Skip to main content
SpringerLink
Log in

TNFerade, an Adenovector Carrying the Transgene for Human Tumor Necrosis Factor α, for Patients With Advanced Solid Tumors: Surgical Experience and Long-Term Follow-Up

  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Over the last several years, attempts have been made to use the tumoricidal effects of tumor necrosis factor (TNF)-α to treat cancer. Many of these studies demonstrated dose-limiting systemic side effects from high concentrations of TNF-α. The recent focus has been on developing a local delivery system for TNF-α to minimize the systemic response.

Methods

This study was part of a phase I open-label multi-institutional trial using TNFerade. We focus on the patients treated at Baylor University Medical Center and provide postoperative and long-term follow-up. TNFerade uses a second-generation nonreplicating adenovirus as the vector for delivery of the human transgene TNF-α. An early growth response 1 promoter was placed upstream from the TNF-α gene. This promoter is activated by ionizing radiation, thus allowing for temporal and spatial control of TNF-α release. Tumors were injected over 5 weeks with ionizing radiation given 3 days after injections for 6 weeks. Tumor response was measured by computed tomographic imaging and physical examination.

Results

As described in our original experience, no patients experienced dose-limiting toxicities up to doses of 4 × 1011 particles per injection. Tumors injected demonstrated a response independently of histology. Four patients had complete regression of the tumor injected. Three patients with complete regression have survived ≥2 years from the time of treatment.

Conclusions

Both short-term and long-term safety are observed with TNFerade. These data demonstrate the need for phase II trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Carswell EA, Old LJ, Kassel RL, et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 1975;72:3666–70

    PubMed  Google Scholar 

  2. Feinberg B, Kurzrock R, Talpaz M, et al. A phase I trial of intravenously-administered recombinant tumor necrosis factor-alpha in cancer patients. J Clin Oncol 1988;6:1328–34

    PubMed  Google Scholar 

  3. Mannel DN, Moore RN, Mergenhagen SE. Macrophages as a source of tumoricidal activity (tumor-necrotizing factor). Infect Immun 1980;30:523–30

    PubMed  Google Scholar 

  4. Larrick JW, Wright SC. Cytotoxic mechanism of tumor necrosis factor-alpha. FASEB J 1990;4:3215–23

    Google Scholar 

  5. Asher A, Mule JJ, Reichert CM, et al. Studies on the anti-tumor efficacy of systemically administered recombinant tumor necrosis factor against several murine tumors in vivo. J Immunol 1987;138:963–74

    PubMed  Google Scholar 

  6. Tcherkasowa AE, Adam-Klages S, Kruse ML, et al. Interaction with factor associated with neutral sphingomyelinase activation, a WD motif-containing protein, identifies receptor for activated C-kinase 1 as a novel component of the signaling pathways of the p55 TNF receptor. J Immunol 2002;169:5161–70

    PubMed  Google Scholar 

  7. Wallach D, Varfolomeev EE, Malinin NL, et al. Tumor necrosis factor receptor and Fas signaling mechanisms. Ann Rev Immunol 1999;17:331–67

    Article  Google Scholar 

  8. Schwandner R, Wiegmann K, Bernardo K, et al. TNF receptor death domain-associated proteins TRADD and FADD signal activation of acid sphingomyelinase. J Biol Chem 1998;273:5916–22

    Google Scholar 

  9. Kulik G, Carson JP, Vomastek T, et al. Tumor necrosis factor alpha induces BID cleavage and bypasses antiapoptotic signals in prostate cancer LNCaP cells. Cancer Res 2001;61:2713–9

    PubMed  Google Scholar 

  10. Kimura K, Gelmann EP. Tumor necrosis factor-alpha and Fas activate complementary Fas-associated death domain-dependent pathways that enhance apoptosis induced by gamma-irradiation. J Biol Chem 2000;275:8610–7

    Google Scholar 

  11. Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 2001;11:372–7

    Article  PubMed  Google Scholar 

  12. Villa P, Kaufmann SH, Earnshaw WC. Caspases and caspase inhibitors. Trends Biochem Sci 1997;22:388–93

    Article  PubMed  Google Scholar 

  13. Dbaibo GS, Perry DK, Gamard CJ, et al. Cytokine response modifier A (CrmA) inhibits ceramide formation in response to tumor necrosis factor (TNF)-alpha: CrmA and Bcl-2 target distinct components in the apoptotic pathway. J Exp Med 1997;185:481–90

    Article  PubMed  Google Scholar 

  14. Wiegmann K, Schutze S, Machleidt T, et al. Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling. Cell 1994;78:1005–15

    Article  PubMed  Google Scholar 

  15. Green DR. Apoptosis. Death deceiver (comment). Nature 1998;396:629–30

    Article  PubMed  Google Scholar 

  16. Mauceri HJ, Hanna NN, Wayne JD, et al. Tumor necrosis factor alpha (TNF-alpha) gene therapy targeted by ionizing radiation selectively damages tumor vasculature. Cancer Res 1996;56:4311–4

    PubMed  Google Scholar 

  17. Mahadevan V, Malik ST, Meager A, et al. Role of tumor necrosis factor in flavone acetic acid-induced tumor vasculature shutdown. Cancer Res 1990;50:5537–42

    PubMed  Google Scholar 

  18. Fukumura D, Salehi HA, Witwer B, et al. Tumor necrosis factor alpha-induced leukocyte adhesion in normal and tumor vessels: effect of tumor type, transplantation site, and host strain. Cancer Res 1995;55:4824–9

    PubMed  Google Scholar 

  19. Balkwill FR, Lee A, Aldam G, et al. Human tumor xenografts treated with recombinant human tumor necrosis factor alone or in combination with interferons. Cancer Res 1986;46:3990–3

    Google Scholar 

  20. Korpelainen EI, Gamble JR, Smith WB, et al. The receptor for interleukin 3 is selectively induced in human endothelial cells by tumor necrosis factor alpha and potentiates interleukin 8 secretion and neutrophil transmigration. Proc Natl Acad Sci U S A 1993;90:11137–41

    PubMed  Google Scholar 

  21. Pilaro AM, Taub DD, McCormick KL, et al. TNF-alpha is a principal cytokine involved in the recruitment of NK cells to liver parenchyma. J Immunol 1994;153:333–42

    PubMed  Google Scholar 

  22. Seung LP, Mauceri HJ, Beckett MA, et al. Genetic radiotherapy overcomes tumor resistance to cytotoxic agents. Cancer Res 1995;55:5561–5

    PubMed  Google Scholar 

  23. Hallahan DE, Spriggs DR, Beckett MA, et al. Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation. Proc Natl Acad Sci U S A 1989;86:10104–7

    PubMed  Google Scholar 

  24. Sugarman BJ, Aggarwal BB, Hass PE, et al. Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science 1985;230:943–5

    Google Scholar 

  25. Fransen L, Van der Heyden J, Ruysschaert R, Fiers W. Recombinant tumor necrosis factor: its effect and its synergism with interferon-gamma on a variety of normal and transformed human cell lines. Eur J Cancer Clin Oncol 1986;22:419–26

    Google Scholar 

  26. Chapman PB, Lester TJ, Casper ES, et al. Clinical pharmacology of recombinant human tumor necrosis factor in patients with advanced cancer. J Clin Oncol 1987;5:1942–51

    PubMed  Google Scholar 

  27. Spriggs DR, Sherman ML, Michie H, et al. Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I and pharmacologic study. J Natl Cancer Inst 1988;80:1039–44

    PubMed  Google Scholar 

  28. Hieber U, Heim ME. Tumor necrosis factor for the treatment of malignancies. Oncology 1994;51:142–53

    PubMed  Google Scholar 

  29. Lienard D, Ewalenko P, Delmotte JJ, et al. High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol 1992;10:52–60

    Google Scholar 

  30. Thom AK, Alexander HR, Andrich MP, et al. Cytokine levels and systemic toxicity in patients undergoing isolated limb perfusion with high-dose tumor necrosis factor, interferon gamma, and melphalan. J Clin Oncol 1995;13:264–73

    PubMed  Google Scholar 

  31. Fraker D, Alexander H, Pass H. Biologic therapy with TNF systemic and regional administration. In: DeVita VT, Jr, Hellman S, Rosenberg SA, eds. Biologic Therapy of Cancer. Philadelphia: Lippincott, 1994:62–9.

    Google Scholar 

  32. Marr RA, Hitt M, Muller WJ, et al. Tumour therapy in mice using adenovirus vectors expressing human TNFa. Int J Oncol 1998;12:509–15

    PubMed  Google Scholar 

  33. Rasmussen H, Rasmussen C, Lempicki M, et al. TNFerade biologic: preclinical toxicology of a novel adenovector with a radiation-inducible promoter, carrying the human tumor necrosis factor alpha gene. Cancer Gene Ther 2002;9:951–7

    Google Scholar 

  34. Senzer N, Mani S, Rosemurgy A, et al. TNFerade biologic, an adenovector with radiation-inducible promoter, carrying the human tumor necrosis factor alpha gene: a phase I study in patients with solid tumors. J Clin Oncol 2004;22:592–601

    Article  PubMed  Google Scholar 

  35. Mundt AJ, Vijayakumar S, Nemunaitis J, et al. A phase I trial of TNFerade biologic in patients with soft tissue sarcoma in the extremities. Clin Cancer Res 2004;10:5747–53.

    Google Scholar 

  36. Datta R, Rubin E, Sukhatme V, et al. Ionizing radiation activates transcription of the EGR1 gene via CArG elements. Proc Natl Acad Sci U S A 1992;89:10149–53

    PubMed  Google Scholar 

  37. Vorburger SA, Hunt KK. Adenoviral gene therapy. Oncologist 2002;7:46–59

    Article  Google Scholar 

  38. Brough DE, Lizonova A, Hsu C, et al. A gene transfer vector-cell line system for complete functional complementation of adenovirus early regions E1 and E4. J Virol 1996;70:6497–501

    PubMed  Google Scholar 

  39. Creaven PJ, Plager JE, Dupere S, et al. Phase I clinical trial of recombinant human tumor necrosis factor. Cancer Chemother Pharmacol 1987;20:137–44

    PubMed  Google Scholar 

  40. Talmadge JE, Phillips H, Schneider M, et al. Immunomodulatory properties of recombinant murine and human tumor necrosis factor. Cancer Res 1988;48:544–50

    PubMed  Google Scholar 

  41. Johnson JP. The role of ICAM-1 in tumor development. Chem Immunol 1991;50:143–63

    PubMed  Google Scholar 

  42. Laster SM, Wood JG, Gooding LR. Tumor necrosis factor can induce both apoptotic and necrotic forms of cell lysis. J Immunol 1988;141:2629–34

    PubMed  Google Scholar 

Download references

Acknowledgments

Supported by a grant from GenVec, Inc.

Author information

Authors and Affiliations

  1. Department of Surgery, Sammons Cancer Center of Baylor University Medical Center, Worth Street #420, Dallas, Texas, 75246

    James M. McLoughlin MD, Todd M. McCarty MD & Joseph A. Kuhn MD

  2. Mary Crowley Medical Research Center, Texas Oncology PA, 3500 Gaston Avenue, Dallas, Texas, 75246

    Casey Cunningham MD, Valerie Clark RN, Neil Senzer MD & John Nemunaitis MD

Authors
  1. James M. McLoughlin MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Todd M. McCarty MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Casey Cunningham MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Valerie Clark RN
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Neil Senzer MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John Nemunaitis MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Joseph A. Kuhn MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Todd M. McCarty MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

McLoughlin, J.M., McCarty, T.M., Cunningham, C. et al. TNFerade, an Adenovector Carrying the Transgene for Human Tumor Necrosis Factor α, for Patients With Advanced Solid Tumors: Surgical Experience and Long-Term Follow-Up. Ann Surg Oncol 12, 825–830 (2005). https://doi.org/10.1245/ASO.2005.03.023

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/ASO.2005.03.023

Keywords

Search

Navigation