Summary
Glioblastoma multiforme (GBM) is an incurable brain tumor resistant to standard treatment modalities such as surgery, radiation, and chemotherapy. Since recurrent GBM tends to develop predominantly within the infiltrative rim surrounding the primary tumor focus, novel therapy strategies need in addition to focal tumor destruction to target this somewhat diffuse area.
This is a phase I/II clinical study in adult patients with recurrent GBM which is aimed at evaluating biological safety, maximum tolerated dose, and antitumor efficacy of a genetically modified replication-disabled Semliki forest virus vector (SFV) carrying the human interleukin 12 (IL-12) gene and encapsulated in cationic liposomes (LSFV-IL12). The vector will be administered in doses of 1 × 107 − 1 × 109 infectious particles by continuous intratumoral infusion, thus exploiting the advantages of convection-enhanced drug delivery in the brain. The present protocol is also designed to investigate systemic and local immune response and to identify factors predicting tumor response to LSFV-IL12 therapy, such as volume of extracellular space of the tumor, volume of contrast enhancing lesion, and immune status of the patients.
SFV, an insect alphavirus, infects mitotic and non-mitotic cells and triggers apoptosis in tumor cells within 48–72 h. Preclinical work with the LSFV-IL12 vector in breast and prostate cancer animal models demonstrated its biosafety and some antitumor efficacy. An ongoing phase I clinical study in patients with melanoma and renal cell carcinoma seems also to confirm the biosafety of intravenously administered vectors.
This protocol will be the first study of SFV-IL12 therapy of human recurrent GBM.
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References
Black PM: Surgery for cerebral gliomas: past, present, and future. Clin Neurosurg 47: 21–45, 2000
Salford LG, Brun A, Nirfalk S: Ten-year survival among patients with supratentorial astrocytomas grade III and IV. J Neurosurg 69: 506–509, 1988
Shapiro WR: Therapy of adult malignant brain tumors: what have the clinical trials taught us? Semin Oncol 13: 38–45, 1986
Ammirati M, Galicich JH, Arbit E, Liao Y: Reoperation in the treatment of recurrent intracranial malignant gliomas. Neurosurgery 21: 607–614, 1987
Rajan B, Ross G, Lim CC, Ashley S, Goode D, Traish D, Brada M: Survival in patients with recurrent glioma as a measure of treatment efficacy: prognostic factors following nitrosourea chemotherapy. Eur J Cancer 12: 1809–1815, 1994
Mach N, Dranoff G: Cytokine-secreting tumor cell vaccines. Curr Opin Immunol 12: 571–575, 2000
Niranjan A, Moriuchi S, Lunsford LD, Kondziolka D, Flickinger JC, Fellows W, Rajendiran S, Tamura M, Cohen JB, Glorioso JC: 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 2: 114–120, 2000
Mackensen A, Lindemann A, Martelsmann R: Immuno-stimulatory cytokines in somatic cells and gene therapy of cancer. Cytokine Growth Factor Rev 8: 119–128, 1997
Qian HN, Liu GZ, Cao SJ, Feng J, Ye X: Experimental study of ovarian carcinoma vaccine modified by human B7-1 and IFN-gamma genes. Int J Gynecol Cancer 12: 80–85, 2002
Boulikas T: Status of gene therapy in 1997: molecular mechanisms, disease targets, and clinical applications. Gene Ther Mol Biol 1: 1–172, 1998
Wigginton JM, Gruys E, Geiselhart L, Subleski J, Komschlies KL, Park JW, Wiltrout TA, Nagashima K, Back TC, Wiltrout RH: IFN-gamma and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy. J Clin Invest 108: 51–62, 2001
Colombo MP, Trinchieri G: Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev 13: 155–168, 2002
Liu Y, Ehtesham M, Samoto K, Wheeler CJ, Thompson RC, Villarreal LP, Black KL, Yu JS:In situ adenoviral interleukin 12 gene transfer confers potent and long-lasting cytotoxic immunity in glioma. Cancer Gene Ther 9: 9–15, 2002
Trinchieri G, Scott P: Interleukin-12: basic principles and clinical applications. Curr Top Microbiol Immunol 238: 57–78, 1999
Asselin-Paturel C, Lassau N, Guinebretiere JM, Zhang J, Gay F, Bex F, Hallez S, Leclere J, Peronneau P, Mami-Chouaib F, Chouaib S: Transfer of the murine interleukin-12 genein vivo by a Semliki forest virus vector induces B16 tumor regression through inhibition of tumor blood vessel formation monitored by Doppler ultrasonography. Gene Ther 6: 606–615, 1999
Wolf SF, Lee K, Swiniarski H, O’Toole M, Sturmhoefel K: Cytokines and cancer immunotherapy. Immunol Invest 29: 143–146, 2000
Hiscox S, Jiang WG: Regulation of endothelial CD44 expression and endothelium-tumour cell interactions by hepatocyte growth factor/scatter factor. Biochem Biophys Res Commun 233: 1–5, 1997
Salgaller ML, Lodge PA: Use of cellular and cytokine adjuvants in the immunotherapy of cancer. J Surg Oncol 68: 122–138, 1998
Smyth MJ, Godfrey DI, Trapani JA: A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol 2: 293–299, 2001
Yamanaka R, Zullo SA, Tanaka R, et al.: Induction of a therapic antitumor immunological response by intratumoral injection of genetically engineered Semliki forest virus to produce IL-12. Neurosurg Focus 9: 1–6, 2000
Lundstrom K, Schweitzer C, Richards JG, Ehrengruber MU, Jenck F, Mülhardt C: Semliki forest virus vectors forin vitro andin vivo applications. Gene Ther Mol Biol 4: 23–31, 1999
Lundstrom K: Novel developments for applications of alphavirus vectors in gene therapy. Gene Ther Mol Biol 6: 25–31, 2001
Lundstrom K: Alphavirus vectors: applications for DNA vaccine production and gene expression. Intervirology 43: 247–257, 2000
Hardy PA, Mazzini MJ, Schweitzer C, Lundstrom K, Glode LM: Recombinant Semliki forest virus infects and kills human prostate cancer cell lines and prostatic duct epithelial cellsex vivo. Int J Mol Med 5: 241–245, 2000
Murphy A-M, Morris-Downes MM, Sheahan BJ, Atkins GJ: Inhibition of human lung carcinoma cell growth by apoptosis induction using Semliki forest virus recombinant particles. Gene Ther 7: 1477–1482, 2000
Lundstrom K, Richards JG, Pink JR, Jenck F: Efficientin vivo expression of a reporter gene in rat brain after injection of recombinant replication-deficient Semliki forest virus. Gene Ther Mol Biol 3: 15–23, 1999
Yamanaka R, Zullo SA, Tanaka R, Blaese M, Xanthopoulos KG: Enhancement of antitumor immune response in glioma models in mice by genetically modified dendritic cells pulsed with Semliki forest virus-mediated complementary DNA. J Neurosurg 94: 474–481, 2001
Colmenero P, Liljeström P, Jondal M: Induction of P185 tumor immunity by recombinant Semliki forest virus expressing the P1A gene. Gene Ther 6: 1728–1733, 1999
Ying H, Zaks TZ, Wang RF, Irvine KR, Kammula US, Marincola FM, Leitner WW, Restifo NP: Cancer therapy using a self-replicating RNA vaccine. Nat Med 5: 823–827, 1999
Daemen T, Pries F, Bungener L, Kraak M, Regts J, Wilschut J: Genetic immunization against cervical carcinoma: induction of cytotoxic T lymphocyte activity with a recombinant alphavirus vector expressing human papillomavirus type 16E6 and E7. Gene Ther 7: 1859–1866, 2000
Atkins GJ, Sheahan BJ, Liljestrom P: Manipulation of the Semliki forest virus genome and its potential for vaccine construction. Mol Biotechnol 5: 33–38, 1996
Martin F, Boulikas T: The challenge of liposomes in gene therapy. Gene Ther Mol Biol 1: 173–214, 1998
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Ren, H., Boulikas, T., Söling, A. et al. Immunogene therapy of recurrent glioblastoma multiforme with a liposomally encapsulated replication-incompetent Semliki forest virus vector carrying the human interleukin-12 gene — a phase I/II clinical protocol. J Neuro-Oncol 64, 147–154 (2003). https://doi.org/10.1007/BF02700029
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DOI: https://doi.org/10.1007/BF02700029