL-12 on human ovarian tumors engrafted into SCID mice. Gynecol Oncol 1999; 72: 154–160.

    Article  CAS  PubMed  Google Scholar 

  21. DeCesare SL, Michelini-Norris B, Blanchard DK, Barton DP, Cavanagh D, Roberts WS et al. Interleukin-12-mediated tumoricidal activity of patient lymphocytes in an autologous in vitro ovarian cancer assay system. Gynecol Oncol 1995; 57: 86–95.

    Article  CAS  PubMed  Google Scholar 

  22. Sanches R, Kuiper M, Penault-Llorca F, Aunoble B, D’Incan C, Bignon YJ . Antitumoral effect of interleukin-12-secreting fibroblasts in a mouse model of ovarian cancer: implications for the use of ovarian cancer biopsy-derived fibroblasts as a vehicle for regional gene therapy. Cancer Gene Ther 2000; 7: 707–720.

    Article  CAS  PubMed  Google Scholar 

  23. Akira M, Yamasaki S, Inoue N, Yang W, Nakau M, Yasuda S . Interleukin-12-gene transduction makes DCs from tumor-bearing mice an effective inducer of tumor-specific immunity in a peritoneal dissemination model. Immunol Lett 2002; 83: 13–20.

    Article  Google Scholar 

  24. Lenzi R, Rosenblum M, Verschraegen C, Kudelka AP, Kavanagh JJ, Hicks ME et al. Phase I study of intraperitoneal recombinant human interleukin-12 in patients with Mullerian carcinoma, gastrointestinal primary malignancies, and mesothelioma. Clin Cancer Res 2002; 8: 3686–3695.

    CAS  PubMed  Google Scholar 

  25. Atkins MB, Robertson MJ, Gordon M, Lotze MT, DeCoste M, DuBio JS et al. Phase I trial evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin Cancer Res 1997; 3: 409–417.

    CAS  PubMed  Google Scholar 

  26. Gollob JA, Mier JW, Veenstra K, McDermott DF, Clancy D, Clancy M et al. Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: ability to maintain IFN-γ induction is associated with clinical response. Clin Cancer Res 2000; 6: 1678–1692.

    CAS  PubMed  Google Scholar 

  27. Cebon J, Jager E, Shackleton MJ, Gibbs P, Davis ID, Hopkins W et al. Two phase I studies of low dose recombinant human IL-12 with melan-A and influenza peptides in patients with advanced malignant melanoma. Cancer Immunol 2003; 16: 3–7.

    Google Scholar 

  28. Rook AH, Wood GS, Yoo EK, Elenitsas R, Kao DM, Sherman ML et al. Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses. Blood 1999; 94: 902–908.

    CAS  PubMed  Google Scholar 

  29. Bajetta E, Del Vecchio M, Mortarini R, Nadeau R, Rakhit A, Rimassa L et al. Pilot study of subcutaneous recombinant human interleukin 12 in metastatic melanoma. Clin Cancer Res 1998; 4: 75–85.

    CAS  PubMed  Google Scholar 

  30. Marshall E . Cancer trial of interleukin-12 halted. Science 1995; 268: 1555.

    Article  Google Scholar 

  31. Fewell J, Matar M, Slobodkin G, Rice J, Hovanes B, Anwer K . Synthesis and application of biocompatible non-viral gene delivery system for immunogene therapy of cancer. J Control Release 2005; 109: 288–298.

    Article  CAS  PubMed  Google Scholar 

  32. Fewell JG, Rice JK, Matar M, Slobodkin G, Lewis DH, Anwer K . Combination interleukin-12 intraperitoneal gene therapy with chemotherapy for treatment of disseminated ovarian cancer. Proc Am Assoc Cancer Res 2006; 47: 2112.

    Google Scholar 

  33. Brunhoeber E, Matar M, Anwer K, Fewell J . Biodistribution and clearance following intraperitoneal injection of murine interleukin-12 plasmid formulated with a novel polymeric delivery system. Mol Ther 2006; 13 (Suppl 109): 286.

    Google Scholar 

  34. Fewell JG, Rice J, Matar M, Anwer K . Safety and toxicity following intraperitoneal injection of murine interleukin-12 plasmid formulated with a novel polymeric delivery system. Mol Ther 2006; 13 (Suppl 109): 287.

    Google Scholar 

  35. Strippoli GF, Tong A, Johnson D, Schena FP, Craig JC . Catheter type, placement and insertion techniques for preventing peritonitis in peritoneal dialysis patients. Cochrane Database Syst Rev 2004; 4: CD004680.

    Google Scholar 

  36. Hortobagyi GN, Ueno NT, Xia W, Zhang S, Wolf JK, Putnam JB et al. Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biological effects: a phase I clinical trial. J Clin Oncol 2001; 19: 4183–4184.

    Article  Google Scholar 

  37. Fewell JG, Rice J, Matar M, Brunhoeber E, Pence C, Slobodkin G et al. Use of interleukin-12 gene nanocomplexes as a general treatment against disseminated peritoneal malignancies. Proc Am Assoc Cancer Res 2007; 48: 3304.

    Google Scholar 

  38. Fewell JG, Matar M, Rice JS, Brunhoeber E, Slobodkin G, Pence C et al. Treatment of disseminated ovarian cancer using nonviral interleukin-12 gene therapy delivered intraperitoneally. J Gene Med 2009; 11: 718–728.

    Article  CAS  PubMed  Google Scholar 

  39. Markman M . Intraperitoneal chemotherapy as primary treatment of advanced ovarian cancer: efficacy, toxicity, and future directions. Rev Recent Clin Trials 2007; 2: 169–173.

    Article  CAS  PubMed  Google Scholar 

  40. Armstrong DK, Bundy B, Wanzel L, Huang HQ, Baergen R, Shashikant L . Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006; 354: 34–43.

    Article  CAS  PubMed  Google Scholar 

  41. Lenzi R, Edward R, June C, Seiden MV, Garcia ME, Rosenblum M et al. Phase II study of intraperitoneal recombinant interleukin-12 (rhIL-12) in patients with peritoneal carcinomatosis (residual disease &lt;1 cm) associated with ovarian cancer or primary peritoneal carcinoma. J Transl Med 2007; 5: 66–72.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Heinzerling L, Burg G, Dummer R, Maier T, Oberholzer PA, Schultz J et al. Intratumoral injection of DNA encoding human interleukin 12 into patients with metastatic melanoma: clinical efficacy. Hum Gene Ther 2005; 16: 35–48.

    Article  CAS  PubMed  Google Scholar 

  43. Triozzi PL, Strong TV, Bucy RP, Allen KO, Carlisle RR, Moore SE et al. Intratumoral administration of a recombinant Canarypox virus expressing interleukin 12 in patients with metastatic melanoma. Hum Gene Ther 2005; 16: 91–100.

    Article  CAS  PubMed  Google Scholar 

  44. Sonabend AM, Velicu S, Ulasov IV, Han Y, Tyler B, Brem H et al. A safety and efficacy study of local delivery of IL-12 transgene by PPC polymer in a model of experimental glioma. Anticancer Drug 2008; 19: 133–142.

    Article  CAS  Google Scholar 

  45. Orsi F, Vigna PD, Bonomo G, Belloni M . Percutaneous placement of peritoneal port-catheter in oncologic patients. Eur Radiol 2004; 14: 2020–2024.

    Article  PubMed  Google Scholar 

  46. Mosteller RD . Simplified calculation of body-surface area. N Engl J Med 1987; 317: 1098–1101.

    CAS  PubMed  Google Scholar 

  47. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Jolane Gable, Thelma Webb and Aparna Tamhane of the University of Alabama in Birmingham, Dr Marshall Schreeder of Clearview Cancer Center, Huntsville, Alabama, Dr Mathew Anderson of Baylor College of Medicine and Dirk Kieback for valuable contribution and input into this study.

Author information

Authors and Affiliations

  1. EGEN Inc., Huntsville, AL, USA

    K Anwer, J Fewell & D H Lewis

  2. Department of OB/GYN, University of Alabama at Birmingham, Birmingham, AL, USA

    M N Barnes & R D Alvarez

Authors
  1. K Anwer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M N Barnes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Fewell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D H Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R D Alvarez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K Anwer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Anwer, K., Barnes, M., Fewell, J. et al. Phase-I clinical trial of IL-12 plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer. Gene Ther 17, 360–369 (2010). https://doi.org/10.1038/gt.2009.159

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2009.159

Keywords

This article is cited by

Search

Advanced search

Quick links