Human Gene Therapy Subcommittee - July 29-30, 1991 
patient; (2) the effects on tumor cells when they are grown for a length of time, 
thereby selecting for growth and possibly metastatic potential; and (3) the effects of 
cytokine gene introduction into the tumor cells. The IBC considered that the 
untransduced tumor cells would provide valuable information. There are data from the 
lung metastasis model that show the TIL from the subcutaneous tumor to be more 
effective than TILs from the lung, even where the tumor cells are not transduced. In 
some of these patients, the tumor cells might not need to be transduced. The IBC was 
primarily concerned with what happens when the tumor cells are reintroduced into the 
patient. The IBC is requesting an experiment to address the short-term toxicity. This 
experiment may turn out to be quite beneficial. 
Mr. Capron asked Dr. Rosenberg if he rejects the IBCs view that the unmodified 
tumor cells might prove beneficial, thereby obviating the need for the gene-modified 
tumor cells. Dr. Rosenberg replied that he was not successful in generating the TILs 
with unmodified cells. Also, other scientists in the field do not see the effects with 
unmodified tumor cells. He agreed with Dr. Carter that it would be valuable 
information, but it is difficult to obtain from patients. 
Dr. D. Miller said the animal model would suggest that it is more beneficial to 
administer the cytokine genes in the tumor cells. 
Dr. Leventhal said it was somewhat reassuring that the modified cells failed to grow in 
nude mice relative to the unmodified cells. TTie investigators should perform 
additional nude mouse experiments using other cell lines. There is a serious risk that 
the unmodified cells are more dangerous than the modified cells. Dr. Rosenberg 
added that there are some animal data (to the extent that the animal data are valid) 
that suggest that the gene modification will be necessary. 
Dr. Neiman asked about data that demonstrate a requirement for injection of living 
gene-transduced expressed cells, as opposed to merely co-injection of unmodified tumor 
cells and cytokine at the site. Dr. Rosenberg replied that if TNF or IL-2 is injected 
subcutaneously, it has a half-life of about 4 minutes. It requires multiple injections of 
the cytokines into solid tumors to see minimal effects. 
Dr. Parkman asked if irradiation of transduced cells prior to administration decreases 
efficacy. Dr. Rosenberg replied that he had not done that experiment, but that there 
are data showing that maximum immunity is obtained when the cells are allowed to 
grow, as opposed to administering the same number of irradiated cells. 
Dr. D. Miller moved that the protocol be approved with the following stipulation, that 
only the gene-modified cells should be used in these protocols, even though the NIH 
IBC requested a preliminary experiment using unmodified tumor cells. Mr. Brewer 
seconded the motion. 
Recombinant DNA Research, Volume 14 
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