Thymidine kinase activation of ganciclovir in recurrent malignant gliomas: a gene-marking and neuropathological study.
OBJECTIVE
The gene therapy paradigm of intratumoral activation of ganciclovir (GCV) following transduction of tumor cells by retroviral vectors bearing the thymidine kinase (tk) gene has produced dramatic remissions of malignant gliomas in animal models. In human trials, although the technique has been deemed safe, little antitumor effect has been demonstrated. To evaluate the basis of this inefficacy in human gliomas, the authors conducted a gene-marking trial involving neuropathological and biochemical studies of treated tumor specimens.


METHODS
Five patients with malignant recurrent gliomas underwent stereotactic biopsy sampling and intratumoral implantation procedures with three aliquots of 10(6) vector-producing cells (VPCs) in columns. After 5 days, the tumor was resected and the tumor bed reimplanted with VPCs, and a course of GCV was given. Patients received clinical and radiological follow up for 6 months. Tumor specimens were analyzed neuropathologically and for tk gene expression by anti-TK immunohistochemistry and TK enzymatic activity. Four patients tolerated the treatment well but experienced tumor progression. The other developed an abscess after the second operation and died. Increased TK enzymatic activity was demonstrated in the one tumor specimen analyzed. Immunohistochemical evidence of tk gene expression was limited to VPCs. Transduction of tumor cells was not seen. Viable tumor cells were seen near VPCs containing TK. The lymphocytic immune response was mild.


CONCLUSIONS
Except for the risk of infection inherent in reoperation, this tk-GCV paradigm was both feasible and safe. Pathological studies indicated that limited dissemination of VPCs and vector from the infusion site and failure to transduce tumor cells with the tk gene are major barriers to efficacy.
Harsh
G R
GR
Department of Neurology, Massachusetts General Hospital Brain Tumor Center, USA. gharsh@stanford.edu
Deisboeck
T S
TS
Louis
D N
DN
Hilton
J
J
Colvin
M
M
Silver
J S
JS
Qureshi
N H
NH
Kracher
J
J
Finkelstein
D
D
Chiocca
E A
EA
Hochberg
F H
FH
D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use*; D001922:Brain Abscess / Q000209:etiology; D001932:Brain Neoplasms / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D004195:Disease Models, Animal; D018450:Disease Progression; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D015774:Ganciclovir / Q000627:therapeutic use*; D005822:Genetic Vectors; D005910:Glioma / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D015552:Injections, Intralesional; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D012074:Remission Induction; D012190:Retroviridae / Q000235:genetics; D013238:Stereotaxic Techniques; D013937:Thymidine Kinase / Q000235:genetics*; D014161:Transduction, Genetic
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir