Adenovirus-mediated delivery of herpes simplex virus thymidine kinase administration improves outcome of recurrent high-grade glioma

Nan Ji, Danhui Weng, Cang Liu, Zheng Gu, Shizhang Chen, Ying Guo, Zhong Fan, Xiao Wang, Jianfei Chen, Yanyan Zhao, Jianfeng Zhou, Jisheng Wang, Ding Ma, Ning Li, Nan Ji, Danhui Weng, Cang Liu, Zheng Gu, Shizhang Chen, Ying Guo, Zhong Fan, Xiao Wang, Jianfei Chen, Yanyan Zhao, Jianfeng Zhou, Jisheng Wang, Ding Ma, Ning Li

Abstract

Background: This randomized, open-label, multicenter, phase II clinical trial was conducted to assess the anti-tumor efficacy and safety of replication-deficient adenovirus mutant thymidine kinase (ADV-TK) in combination with ganciclovir administration in patients with recurrent high-grade glioma (HGG).

Patients and methods: 53 patients with recurrent HGG were randomly allocated to receive intra-arterial cerebral infusion of ADV-TK or conventional treatments. The primary end point was 6-month progression-free survival (PFS-6). Secondary end points included progression-free survival (PFS), overall survival (OS), safety, and clinical benefit. This trial is registered with Clinicaltrials.gov, NCT00870181.

Results: In ADV-TK group, PFS-6 was 54.5%, the median PFS was 29.6 weeks, the median OS was 45.4 weeks, and better survivals were achieved when compared with control group. The one-year PFS and OS were 22.7% and 44.6% in ADV-TK group respectively, and clinical benefit was 68.2%. There are 2 patients alive for more than 4 years without progression in ADV-TK group. In the subgroup of glioblastoma received ADV-TK, PFS-6 was 71.4%, median PFS was 34.9 weeks, median OS was 45.7 weeks respectively, much better than those in control group. The one-year PFS and OS were 35.7% and 50.0% in ADV-TK group respectively. ADV-TK/ganciclovir gene therapy was well tolerated, and no treatment-related severe adverse events were noted.

Conclusion: Our study demonstrated a notable improvement of PFS-6, PFS and OS in ADV-TK treated group, and the efficacy and safety appear to be comparable to other reported treatments used for recurrent HGG. ADV-TK gene therapy is therefore a valuable therapeutic option for recurrent HGG.

Keywords: ADV-TK; gene therapy; glioblastoma; recurrent high-grade glioma.

Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

Figures

Figure 1. CONSORT diagram
Figure 1. CONSORT diagram
Figure 2. Kaplan-Meier plots for Progression-free Survival…
Figure 2. Kaplan-Meier plots for Progression-free Survival (PFS) and Overall Survival (OS)
A. PFS for ADV-TK group versus Control group. B. OS for ADV-TK group versus Control group.
Figure 3. Kaplan-Meier plots for Progression-free Survival…
Figure 3. Kaplan-Meier plots for Progression-free Survival (PFS) and Overall Survival (OS) in GBM subgroup
A. PFS for ADV-TK group versus Control group. B. OS for ADV-TK group versus Control group.

References

    1. National Comprehensive Cancer Network. NCCN Guidelines Version 2.2011: Central Nervous System Cancers. Available at: . Accessed August 16, 2011.
    1. Phase I study of cytokine-gene modified autologous neuroblastoma cells for treatment of relapsed/refractory neuroblastoma. Human Gene Therapy. 1992;3:665–76. doi: 10.1089/hum.1992.3.6-665.
    1. Oldfield EH, Ram Z, Culver KW, Blaese RM, DeVroom HL, Anderson WF. Gene therapy for the treatment of brain tumors using intra-tumoral transduction with the thymidine kinase gene and intravenous ganciclovir. Hum Gene Ther. 1993;4:39–69. doi: 10.1089/hum.1993.4.1-39.
    1. Ram Z, Culver KW, Oshiro EM, Viola JJ, DeVroom HL, Otto E, Long Z, Chiang Y, McGarrity GJ, Muul LM, Katz D, Blaese RM, Oldfield EH. Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells. Nat Med. 1997;3:1354–61.
    1. Klatzmann D, Valéry CA, Bensimon G, Marro B, Boyer O, Mokhtari K, Diquet B, Salzmann JL, Philippon J. A phase I/II study of herpes simplex virus type 1 thymidine kinase “suicide” gene therapy for recurrent glioblastoma. Study Group on Gene Therapy for Glioblastoma. Hum Gene Ther. 1998;9:2595–604. doi: 10.1089/hum.1998.9.17-2595.
    1. Puumalainen AM, Vapalahti M, Agrawal RS, Kossila M, Laukkanen J, Lehtolainen P, Viita H, Paljärvi L, Vanninen R, Ylä-Herttuala S. Beta-galactosidase gene transfer to human malignant glioma in vivo using replication-deficient retroviruses and adenoviruses. Hum Gene Ther. 1998;9:1769–74. doi: 10.1089/hum.1998.9.12-1769.
    1. Sandmair AM, Loimas S, Puranen P, Immonen A, Kossila M, Puranen M, Hurskainen H, Tyynelä K, Turunen M, Vanninen R, Lehtolainen P, Paljärvi L, Johansson R, et al. Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses. Hum Gene Ther. 2000;11:2197–205. doi: 10.1089/104303400750035726.
    1. Immonen A, Vapalahti M, Tyynelä K, Hurskainen H, Sandmair A, Vanninen R, Langford G, Murray N, Ylä-Herttuala S. AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study. Mol Ther. 2004;10:967–72. doi: 10.1016/j.ymthe.2004.08.002.
    1. Westphal M, Ylä-Herttuala S, Martin J, Warnke P, Menei P, Eckland D, Kinley J, Kay R, Ram Z ASPECT Study Group. Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:823–33. doi: 10.1016/S1470-2045(13)70274-2.
    1. Li N, Zhou J, Weng D, Zhang C, Li L, Wang B, Song Y, He Q, Lin D, Chen D, Chen G, Gao Q, Wang S, et al. Adjuvant adenovirus-mediated delivery of herpes simplex virus thymidine kinase administration improves outcome of liver transplantation in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2007;13:5847–54. doi: 10.1158/1078-0432.CCR-07-0499.
    1. Xu F, Li S, Li XL, Guo Y, Zou BY, Xu R, Liao H, Zhao HY, Zhang Y, Guan ZZ, Zhang L. Phase I and biodistribution study of recombinant adenovirus vector-mediated herpes simplex virus thymidine kinase gene and ganciclovir administration in patients with head and neck cancer and other malignant tumors. Cancer Gene Ther. 2009;16:723–30. doi: 10.1038/cgt.2009.19.
    1. Dewey RA, Morrissey G, Cowsill CM, Stone D, Bolognani F, Dodd NJ, Southgate TD, Klatzmann D, Lassmann H, Castro MG, Löwenstein PR. Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: implications for clinical trials. Nat Med. 1999;5:1256–63. doi: 10.1038/15207.
    1. Trask TW, Trask RP, Aguilar-Cordova E, Shine HD, Wyde PR, Goodman JC, Hamilton WJ, Rojas-Martinez A, Chen SH, Woo SL, Grossman RG. Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors. Mol Ther. 2000;1:195–203. doi: 10.1006/mthe.2000.0030.
    1. Judy K, Eck SL. The use of suicide gene therapy for the treatment of malignancies of the brain. In: Lattime EC, Stanton LC, editors. Gene Therapy of Cancer. 2. San Diego: Academic Press; 2002. pp. 505–512.
    1. Germano IM, Fable J, Gultekin SH, Silvers A. Adenovirus/herpes simplex-thymidine kinase/ganciclovir complex: preliminary results of a phase I trial in patients with recurrent malignant gliomas. J Neurooncol. 2003;65:279–89.
    1. Smitt PS, Driesse M, Wolbers J, Kros M, Avezaat C. Treatment of relapsed malignant glioma with an adenoviral vector containing the herpes simplex thymidine kinase gene followed by ganciclovir. Mol Ther. 2003;7:851–58.
    1. Lang FF, Bruner JM, Fuller GN, Aldape K, Prados MD, Chang S, Berger MS, McDermott MW, Kunwar SM, Junck LR, Chandler W, Zwiebel JA, Kaplan RS, et al. Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results. J Clin Oncol. 2003;21:2508–18.
    1. Chiocca EA, Abbed KM, Tatter S, Louis DN, Hochberg FH, Barker F, Kracher J, Grossman SA, Fisher JD, Carson K, Rosenblum M, Mikkelsen T, Olson J, et al. A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. Mol Ther. 2004;10:958–66. doi: 10.1016/j.ymthe.2004.07.021.
    1. Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo T, Hunter WD, Palmer CA, Feigenbaum F, Tornatore C, Tufaro F, Martuza RL. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther. 2000;7:867–74. doi: 10.1038/sj.gt.3301205.
    1. Markert JM, Liechty PG, Wang W, Gaston S, Braz E, Karrasch M, Nabors LB, Markiewicz M, Lakeman AD, Palmer CA, Parker JN, Whitley RJ, Gillespie GY. Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM. Mol Ther. 2009;17:199–207. doi: 10.1038/mt.2008.228.
    1. Rampling R, Cruickshank G, Papanastassiou V, Nicoll J, Hadley D, Brennan D, Petty R, MacLean A, Harland J, McKie E, Mabbs R, Brown M. Toxicity evaluation of replication-competent herpes simplex virus (ICP 34. 5 null mutant 1716) in patients with recurrent malignant glioma. Gene Ther. 2000;7:859–66.
    1. Papanastassiou V, Rampling R, Fraser M, Petty R, Hadley D, Nicoll J, Harland J, Mabbs R, Brown M. The potential for efficacy of the modified (ICP 345(−)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study. Gene Ther. 2002;9:398–406. doi: 10.1038/sj.gt.3301664.
    1. Harrow S, Papanastassiou V, Harland J, Mabbs R, Petty R, Fraser M, Hadley D, Patterson J, Brown SM, Rampling R. HSV1716 injection into the brain adjacent to tumour following surgical resection of high-grade glioma: safety data and long-term survival. Gene Ther. 2004;11:1648–58. doi: 10.1038/sj.gt.3302289.
    1. Ropper AH. Management of raised intracranial pressure and hyperosmolar therapy. Pract Neurol. 2014;14:152–8. doi: 10.1136/practneurol-2014-000811.
    1. Stocchetti N, Maas AI. Traumatic intracranial hypertension. N Engl J Med. 2014;370:2121–30. doi: 10.1056/NEJMra1208708.
    1. Greenwood J, Luthert PJ, Pratt OE, Lantos PL. Hyperosmolar opening of the blood-brain barrier in the energy-depleted rat brain. Part 1. Permeability studies. J Cereb Blood Flow Metab. 1988;8:9–15.
    1. Neuwelt EA, Goldman DL, Dahlborg SA, Crossen J, Ramsey F, Roman-Goldstein S, Braziel R, Dana B. Primary CNS lymphoma treated with osmotic blood-brain barrier disruption: prolonged survival and preservation of cognitive function. J Clin Oncol. 1991;9:1580–90.
    1. Gao Q, Chen C, Ji T, Wu P, Han Z, Fang H, Li F, Liu Y, Hu W, Gong D, Zhang Z, Wang S, Zhou J, et al. A systematic comparison of the anti-tumoural activity and toxicity of the three Adv-TKs. PLoS One. 2014;9:e94050. doi: 10.1371/journal.pone.0094050.
    1. Han Z, Hong Z, Gao Q, Chen C, Hao Z, Ji T, Hu W, Yan Y, Feng J, Liao S, Wu P, Wang D, Wang S, et al. A potent oncolytic adenovirus selectively blocks the STAT3 signaling pathway and potentiates cisplatin antitumor activity in ovarian cancer. Hum Gene Ther. 2012;23:32–45. doi: 10.1089/hum.2011.101.
    1. Chen C, Fang H, Han Z, Ye F, Ji T, Gong D, Li F, Zhou J, Ma D, Gao Q. Novel permissive murine immunocompetent orthotopic colon carcinoma model for comparison of the antitumoral and safety profiles of three Adv-TKs. Gene Ther. 2014;21:975–83. doi: 10.1038/gt.2014.118.

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