Recombinant DNA Advisory Committee - 12/3-4/92 
clinical protocol and not unique to the gene therapy protocol. Dr. O'Shaughnessy 
referred Dr. Doi's question regarding ABM transplant survival to her co-investigators 
Drs. Arthur Nienhuis and Kevin McDonagh. The changes to the informed consent 
document suggested by Ms. Meyers will be incorporated in addition to the terminology 
Stage IV to describe the stage of disease. 
Dr. Dronamraju asked what proportion of the patient population will be in the 
lactation/pregnancy age range? Dr. O'Shaughnessy answered that 10 to 20% of the 
proposed breast cancer patients would be in this age range. 
Dr. Post asked about the total number of CD34( + ) cells that would be reinfused. Dr. 
O'Shaughnessy said that the patients will receive between 1 and 5 x 10 7 CD34( + ) cells. 
These cells are a pool of both ABM and peripheral blood cells. Dr. Post asked if 
immunohistochemical staining will be performed prior to reinfusion. Dr. O'Shaughnessy 
responded that the immunohistochemistry information would not be available until after 
the patient is treated, because the staining will be performed simultaneously with 
reinfusion. 
Dr. Geiduschek asked if drug selection of nontransduced ABM cells will result in the 
enrichment of tumor cells. Dr. O'Shaughnessy noted that this protocol does not include 
drug selection of the ABM cells; however, she noted that tumor cell enrichment would 
depend on the specific drug. For example, 4-hydroxy cyclophosphamide preferentially 
kills tumor cells. 
Dr. Leventhal asked if MDR can be induced in ABM cells at a level that exceeds natural 
tumor cell resistance resulting from previous drug exposure. Dr. O'Shaughnessy stated 
that the level of MDR Pgp expression required to induce clinical drug resistance in 
human breast cancer patients is unknown; however, sufficient levels of Pgp expression 
can be obtained in transduced hematopoietic cells to confer resistance. Dr. Leventhal 
noted that since the absolute levels of MDR expression are unknown, it is unclear how 
the protocol design will determine this answer. Dr. O'Shaughnessy stated that Drs. 
Nienhuis and McDonagh will address MDR expression in primate and murine systems. 
Dr. Parkman informed the RAC members that the investigators have chosen the breast 
tumor model because these cells are known to express MDR naturally as a result of 
chemotherapy exposure. The scientific question that needs to be addressed is whether 
the transduction of hematopoietic stem cells results in levels of MDR-1 expression that 
are sufficient to induce a biological effect. If a significant clinical effect is observed, than 
this procedure may be applied to the treatment of a variety of tumors. 
Dr. Leventhal said that it is unclear that the protocol is designed to demonstrate 
anything other than gene expression. How will the protective effect of this gene 
expression be demonstrated? Dr. O'Shaughnessy explained that the protocol is designed 
Recombinant DNA Research, Volume 16 
[541] 
