Recombinant DNA Advisory Committee - 06/7-8/93 
Dr. Chase stated that he primarily considers safety and the responses to the Points to 
Consider in the Design and Submission of Protocols for the Transfer of Recombinant DNA 
into the Genome of Human Subjects (Points to Consider) when reviewing human gene 
transfer protocols, not necessarily that the best experiment has been proposed. Dr. 
Walters added that the RAC should make a threshold judgment that there is a 
reasonable hope of success. Dr. Leventhal agreed that it is not ethical to allow a patient 
to participate in an experiment that is so poorly designed that no useful information will 
be obtained. 
Dr. Carmen suggested simplified language that would make the Informed Consent 
document more understandable to lay persons. Drs. Post and Smith asked the 
investigators to clarify the bone marrow culture and transduction procedures. Dr. 
Geiduschek raised a concern about the adequacy of testing a small fraction of the vector 
supernatant for replication-competent retrovirus (RCR), and objected to the use of the 
term "safety modified viruses" throughout the Informed Consent document and in the 
protocol title. Dr. Walters recommended that the word "stem" should be omitted from 
the titles of both the protocol and the Informed Consent document. 
Investigator Response--Dr. Deisseroth 
Dr. Deisseroth explained that he would limit his response to the issue of MDR-1 
expression in hematopoietic cells followed by specific questions raised by the RAC 
members. He presented data demonstrating that MDR-1 transduced CD34( + ) cells 
"pump out" the control rhodamine dye more efficiently than untransduced CD34( + ) 
cells. Since these transduced cells express a higher level of MDR-1 gene product, 
protection against Taxol toxicity is conferred. Expression of mRNA by transduced cells 
was detected by PCR analysis. The transduced gene was distinguishable from the 
endogenous cellular gene by a point mutation. 
Dr. Deisseroth described the schema for the proposed clinical protocol. Following 
collection of peripheral blood and bone marrow cell for transduction, a conditioning 
regimen of thiotepa-cyclophosphamide will be delivered to reduce the total body tumor 
burden and to eradicate the bone marrow. Following autologous bone marrow (ABM) 
transplantation, a fraction of which has been transduced with the MDR-1 gene, patients 
will undergo a period of recovery prior to Taxol treatment. He stated that in the clinical 
protocol that does not involve gene transfer, only 1 out of 30 patients who received the 
conditioning regimen experienced mild marrow failure. Responding to questions about 
possible toxicity associated with retrovirus transduction of ABM cells, he cited the 
retrovirus transduction marking data obtained from studies conducted both at MD 
Anderson and St. Jude demonstrates that no difference in engraftment frequency has 
been observed by 30 days in patients receiving either marked or unmarked ABM cells. 
[554] 
Recombinant DNA Research, Volume 17 
