Recombinant DNA Advisory Committee - 12/3-4/92 
characterization of the producer clone and probably 3 to 4 months before Food and 
Drug Administration (FDA) approval is obtained. 
Dr. Nienhuis responded to Dr. Leventhal's concerns regarding the detection of clinical 
benefit to patients. Will there be an amplification of the retrovirally-transduced cells as 
the patients receive taxol and vinblastine and undergo bone marrow suppression and 
regeneration? Amplification will be the primary determinant as to whether there is an 
incremental increase in the number of retrovirally-marked cells. In the murine system, 
MDR-1 amplification can be compared to neo R . In the human study, MDR-1 
amplification can be compared to patients receiving neo R transduced cells. The issue of 
bone marrow protection, however, remains to be determined. Dr. O'Shaughnessy agreed 
that each patient will act as his/her own control. Repeated taxol administration clearly 
results in cumulative bone marrow toxicity. If no improvement is observed in the 
neutrophil nadir or its duration following subsequent cycles of taxol administration, 
important information will be obtained. Dr. Leventhal said that the evaluation criteria 
should be formalized. Dr. Nienhuis suggested that a positive response could be 
considered an increase from 1 to 10% retrovirally-transduced cells following 3 cycles of 
treatment. 
Dr. D. Miller asked the investigators if they will continue to enroll patients into the neo R 
protocol that has already been approved by the RAC. Dr. Nienhuis said that the gene 
marking protocol will continue. The objective of the neo R marking protocol is to 
compare reconstitution by marking peripheral blood and bone marrow cells with 
different vectors. This breast cancer protocol uses only one vector, the MDR vector, to 
transduce both peripheral blood and marrow cells. The comparison of the patient 
populations between the two protocols will be critical in interpreting the data. Dr. D. 
Miller asked the investigators if they anticipate the generation of data in the next 3 
months demonstrating the ability to mark stem cells. Dr. Nienhuis explained that the 
first patient on the neo R marking protocol was just recently treated. Since there will be 
variability in the levels of transduction between patients, it is appropriate to initiate both 
protocols concurrently. 
The motion to defer approval of the protocol passed by a vote of 17 in favor, 0 opposed, 
and no abstentions. Approval of the protocol was deferred until the investigators submit 
the following addition^ information and data to the RAC: (1) data will be provided 
demonstrating that human CD34( + ) cells have been transduced in vitro with the vector 
that will be used in the clinical protocol; (2) description of all of the assays that will be 
used to measure gene expression, and demonstrate how this expression will be monitored 
in bone marrow and tumor cells; and (3) a description of the endpoint for determining 
efficacy (evaluation criteria), i.e., comparison of gene amplification and the rate of white 
blood cell recovery following taxol treatments 1 and 3. 
Recombinant DNA Research, Volume 16 
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