administration were all negative for evidence of exposure to virus as well. 
These studies demonstrated that gene modification of the TIL could be 
performed and that these TIL could be infused with no exposure of the patient 
to a replication competent virus. These studies provided us with valuable 
experience to perform subsequent studies of TIL modified with the gene for 
tumor necrosis factor (TNF) . These studies began on January 29 , 1991 and thus 
far two patients have been treated with escalating doses of TIL transduced 
with the gene for TNF. Thus far no side effects have been seen in these two 
patients. 
2. Tumor necrosis factor. The injection of recombinant TNF can mediate 
the necrosis and regression of a variety of established experimental murine 
cancers (13-15). The combined administration of TNF and IL-2 mediated far 
greater antitumor effects against subcutaneous and liver tumors than either 
cytokine alone (16). The exact mechanisms of TNF antitumor effects are not 
clearly understood, although it appears that TNF has a significant effect on 
the vascular supply of tumors and CD8+ cells (15). Membrane-bound TNF may be 
involved in direct tumor lysis as well (17). These animal experiments have 
led to extensive tests of recombinant human TNF administered to humans with 
advanced cancer (3,18-21). In the Surgery Branch, NCI, we treated 38 patients 
with advanced cancer using escalating doses of recombinant TNF (supplied by 
the Cetus Corp. , Emeryville, California) administered in conjunction with IL-2 
(3). No antitumor effects of TNF administration have been seen in humans." 
However, when high local concentrations of TNF are achieved at tumor sites by 
direct intralesional TNF rejection, tumor regression in humans has been seen. 
Extensive studies of the difference between the dramatic response of 
mice to the systemic injection of TNF and the lack of effect in humans have 
focused on the substantial differences in tolerance of mice and man to the 
administration of TNF. Tumor bearing mice can tolerate from 400-500 ug/kg TNF 
and these doses are required to mediate tumor regression; the administration 
of less TNF is far less effective (15). In contrast, the maximum tolerated 
Recombinant DNA Research, Volume 15 
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