Human Gene Therapy Subcommittee - 11/21-22/91 
first two concerns, and the third concern is probably not within the purview of the 
HGTS. Dr. Walters stated that the subcommittee could offer suggestions to the IRB; 
however, the actual decisions regarding the informed consent document are made by the 
institution. 
Dr. Parkman asked Dr. Cometta to describe the differences between his protocol and 
the protocol submitted by Dr. Brenner of St. Jude Children's Hospital, Memphis, 
Tennessee. Dr. Cometta explained that both protocols are designed to answer the same 
question regarding the contribution of transplanted marrow to patient relapse. However, 
each of these protocols addresses a different patient population. Dr. Cometta explained 
that his protocol is designed to study adult leukemia; Dr. Brenner will be studying 
childhood leukemia. In addition, Dr. Cornetta said that he is studying patients in second 
or later remission as opposed to first remission patients. 
Dr. Mclvor stated that there are three components to consider regarding the contribution 
of marked cells to patient relapse: (1) the transduction frequency, (2) the number of 
cells transduced in the marrow, and (3) the proportion of cells contributing to relapse. 
In the murine EL4 tumor model, not all of the tumor cells contribute to relapse. There 
should be more clonality of tumor cells in humans than in the murine model. He asked 
if the investigators were aware of any data regarding the clonality of these cells. Dr. 
Cometta presented data demonstrating that the leukemic cells were not clonal. With 
regard to the issue of marking frequency, Dr. Cometta stated that transduction frequency 
of the leukemic cells cannot be determined at the time of harvest because they cannot 
be separated from the normal marrow cells. The only data that will be available at the 
time of harvest will be the transduction frequency of normal cells; a correlation will have 
to be drawn for leukemic cells. 
Dr. Cometta stated that the frequency of transduction of marrow cells is approximately 
1%. If 30% of the marrow is transduced, than the frequency of marking is 
approximately 0.3%. Dr. Cornetta stated that this number probably underestimates the 
number of detectable cells. Dr. Epstein noted that this frequency is the anticipated 
number of marked cells in the marrow, not the number of cells contributing to relapse. 
Dr. Leventhal explained that if the frequency of transduction of marrow cells is 1% and 
if approximately 100 cells contributed to relapse, the ability to detect a marked relapse 
will be low. Dr. Cometta concurred with Dr. Leventhal's statement and added that there 
may be no detectable marked cells in 1 out of 10 patients. Dr. Parkman stated that the 
conclusions that could be drawn from negative patients are either: (1) that relapse 
originates from an extremely small number of cells, or (2) that transplanted marrow cells 
do not contribute to relapse. Unless a large number of patients are entered into the 
protocol, the source of relapse may not be definitively answered. There are too many 
variables in this protocol. Dr. Cornetta said that there is no evidence that marrow 
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