Recombinant DNA Advisory Committee- 9/12-13/94 
Dr. Smith, Chair of the Working Group on Data Management, noted the following items 
of correspondence that were included in the meeting materials. Dr. Michael Knowles 
(Protocol #9303-042) reported in his cystic fibrosis study that adenovirus vector (Ad5-CB- 
CFTR) could be cultured on 293 cells from nostril swabs up to 1 to 2 days after dosing; 
and by a more sensitive polymerase chain reaction (PCR) assay, the vector sequences 
were detected up to 5 days. There are two adverse events reported in association with the 
brain tumor protocols. In Dr. Oldfield’s study to treat leptomeningeal carcinomatosis by 
the Herpes simplex thymidine kinase gene /ganciclovir (GCV) strategy (Protocol #9312- 
059), one patient developed symptoms of acute meningitis after injection of the vector 
producer cells into the meninges through an Ommaya reservoir. In Dr. Culver’s study to 
treat glioblastoma multiforme by a similar method (Protocol #9303-037), serious adverse 
reactions of neck pain, fever, and hypertension (238/128) were experienced after injection 
of the vector producer cells through the Ommaya reservoir. 
Ms. Meyers asked if a health care worker could be infected with the adenovirus vector 
during those 5 days when the virus is detectable. Dr. Smith said that in the cystic fibrosis 
trials, the patients are kept in isolation and are required to wear masks during that period. 
Dr. Straus inquired about the frequency of adverse effects when patients receive cells 
through the Ommaya reservoir. Dr. Smith said only 1 patient has been treated in Dr. 
Oldfield’s protocol, and Dr. Culver reported that he treated 4 patients with only 1 patient 
experiencing adverse effects. Dr. Smith added that 15 patients have been treated by Dr. 
Oldfield. Dr. Straus asked if the adverse effects had been ever observed in preclinical 
studies with animals. Dr. Culver said that he did not have first hand information; but in 
other studies, no similar effects have been observed in rodents and rhesus monkeys. The 
injected vector producer cells are of mouse origin. Dr. Straus expressed his concern about 
the acute adverse reactions in these types of gene therapy protocols and stated that the 
cause of the adverse effects should be determined. Dr. Chase asked if patients are told 
about the adverse effects and if there is a threshold of adverse events that will trigger 
RAC review of the safety issues. Mr. Capron asked if the injection rate or the injection 
method could contribute to the adverse effects. Dr. Straus suspected that there is some 
kind of immediate hypersensitivity reaction. Mr. Capron remarked that a revised 
Informed Consent document should reflect this new knowledge about risks. Ms. Meyers 
asked if there is any benefit to the treated patients. Dr. Culver said that the first patient 
is in satisfactory condition although there is no sign of tumor size change by magnetic 
resonance imaging (MRI). The second patient’s tumor is close to the ventricle, and Dr. 
Culver suspects that cell leakage into the meningeal space may have contributed to the 
adverse effects. Tests showed no evidence of infection. Dr. Parkman reminded RAC 
members that these are Phase I toxicity studies not designed to evaluate efficacy, and it is 
not appropriate to ask investigators to demonstrate efficacy. 
Dr. Smith said that the adverse effects will be closely followed up in the upcoming data 
management report at the December RAC meeting. Dr. Dronamraju asked if a revised 
Informed Consent document addressing the adverse effects should be submitted for RAC 
review. Mr. Capron said that the local Institutional Review Board (IRB) should be 
informed and necessary changes in the Informed Consent document can be made and 
Recombinant DNA Research, Volume 20 
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