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Treatment of intracranial glioma with in situ interferon-gamma and tumor necrosis factor-alpha gene transfer

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Abstract

Interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) are potent immunostimulatory cytokines with demonstrated tumoricidal effects in a variety of cancers. With the aim of investigating their ability to generate antitumor immune responses in malignant brain tumors, we describe the use of in situ adenoviral-mediated IFNγ and TNFα gene transfer in glioma-bearing rodents. Survival was prolonged in mice treated with AdmIFNγ or AdTNFα compared to AdLacZ- and saline-inoculated controls, and AdmIFNγ- or AdTNFα-treated animals revealed significantly smaller tumors. These effects were accompanied by significant up-regulation of tumor MHC-I expression in AdmIFNγ-inoculated animals, and of MHC-II in AdTNFα-treated tumors. Significantly enhanced intratumoral infiltration with CD4+ and CD8+ T cells was visible in animals treated with AdmIFNγ, AdTNFα, or a combination of AdmIFNγ and AdTNFα. In addition, AdTNFα therapy down-regulated the expression of endothelial Fas ligand, a cell membrane protein implicated as a contributor to immune privilege in cancer. These findings demonstrate the effectiveness of local IFNγ and TNFα gene transfer as a treatment strategy for glioma and illustrate possible physiological pathways responsible for the therapeutic benefit observed.

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References

  1. Zou JP, Yamamoto N, Fujii T et al. Systemic administration of rIL-12 induces complete tumor regression and protective immunity: response is correlated with a striking reversal of suppressed IFN-gamma production by anti-tumor T-cells Int Immunol 1995 7: 1135–1145

    Article  CAS  PubMed  Google Scholar 

  2. Thomas GR, Chen Z, Enamorado I, Bancroft C, Van Waes C . IL-12– and IL-2–induced tumor regression in a new murine model of oral squamous-cell carcinoma is promoted by expression of the CD80 co-stimulatory molecule and interferon-gamma Int J Cancer 2000 86: 368–374

    Article  CAS  PubMed  Google Scholar 

  3. Leonard JP, Sherman ML, Fisher GL et al. Effects of single-dose interleukin-12 exposure on interleukin-12–associated toxicity and interferon-gamma production Blood 1997 90: 2541–2548

    CAS  PubMed  Google Scholar 

  4. Lauta VM . Pharmacological elements in clinical application of synthetic peptides Fundam Clin Pharmacol 2000 14: 425–442

    Article  CAS  PubMed  Google Scholar 

  5. Mahaley MS Jr, Brooks WH, Roszman TL, Bigner DD, Dudka L, Richardson S . Immunobiology of primary intracranial tumors: Part 1. Studies of the cellular and humoral general immune competence of brain-tumor patients J Neurosurg 1977 46: 467–476

    Article  PubMed  Google Scholar 

  6. Roszman TL, Brooks WH, Elliott LH . Inhibition of lymphocyte responsiveness by a glial tumor cell–derived suppressive factor J Neurosurg 1987 67: 874–879

    Article  CAS  PubMed  Google Scholar 

  7. Morford LA, Elliott LH, Carlson SL, Brooks WH, Roszman TL . T cell receptor–mediated signaling is defective in T cells obtained from patients with primary intracranial tumors J Immunol 1997 159: 4415–4425

    CAS  PubMed  Google Scholar 

  8. Barba D, Saris SC, Holder C, Rosenberg SA, Oldfield EH . Intratumoral LAK cell and interleukin-2 therapy of human gliomas J Neurosurg 1989 70: 175–182

    Article  CAS  PubMed  Google Scholar 

  9. Merchant RE, McVicar DW, Merchant LH, Young HF . Treatment of recurrent malignant glioma by repeated intracerebral injections of human recombinant interleukin-2 alone or in combination with systemic interferon-alpha. Results of a phase I clinical trial J Neuro-Oncol 1992 12: 75–83

    Article  CAS  Google Scholar 

  10. Yu JS, Wei MX, Chiocca EA, Martuza RL, Tepper RI . Treatment of glioma by engineered interleukin 4–secreting cells Cancer Res 1993 53: 3125–3128

    CAS  PubMed  Google Scholar 

  11. Okada H, Villa L, Attanucci J et al. Cytokine gene therapy of gliomas: effective induction of therapeutic immunity to intracranial tumors by peripheral immunization with interleukin-4 transduced glioma cells Gene Ther 2001 8: 1157–1166

    Article  CAS  PubMed  Google Scholar 

  12. Jean WC, Spellman SR, Wallenfriedman MA, Hall WA, Low WC . Interleukin-12–based immunotherapy against rat 9L glioma Neurosurgery 1998 42: 850–856

    Article  CAS  PubMed  Google Scholar 

  13. Liu Y, Ehtesham M, Samoto K et al. In situ adenoviral interleukin 12 gene transfer confers potent and long-lasting cytotoxic immunity in glioma Cancer Gene Ther 2002 9: 9–15

    Article  CAS  PubMed  Google Scholar 

  14. Saiki I, Sato K, Yoo YC et al. Inhibition of tumor-induced angiogenesis by the administration of recombinant interferon-gamma followed by a synthetic lipid-A subunit analogue (GLA-60) Int J Cancer 1992 51: 641–645

    Article  CAS  PubMed  Google Scholar 

  15. Sato N, Fukuda K, Nariuchi H, Sagara N . Tumor necrosis factor inhibiting angiogenesis in vitro J Natl Cancer Inst 1987 79: 1383–1391

    CAS  PubMed  Google Scholar 

  16. Old LJ . Tumor necrosis factor Science 1985 230: 630–634

    Article  CAS  PubMed  Google Scholar 

  17. Polunovsky VA, Wendt CH, Ingbar DH, Peterson MS, Bitterman PB . Induction of endothelial cell apoptosis by TNF alpha: modulation by inhibitors of protein synthesis Exp Cell Res 1994 214: 584–594

    Article  CAS  PubMed  Google Scholar 

  18. Seder RA, Paul WE . Acquisition of lymphokine-producing phenotype by CD4+ T cells Annu Rev Immunol 1994 12: 635–673

    Article  CAS  PubMed  Google Scholar 

  19. Sidky YA, Borden EC . Inhibition of angiogenesis by interferons: effects on tumor- and lymphocyte-induced vascular responses Cancer Res 1987 47: 5155–5161

    CAS  PubMed  Google Scholar 

  20. Dufour A, Corsini E, Gelati M et al. Modulation of ICAM-1, VCAM-1 and HLA-DR by cytokines and steroids on HUVECs and human brain endothelial cells J Neurol Sci 1998 157: 117–121

    Article  CAS  PubMed  Google Scholar 

  21. Krakauer T, Vilcek J, Oppenheim JJ . Proinflammatory cytokines, TNF and IL-1 families, chemokines, TGF-β, and others In: Paul WE, ed Fundamental Immunology Philadelphia, PA: Lippincott-Raven 1999 775–812

    Google Scholar 

  22. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B . An endotoxin-induced serum factor that causes necrosis of tumors Proc Natl Acad Sci USA 1975 72: 3666–3670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Akbasak A, Oldfield EH, Saris SC . Expression and modulation of major histocompatibility antigens on murine primary brain tumor in vitro J Neurosurg 1991 75: 922–929

    Article  CAS  PubMed  Google Scholar 

  24. Saleh M, Jonas NK, Wiegmans A, Stylli SS . The treatment of established intracranial tumors by in situ retroviral IFN-gamma transfer Gene Ther 2000 7: 1715–1724

    Article  CAS  PubMed  Google Scholar 

  25. Fathallah-Shaykh HM, Zhao LJ, Kafrouni AI, Smith GM, Forman J . Gene transfer of IFN-gamma into established brain tumors represses growth by antiangiogenesis J Immunol 2000 164: 217–222

    Article  CAS  PubMed  Google Scholar 

  26. Niranjan A, Moriuchi S, Lunsford LD et al. Effective treatment of experimental glioblastoma by HSV vector–mediated TNF alpha and HSV-tk gene transfer in combination with radiosurgery and ganciclovir administration Mol Ther 2000 2: 114–120

    Article  CAS  PubMed  Google Scholar 

  27. Walsh K, Sata M . Is extravasation a Fas-regulated process? Mol Med Today 1999 5: 61–67

    Article  CAS  PubMed  Google Scholar 

  28. Schaack J, Langer S, Guo X . Efficient selection of recombinant adenoviruses by vectors that express beta-galactosidase J Virol 1995 69: 3920–3923

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu Y, Hashizume K, Samoto K et al. Repeated, short-term ischemia augments bradykinin-mediated opening of the blood–tumor barrier in rats with RG2 glioma Neurol Res 2001 23: 631–640

    Article  CAS  PubMed  Google Scholar 

  30. Samoto K, Ehtesham M, Perng GC et al. A herpes simplex virus type 1 mutant with γ34.5 and LAT deletions effectively oncolyses human U87 glioblastomas in nude mice Neurosurgery 2002 3: 599–605

    Google Scholar 

  31. Carpentier AF, Xie J, Mokhtari K, Delattre JY . Successful treatment of intracranial gliomas in rat by oligodeoxynucleotides containing CpG motifs Clin Cancer Res 2000 6: 2469–2473

    CAS  PubMed  Google Scholar 

  32. Black KL, Chen K, Becker DP, Merrill JE . Inflammatory leukocytes associated with increased immunosuppression by glioblastoma J Neurosurg 1992 77: 120–126

    Article  CAS  PubMed  Google Scholar 

  33. Roussel E, Gingras MC, Grimm EA, Bruner JM, Moser RP . Predominance of a type 2 intratumoural immune response in fresh tumour-infiltrating lymphocytes from human gliomas Clin Exp Immunol 1996 105: 344–352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Maxwell M, Galanopoulos T, Neville-Golden J, Antoniades HN . Effect of the expression of transforming growth factor-beta 2 in primary human glioblastomas on immunosuppression and loss of immune surveillance J Neurosurg 1992 76: 799–804

    Article  CAS  PubMed  Google Scholar 

  35. Zou JP, Morford LA, Chougnet C et al. Human glioma–induced immunosuppression involves soluble factor(s) that alters monocyte cytokine profile and surface markers J Immunol 1999 162: 4882–4892

    CAS  PubMed  Google Scholar 

  36. Saas P, Walker PR, Hahne M et al. Fas ligand expression by astrocytoma in vivo: maintaining immune privilege in the brain? J Clin Invest 1997 99: 1173–1178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Benedetti S, Bruzzone MG, Pollo B et al. Eradication of rat malignant gliomas by retroviral-mediated, in vivo delivery of the interleukin 4 gene Cancer Res 1999 59: 645–652

    CAS  PubMed  Google Scholar 

  38. Baher AG, Andres ML, Folz-Holbeck J, Cao JD, Gridley DS . A model using radiation and plasmid-mediated tumor necrosis factor-alpha gene therapy for treatment of glioblastomas Anticancer Res 1999 19: 2917–2924

    CAS  PubMed  Google Scholar 

  39. Staba MJ, Mauceri HJ, Kufe DW, Hallahan DE, Weichselbaum RR . Adenoviral TNF-alpha gene therapy and radiation damage tumor vasculature in a human malignant glioma xenograft Gene Ther 1998 5: 293–300

    Article  CAS  PubMed  Google Scholar 

  40. Rabinowich H, Reichert TE, Kashii Y, Gastman BR, Bell MC, Whiteside TL . Lymphocyte apoptosis induced by Fas ligand–expressing ovarian carcinoma cells. Implications for altered expression of T cell receptor in tumor-associated lymphocytes J Clin Invest 1998 101: 2579–2588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hahne M, Rimoldi D, Schroter M et al. Melanoma cell expression of Fas (Apo-1/CD95) ligand: implications for tumor immune escape Science 1996 274: 1363–1366

    Article  CAS  PubMed  Google Scholar 

  42. O'Connell J, O'Sullivan GC, Collins JK, Shanahan F . The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand J Exp Med 184: 1075–1082

    Article  CAS  Google Scholar 

  43. O'Connell J, Bennett MW, O'Sullivan GC, O'Callaghan J, Collins JK, Shanahan F . Expression of Fas (CD95/APO-1) ligand by human breast cancers: significance for tumor immune privilege Clin Diagn Lab Immunol 1999 6: 457–463

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Bennett MW, O'Connell J, O'Sullivan GC et al. The Fas counterattack in vivo: apoptotic depletion of tumor-infiltrating lymphocytes associated with Fas ligand expression by human esophageal carcinoma J Immunol 1998 160: 5669–5675

    CAS  PubMed  Google Scholar 

  45. Sata M, Walsh K . TNF alpha regulation of Fas ligand expression on the vascular endothelium modulates leukocyte extravasation Nat Med 1998 4: 415–420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported, in part, by NIH Grant NS02232 to John S Yu.

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Authors and Affiliations

  1. Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, California, USA

    Moneeb Ehtesham, Ken Samoto, Peter Kabos, Frank L Acosta, Mervin AR Gutierrez, Keith L Black & John S Yu

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  1. Moneeb Ehtesham
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  2. Ken Samoto
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  3. Peter Kabos
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  7. John S Yu
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Correspondence to John S Yu.

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Ehtesham, M., Samoto, K., Kabos, P. et al. Treatment of intracranial glioma with in situ interferon-gamma and tumor necrosis factor-alpha gene transfer. Cancer Gene Ther 9, 925–934 (2002). https://doi.org/10.1038/sj.cgt.7700516

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  • DOI: https://doi.org/10.1038/sj.cgt.7700516

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