Recombinant DNA Advisory Committee - 09/9-10/93 
subsequent progressive disease will receive Taxol administration on a dose-escalation 
schedule. Although the protocol has adequate preclinical data, a major problem raised 
in the last review was that most preclinical data were obtained employing a vector based 
on the Harvey murine sarcoma virus, which was different from the vector proposed for 
the clinical trial. In this resubmission, the PI has addressed all the significant questions 
raised in the last review including: (1) construction and evaluation of the Moloney 
murine leukemia virus based vector, G1MD, (2) demonstration of the ability of this 
vector to transduce the target human CD34( + ) cells, (3) demonstration of the 
transduced MDR-1 gene in primary hematopoietic cells, (4) demonstration of expertise 
in the polymerase chain reaction (PCR) assay of MDR-1 gene expression, and (5) 
clinical evidence for the ability to transduce CD34( + ) cells with a vector containing a 
neomycin resistance (neo R ) gene. The investigators have deleted one of their previous 
objectives, namely, demonstrating the therapeutic benefit of MDR-1 transduction and 
have focused instead on demonstration of persistence and proliferation of MDR-1 
transduced cells following Taxol administration. Dr. Parkman recommended approval of 
the revised protocol. 
Review-Dr. Brinckerhoff (presented by Dr. Parkman) 
In her written comments, Dr. Brinckerhoff explained that this revised protocol is 
improved over the original submission and directly addresses most of the RACs previous 
concerns. She noted two reservations: (1) Since breast cancer patients demonstrate a 
high incidence of bone marrow metastasis, what percentage of patients will be ineligible 
to participate in this study? Dr. Parkman explained that breast cancer cells do not 
express the CD34 marker; therefore, isolation of CD34( + ) bone marrow cells employing 
a CD34 monoclonal antibody column will eliminate most contaminating metastatic breast 
cancer cells. Dr. Parkman noted that this issue has been raised during the review of 
previously approved protocols. (2) There is a lack of preclinical data demonstrating 
long-term expression of the transduced MDR-1 gene in an animal model. 
Review-Mr. Capron 
Mr. Capron stated that the investigators have adequately responded to the suggested 
changes in the Informed Consent document. Except for a few typographical errors, the 
revised Informed Consent is acceptable. Mr. Capron recommended approval of the 
protocol. 
Other Comments 
Dr. Miller mentioned that some preclinical data were not included in his review 
materials and asked the investigators to present their data. Dr. Post asked the 
investigators to explain in detail the problem of MDR-1 mRNA splicing and the two 
different gene products coded for by these spliced MRNA species. Dr. Post noted that 
the stem cell factor used for most of the preclinical studies will not be used in the 
clinical protocol. Will omission of this factor affect the experimental outcome? 
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Recombinant DNA Research, Volume 18 
