Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors.
Between December 1996 and September 1998, 13 patients with advanced recurrent malignant brain tumors (9 with glioblastoma multiforme, 1 with gliosarcoma, and 3 with anaplastic astrocytoma) were treated with a single intratumoral injection of 2 x 10(9), 2 x 10(10), 2 x 10(11), or 2 x 10(12) vector particles (VP) of a replication-defective adenoviral vector bearing the herpes simplex virus thymidine kinase gene driven by the Rous sarcoma virus promoter (Adv.RSVtk), followed by ganciclovir (GCV) treatment. The VP to infectious unit ratio was 20:1. Our primary objective was to determine the safety of this treatment. Injection of Adv.RSVtk in doses <==2 x 10(11) VP, followed by GCV, was safely tolerated. Patients treated with the highest dose, 2 x 10(12) VP, exhibited central nervous system toxicity with confusion, hyponatremia, and seizures. One patient is living and stable 29.2 months after treatment. Two patients survived >25 months before succumbing to tumor progression. Ten patients died within 10 months of treatment, 9 from tumor progression and 1 with sepsis and endocarditis. Neuropathologic examination of postmortem tissue demonstrated cavitation at the injection site, intratumoral foci of coagulative necrosis, and variable infiltration of the residual tumor with macrophages and lymphocytes.
Trask
T W
TW
Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA. ttrask@bcm.tmc.edu
Trask
R P
RP
Aguilar-Cordova
E
E
Shine
H D
HD
Wyde
P R
PR
Goodman
J C
JC
Hamilton
W J
WJ
Rojas-Martinez
A
A
Chen
S H
SH
Woo
S L
SL
Grossman
R G
RG
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001254:Astrocytoma / Q000235:genetics / Q000401:mortality / Q000628:therapy; D001358:Avian Sarcoma Viruses / Q000235:genetics; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage / Q000494:pharmacology*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000235:genetics / Q000401:mortality / Q000628:therapy; D018316:Gliosarcoma / Q000235:genetics / Q000401:mortality / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011859:Radiography; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics*; D013997:Time Factors; D016896:Treatment Outcome
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir