Gr. Harsh et al., Thymidine kinase activation of ganciclovir in recurrent malignant gliomas:a gene-marking and neuropathological study, J NEUROSURG, 92(5), 2000, pp. 804-811
Object. 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 malignan
t gliomas in animal models. In human trials, although the technique has bee
n deemed safe, little antitumor effect has been demonstrated. To evaluate t
he basis of this inefficacy in human gliomas, the authors conducted a gene-
marking trial involving neuropathological and biochemical studies of treate
d tumor specimens.
Methods. Five patients with malignant recurrent gliomas underwent stereotac
tic biopsy sampling and intratumoral implantation procedures with three ali
quots 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 progressio
n. The other developed an abscess after the second operation and died. Incr
eased TK enzymatic activity was demonstrated in the one tumor specimen anal
yzed. Immunohistochemical evidence of tk gene expression was limited to VPC
s. Transduction of tumor cells was not seen. Viable tumor cells were seen n
ear 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 f
ailure to transduce tumor cells with the tk gene are major barriers to effi
cacy.