Treatment of Relapsed Malignant Glioma with an Adenoviral Vector Containing the Herpes Simplex Thymidine Kinase Gene Followed by Ganciclovir

doi:doi:10.1016/S1525-0016(03)00100-X

Molecular Therapy (2003) 7, 851–858; doi: 10.1016/S1525-0016(03)00100-X

Treatment of Relapsed Malignant Glioma with an Adenoviral Vector Containing the Herpes Simplex Thymidine Kinase Gene Followed by Ganciclovir

Peter Sillevis Smitt¹, Maarten Driesse², John Wolbers⁴, Max Kros³ and Cees Avezaat²

¹Department of Neurology, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands
²Department of Neurosurgery, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands
³Department of Pathology, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands
⁴Department of Neurosurgery, Free University Medical Center, Amstelveenseweg 641, 1081 JD, Amsterdam, The Netherlands

Correspondence: Peter Sillevis Smitt, Fax: +31-10-463 3208. E-mail: sillevis@neuh.azr.nl

Received 10 January 2002; Accepted 24 February 2003.

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Abstract

Between November 1998 and December 2001, we treated 14 patients with advanced recurrent high-grade gliomas with a total dose of 4.6 $times$ 10⁸, 4.6 $times$ 10⁹, 4.6 $times$ 10¹⁰, or 4.6 $times$ 10¹¹ viral particles (VP) of a replication-incompetent adenoviral vector harboring the herpes simplex virus thymidine kinase gene driven by the adenoviral major late promoter (IG.Ad.MLPI.TK), followed by ganciclovir (GCV) treatment. The VP-to-infectious-unit ratio was 40. The vector was administered by 50 intraoperative wound-bed injections of 0.2 ml each (total volume 10 ml). The study's primary objective was to determine the safety of this treatment and establish the maximum tolerated dose (MTD). Injection of all doses of IG.Ad.MLPI.TK followed by GCV was safely tolerated and MTD was not reached. All patients had recurrence or progression of the tumor 1–24 months (median 3.5 months) after gene therapy. The overall median survival was 4 months. Four patients survived longer than 1 year following gene therapy. One patient is still alive, with histologically confirmed progression of the tumor, 29 months after treatment. Ten patients died within 8 months of treatment, all from progression of the tumor. In 5 patients residual and measurable tumor was visible on the direct (<48 h) postoperative MRI. No objective radiological response was documented on subsequent MRI. None of the patients came to autopsy. In conclusion, the administration of 4.6 $times$ 10¹¹ VP of IG.Ad.MLPI.TK by 50 injections into the wound bed following resection of recurrent malignant glioma, followed by GCV treatment, was well tolerated.