Treatment of relapsed malignant glioma with an adenoviral vector containing the herpes simplex thymidine kinase gene followed by ganciclovir.
Between November 1998 and December 2001, we treated 14 patients with advanced recurrent high-grade gliomas with a total dose of 4.6 x 10(8), 4.6 x 10(9), 4.6 x 10(10), or 4.6 x 10(11) 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 x 10(11) 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.
Smitt
Peter Sillevis
PS
Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands. sillevis@neuh.azr.nl <sillevis@neuh.azr.nl>
Driesse
Maarten
M
Wolbers
John
J
Kros
Max
M
Avezaat
Cees
C
D000256:Adenoviridae / Q000235:genetics*; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000628:therapy; D003131:Combined Modality Therapy; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D005910:Glioma / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D016879:Salvage Therapy; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics*; D016896:Treatment Outcome
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir