Recombinant DNA Advisory Committee - 6/9-10/94 
of the vector, i.e., between 1 x 10^ and 1 x 10^° plaque forming units (PFU), would be 
required to determine pathology in the human lung. 
Other Comments 
Dr. Doi noted the adverse event reported by Dr. Ronald Crystal (Protocol #9212-034) 
with regard to adenovirus vector administration. Dr. H. Ginsberg said that the major 
pathological response is the result of early cellular immunity, predominantly CTL 
responses. Deletion of Ela does not prevent early gene expression, a fact that will limit 
multiple inoculations of adenovirus vectors. Dr. Haselkom commented that the adverse 
event reported for Dr. Crystal's CF study was related to target cell destruction resulting 
from an antibody response to late viral proteins. Since this proposal involves the 
destruction of tumor cells, such an effect could be beneficial. Dr. Haselkom asked the 
investigators to elaborate on this concern. Drs. Miller, Parkman, and Haselkom asked 
Dr. Roth to address the phenomenon of the "bystander effect." 
Dr. Miller asked about the dose of vims proposed for the human study and whether 
assays have been performed to determine the presence of helper vims. Is sequence data 
available for the junction points of p53 and the vector backbone? How will the vims be 
injected into the tumor mass? 
Dr. Smith asked how this protocol relates to Dr. Roth's previous NSCLC/retrovims 
vector protocol in terms of patient entry. He asked Dr. H. Ginsberg how far the 
adenovims vector might be expected to traffic outside the immediate injection area. Dr. 
H. Ginsberg responded that escape of the vector outside the injection area is unlikely 
because the transgene will only react within the cell. 
Dr. Parkman asked about the percentage of transduced cells necessary to observe the 
"bystander effect." Has the "bystander effect" been observed with the adenovims vector 
as with the retrovims vector? What percentage of cells is expected to be transduced 
using this vector in vivo or in situ? 
Dr. Post noted that the protocol calls for the administration of the adenoviral vector 
alone followed by a combination of the vector and cisplatin. Will the preliminaiy 
administration of the vector alone result in an immune response against the second 
injection? In regard to intrapleural administration, where is the vims expected to target? 
Dr. Saha raised a concern that p53 gene mutations could possibly convert the tumor 
suppressor gene into an oncogene. What is the likelihood of such an occurrence, i.e., 
p53 undergoes somatic mutation? 
Dr. Haselkom explained the bystander effect is a phenomenon where more cells are 
killed than are actually infected or transduced by the vectors. One model for this 
postulates that a diffusible substance is released by dying cells that causes apoptosis of 
surrounding cells. Dr. Parkman explained that apoptosis is a programmed cell death 
triggered by either a natural or pharmacological substance. 
Recombinant DNA Research, Volume 19 
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