Recombinant DNA Advisory Committee- 9/12-13/94 
suggested a statement to indicate that the patient may not benefit from the study, but 
knowledge may be gained that would benefit others. The investigators responded in 
writing that there is some therapeutic intent in this protocol. Ms. Meyers was concerned 
about adverse effects observed in other brain tumor studies. She was not comfortable 
with starting another brain tumor study unless it would provide unique and valuable 
clinical data that would not otherwise be forthcoming from similar experiments. 
Other Comments 
Dr. Parkman commented on Ms. Meyers’ objection to another brain tumor study without 
waiting for the outcome of other similar studies. Dr. Parkman said the present approach 
is significantly different from other brain tumor protocols using a retroviral vector to 
deliver the HSV-TK gene. The target specificity of the adenovirus vector is different. 
Being able to transduce non-dividing cells in addition to dividing tumor cells is a 
significant change in the target of this therapy. Regardless of the outcome of other 
retroviral studies, this approach is significantly different. Dr. Parkman and Mr. Capron 
both agreed with the point made by Ms. Meyers that no therapeutic benefit should be 
implied in the Informed Consent document for this Phase I trial. 
Dr. Samulski stated that this vector is so different in its ability to transduce non-dividing 
cells, one would not accept any other protocols using the retroviral approach to treat brain 
tumors if this protocol shows promise. Dr. Miller added that the HSV-TK gene needs to 
get into a dividing cells in order to have the killing effect of GCV. (The GCV 
metabolites can only be incorporated into DNA of a dividing cell.) 
Ms. Meyers asked about the chance of the adverse effects of the Oldfield protocol 
happening in the present study. Dr. Parkman said that the adverse effects of Oldfield 
protocol are related to the large number of injections of the vector producer cells, and it 
is independent from the nature of the vector. Dr. Wivel added that another variable is 
that some of the Oldfield trials involve the use of Ommaya reservoir. 
Review-Dr. H. Ginsberg 
Dr. H. Ginsberg said that this is an excellent protocol and new information will be 
obtained by using the present vector. 
Dr. H. Ginsberg reiterated a comment he made yesterday during the review of another 
adenovirus protocol about the importance of E3 deletion of the adenovirus vectors. He 
said the E3 region encoding 3 genes is important for protection of cells from the harmful 
effects of viral infection: (1) The gene for the 19 kd protein has the effect of reducing the 
cytotoxic T lymphocyte (CTL) response because it markedly decreases the Class I major 
histocompatibility antigen on the cells; (2) The gene for the 14.7 kd protein protects the 
host against cytokine induction; and (3) The gene for the 11.7 kd protein protects the cell 
against apoptosis. Deleting these genes is harmful to the host. The adenovirus vector 
used in the present study has partial E3 deletion. Dr. H. Ginsberg was uncertain which 
gene has been deleted. This is a critical point regarding the question of virus induced 
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Recombinant DNA Research, Volume 20 
