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 a TGF-β antisense-modified tumor cell vaccine in patients with advanced glioma

Cancer Gene Therapy volume 13, pages 1052–1060 (2006)Cite this article

Abstract

We performed a phase I clinical trial in grade IV astrocytoma to assess the safety of a whole-cell vaccine comprising autologous tumor cells genetically modified by a transforming growth factor-β2 (TGF-β2) antisense vector. Blocking secretion of the immunosuppressive molecule TGF-β in this manner should inhibit one of the major mechanisms by which tumor cells evade immune surveillance and should lead to clinically effective antitumor immunity. Six patients with progressive WHO grade IV astrocytoma were enrolled in the trial. Patients received 2–7 subcutaneous injections of 5 × 106–2 × 107 autologous tumor cells per injection. TGF-β2 secretion by the tumor cells used to vaccinate patients was inhibited by 53–98%. Treatment was well tolerated with only low-grade, transient treatment-related toxicities reported. Two patients had partial regressions and two had stable disease following therapy. The overall median survival was 68 weeks. Median survival of the responding patients was 78 weeks, compared to a historic value of 47 weeks for glioma patients treated conventionally. There were indications of humoral and cellular immunity induced by the vaccine. These findings support further clinical evaluation of vaccines comprised of TGF-β antisense-modified tumor cells.

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
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Legler JM, Ries LA, Smith MA, Warren JL, Heineman EF, Kaplan RS et al. Cancer surveillance series (corrected): brain and other central nervous system cancers: recent trends in incidence and mortality. J Natl Cancer Inst 1999; 91: 1382–1390.

    Article  CAS  PubMed  Google Scholar 

  2. Jukich PJ, McCarthy BJ, Surawicz TS, Freels S, Davis FG . Trends in incidence of primary brain tumors in the United States, 1985–1994. Neuro-oncology 2001; 3: 141–151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Black KL, Emerick T, Hoh C, Hawkins RA, Mazziotta J, Becker DP . Thallium-201 SPECT and positron emission tomography equal predictors of glioma grade and recurrence. Neurol Res 1994; 16: 93–96.

    Article  CAS  PubMed  Google Scholar 

  4. Scott CB, Scarantino C, Urtasun R, Movsas B, Jones CU, Simpson JR et al. Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90-06. Int J Radiat Oncol Biol Phys 1998; 40: 51–55.

    Article  CAS  PubMed  Google Scholar 

  5. Glioma Meta-analysis Trialists (GMT) Group. Chemotherapy for high-grade glioma. Cochrane Database Syst Rev 2002; 3: CD003913-.

  6. McLendon RE, Halperin EC . Is the long-term survival of patients with intracranial glioblastoma multiforme overstated? Cancer 2003; 98: 1745–1748.

    Article  PubMed  Google Scholar 

  7. Padma MV, Said S, Jacobs M, Hwang DR, Dunigan K, Satter M et al. Prediction of pathology and survival by FDG PET in gliomas. J Neurooncol 2003; 64: 227–237.

    Article  CAS  PubMed  Google Scholar 

  8. Constam DB, Philipp J, Malipiero UV, ten Dijke P, Schachner M, Fontana A . Differential expression of transforming growth factor-beta 1, -beta 2, and -beta 3 by glioblastoma cells, astrocytes, and microglia. J Immunol 1992; 148: 1404–1410.

    CAS  PubMed  Google Scholar 

  9. Fakhrai H, Gramatikova S, Safaei R . Downregulation of transforming growth factor-beta as therapeutic approach for brain tumors. In: Liau LM, Cloughsey T, Becker DP, Bigner DD (eds). Brain Tumor Immunology. Humana Press: Totowa, 2000, pp 289–305.

    Chapter  Google Scholar 

  10. Platten M, Wick W, Weller M . Malignant glioma biology: role for TGF-beta in growth, motility, angiogenesis, and immune escape. Microsc Res Tech 2001; 52: 401–410.

    Article  CAS  PubMed  Google Scholar 

  11. Luo JS, Kammerer R, von Kleist S . Comparison of the effects of immunosuppressive factors from newly established colon carcinoma cell cultures on human lymphocyte proliferation and cytokine secretion. Tumour Biol 2000; 21: 11–20.

    Article  CAS  PubMed  Google Scholar 

  12. Ordemann J, Jacobi CA, Braumann C, Schwenk W, Volk HD, Muller JM . Immunomodulatory changes in patients with colorectal cancer. Int J Colorectal Dis 2002; 17: 37–41.

    Article  CAS  PubMed  Google Scholar 

  13. Konno H, Baba M, Shoji T, Ohta M, Suzuki S, Nakamura S . Cyclooxygenase-2 expression correlates with uPAR levels and is responsible for poor prognosis of colorectal cancer. Clin Exp Metast 2002; 19: 527–534.

    Article  CAS  Google Scholar 

  14. Fischer JR, Schindel M, Stein N, Lahm H, Gallati H, Krammer PH et al. Selective suppression of cytokine secretion in patients with small-cell lung cancer. Ann Oncol 1995; 6: 921–926.

    Article  CAS  PubMed  Google Scholar 

  15. Dix AR, Brooks WH, Roszman TL, Morford LA . Immune defects observed in patients with primary malignant brain tumors. J Neuroimmunol 1999; 100: 216–232.

    Article  CAS  PubMed  Google Scholar 

  16. Shim KS, Kim KH, Han WS, Park EB . Elevated serum levels of transforming growth factor-beta1 in patients with colorectal carcinoma: its association with tumor progression and its significant decrease after curative surgical resection. Cancer 1999; 85: 554–561.

    Article  CAS  PubMed  Google Scholar 

  17. Roszman T, Elliott L, Brooks W . Modulation of T-cell function by gliomas. Immunol Today 1991; 12: 370–374.

    Article  CAS  PubMed  Google Scholar 

  18. Fakhrai H, Dorigo O, Shawler DL, Lin H, Mercola D, Black KL et al. Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy. Proc Natl Acad Sci USA 1996; 93: 2909–2914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sobol RE, Fakhrai H, Shawler D, Gjerset R, Dorigo O, Carson C et al. Interleukin-2 gene therapy in a patient with glioblastoma. Gene Therapy 1995; 2: 164–167.

    CAS  PubMed  Google Scholar 

  20. Sobol RE, Shawler DL, Carson C, Van Beveren C, Mercola D, Fakhrai H et al. Interleukin 2 gene therapy of colorectal carcinoma with autologous irradiated tumor cells and genetically engineered fibroblasts: a phase I study. Clin Cancer Res 1999; 5: 2359–2365.

    CAS  PubMed  Google Scholar 

  21. Davis FG, Kupelian V, Freels S, McCarthy B, Surawicz T . Prevalence estimates for primary brain tumors in the United States by behavior and major histology groups. Neuro-oncology 2001; 3: 152–158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sampson JH, Archer GE, Ashley DM, Fuchs HE, Hale LP, Dranoff G et al. Subcutaneous vaccination with irradiated, cytokine-producing tumor cells stimulates CD8+ cell-mediated immunity against tumors located in the ‘immunologically privileged’ central nervous system. Proc Natl Acad Sci USA 1996; 93: 10399–10404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hoover Jr HC, Surdyke M, Dangel RB, Peters LC, Hanna Jr MG . Delayed cutaneous hypersensitivity to autologous tumor cells in colorectal cancer patients immunized with an autologous tumor cell: bacillus Calmette–Guerin vaccine. Cancer Res 1984; 44: 1671–1676.

    PubMed  Google Scholar 

  24. Fakhrai H, Shawler DL, Gjerset R, Naviaux RK, Koziol J, Royston I et al. Cytokine gene therapy with interleukin-2-transduced fibroblasts: effects of IL-2 dose on anti-tumor immunity. Hum Gene Ther 1995; 6: 591–601.

    Article  CAS  PubMed  Google Scholar 

  25. Watanabe Y, Kuribayashi K, Miyatake S, Nishihara K, Nakayama EL, Taniyama T et al. Exogenous expression of mouse interferon gamma cDNA in mouse neuroblastoma C1300 cells results in reduced tumorigenicity by augmented anti-tumor immunity. Proc Natl Acad Sci USA 1989; 86: 9456–9460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tepper RI, Pattengale PK, Leder P . Murine interleukin-4 displays potent anti-tumor activity in vivo. Cell 1989; 57: 503–512.

    Article  CAS  PubMed  Google Scholar 

  27. Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 1993; 90: 3539–3543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sulitzeanu D . Immunosuppressive factors in human cancer. Adv Cancer Res 1993; 60: 247–267.

    Article  CAS  PubMed  Google Scholar 

  29. Miescher S, Whiteside TL, de Tribolet N, von FV . In situ characterization, clonogenic potential, and antitumor cytolytic activity of T lymphocytes infiltrating human brain cancers. J Neurosurg 1988; 68: 438–448.

    Article  CAS  PubMed  Google Scholar 

  30. Hirte H, Clark DA . Generation of lymphokine-activated killer cells in human ovarian carcinoma ascitic fluid: identification of transforming growth factor-beta as a suppressive factor. Cancer Immunol Immunother 1991; 32: 296–302.

    Article  CAS  PubMed  Google Scholar 

  31. Naganuma H, Sasaki A, Satoh E, Nagasaka M, Nakano S, Isoe S et al. Transforming growth factor-beta inhibits interferon-gamma secretion by lymphokine-activated killer cells stimulated with tumor cells. Neurol Med Chir (Tokyo) 1996; 36: 789–795.

    Article  CAS  Google Scholar 

  32. Kobie JJ, Wu RS, Kurt RA, Lou S, Adelman MK, Whitesell LJ et al. Transforming growth factor beta inhibits the antigen-presenting functions and antitumor activity of dendritic cell vaccines. Cancer Res 2003; 63: 1860–1864.

    CAS  PubMed  Google Scholar 

  33. Kao JY, Gong Y, Chen CM, Zheng QD, Chen JJ . Tumor-derived TGF-Beta reduces the efficacy of dendritic cell/tumor fusion vaccine. J Immunol 2003; 170: 3806–3811.

    Article  CAS  PubMed  Google Scholar 

  34. Hirte HW, Clark DA, O'Connell G, Rusthoven J, Mazurka J . Reversal of suppression of lymphokine-activated killer cells by transforming growth factor-beta in ovarian carcinoma ascitic fluid requires interleukin-2 combined with anti-CD3 antibody. Cell Immunol 1992; 142: 207–216.

    Article  CAS  PubMed  Google Scholar 

  35. Sobol RE, Shawler DL, Garrett MA, Van Beveren C, Trojan J, Trauger RJ et al. Induction of T cell responses against autologous tumor following treatment of colorectal carcinoma patients with an IL-2/CD80 genetically modified allogeneic tumor cell vaccine. Proc Am Assoc Cancer Res 2001; 42: 684.

    Google Scholar 

  36. Eaton JD, Perry MJ, Nicholson S, Guckian M, Russell N, Whelan M et al. Allogeneic whole-cell vaccine: a phase I/II study in men with hormone-refractory prostate cancer. BJU Int 2002; 89: 19–26.

    Article  CAS  PubMed  Google Scholar 

  37. Jaffee EM, Hruban RH, Biedrzycki B, Laheru D, Schepers K, Sauter PR et al. Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol 2001; 19: 145–156.

    Article  CAS  PubMed  Google Scholar 

  38. Maio M, Fonsatti E, Lamaj E, Altomonte M, Cattarossi I, Santantonio C et al. Vaccination of stage IV patients with allogeneic IL-4- or IL-2-gene-transduced melanoma cells generates functional antibodies against vaccinating and autologous melanoma cells. Cancer Immunol Immunother 2002; 51: 9–14.

    Article  CAS  PubMed  Google Scholar 

  39. Osanto S, Schiphorst PP, Weijl NI, Dijkstra N, Van Wees A, Brouwenstein N et al. Vaccination of melanoma patients with an allogeneic, genetically modified interleukin 2-producing melanoma cell line. Hum Gene Ther 2000; 11: 739–750.

    Article  CAS  PubMed  Google Scholar 

  40. Chang AE, Li Q, Bishop DK, Normolle DP, Redman BD, Nickoloff BJ . Immunogenetic therapy of human melanoma utilizing autologous tumor cells transduced to secrete granulocyte-macrophage colony-stimulating factor. Hum Gene Ther 2000; 11: 839–850.

    Article  CAS  PubMed  Google Scholar 

  41. Dillman RO, Beutel LD, Barth NM, de Leon C, O'Connor AA, DePriest C et al. Irradiated cells from autologous tumor cell lines as patient-specific vaccine therapy in 125 patients with metastatic cancer: induction of delayed-type hypersensitivity to autologous tumor is associated with improved survival. Cancer Biother Radiopharm 2002; 17: 51–66.

    Article  PubMed  Google Scholar 

  42. Simons JW, Mikhak B, Chang JF, DeMarzo AM, Carducci MA, Lim M et al. Induction of immunity to prostate cancer antigens: results of a clinical trial of vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer. Cancer Res 1999; 59: 5160–5168.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Helen Lin, MD and Ali Haghighi for their helpful contributions to this project. This work was partially supported by grants no. CA96025 and CA105964 from the National Institutes of Health, Bethesda, MD to NovaRx Corporation, San Diego, CA.

Author information

Authors and Affiliations

  1. Advanced Biotherapies, Inc., San Diego, CA, USA

    H Fakhrai & D L Shawler

  2. Wallace-Kettering Neuroscience Institute and Nuclear Medicine/PET, Kettering Medical Center, Kettering, OH, USA

    J C Mantil, G L Nicholson, C S Murphy-Satter & J Ruppert

  3. NovaRx Corporation, San Diego, CA, USA

    L Liu

Authors
  1. H Fakhrai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J C Mantil
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G L Nicholson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C S Murphy-Satter
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Ruppert
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D L Shawler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D L Shawler.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fakhrai, H., Mantil, J., Liu, L. et al. Phase I clinical trial of a TGF-β antisense-modified tumor cell vaccine in patients with advanced glioma. Cancer Gene Ther 13, 1052–1060 (2006). https://doi.org/10.1038/sj.cgt.7700975

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700975

Keywords

This article is cited by

Search

Advanced search

Quick links