Gene Therapy for Meningeal Carcinomatosis 
3.32 Potential Treatment Complications 
Chemical Meningitis 
Despite the lack of a meningeal reaction in our animal models, meningitis or meningitis-like 
symptoms may develop secondary to injection of the vector-producer cells into the subarachnoid 
space. Such symptoms are expected to be self-limiting and ameliorated with symptomatic care 
(analgesics). However, such a reaction may be severe and could produce permanent neurological 
deficits or death. When indicated, additional CSF sampling may be required to rule out infection. 
Hydrocephalus 
Patients who develop hydrocephalus after initiation of the protocol with symptomatic 
increased intracranial pressure will be treated with CSF diversion via the Ommaya reservoir or, 
alternatively, through the lumbar drain if the increased intracranial pressure results from a 
communicating hydrocephalus, in which there is no obstruction to flow of the CSF in the 
ventricular system or basal subarachnoid space. Short term treatment of communicating 
hydrocephalus by lumbar CSF diversion is a standard neurosurgical treatment with minimal risk. 
If hydrocephalus persists, long term treatment with placement of a subcutaneous ventriculo- 
peritoneal shunt will be performed. The conversion of an Ommaya reservoir to a shunt system is a 
minor and routine neurosurgical procedure. To minimize the possibility of murine retroviral 
vector-producer cell transfer from the subarachnoid space to the peritoneal space, treatment with 
GCV will be completed prior to the internalization of the ventriculo-peritoneal shunt, if this is 
required. 
3.33 Ganciclovir Administration 
The GCV used in this trial will be purchased from Syntex corporation (Palo Alto, CA). 
GCV is an FDA approved drug for the treatment of cytomegalovirus (CMV) retinitis in 
immunocompromised individuals. The drug is administered by intravenous infusion over one 
hour at a dose of 5 mg/kg of body weight twice daily for 14 days. 
Our experience with the use of GCV for the treatment of humans as a method to destroy 
herpes TK gene- transduced human cells in the "Intratumoral Transduction of Brain Tumor" 
protocol demonstrates no specific risks or complications of therapy in the 8 patients treated since 
initiation of the protocol. GCV crosses the blood-brain barrier. The cerebral spinal fluid 
(CSF)/plasma ratios have been estimated in three patients at various time points with ratios ranging 
from 0.24 to 0.7 (0.31-0.68 fig/ml in the CSF and 0.44-2.20 |ig/ml in the plasma). Peak plasma 
levels have been documented to reach as high as 9 |!g/ml. These CSF and plasma levels are 
expected to be within the range of GCV levels necessary to kill the HS-tk transduced tumor cells 
based on in vitro studies (0.5 fig/ml will prevent growth of HS-tk-transduced tumor cells). If the 
patient has evidence of renal impairment, the dose will be adjusted as suggested in the GCV 
monograph. 
The most common side effects are granulocytopenia (absolute neutrophil count (ANC) of 
<1000 cells/mm 3 ) in 40% of patients and thrombocytopenia (<50,000 platelets/mm 3 ) in 20%. 
However, these data were collected in immunosuppressed, CMV-infected AIDS patients, who due 
to opportunistic infections and concomitant drug therapy, may have been more susceptible to 
marrow suppression than our patient population. The actual risk to our patient population is 
unknown. In the brain tumor protocol patients, one patient required administration of platelets 
before stereotaxic injection of producer cells because of thrombocytopenia after chemotherapy. He 
had no significant decrease in platelet count during GCV treatment. No granulocytopenia has been 
encountered with a total of 8 patients treated to date. Each patient will be closely monitored for the 
development of granulocytopenia or thrombocytopenia. The development of an ANC of <500 
cells/mm 3 or a platelet count of <25,000 platelets/mm 3 will require dose interruption until the ANC 
>750 cells/mm 3 and platelet count >40,000 platelets/mm 3 . 
Other side effects, which occur in approximately 2% of patients include anemia, fever, rash 
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