Recombinant DNA Advisory Committee - 7/31/90 
2. Steroid administration; and 
3. Administration of anti-TNF antibody. 
Dr. Mclvor said that it had been previously observed in 
preclinical and clinical studies that administration of TNF can 
lead to tumor regression. However, in humans the problem has 
been extreme toxicity; there is a need to investigate local 
expression of TNF at the tumor site to limit systemic toxicity. 
A major question is whether enough TILs will migrate to the tumor 
site to produce regression of the tumor. However, he said the 
HGTS was satisfied that the possibility of an efficacious outcome 
warranted approval of the study. 
Finally, Dr. Mclvor emphasized that the study has been termed a 
"Phase I" study. Therefore, the main focus of the study is to 
determine toxicity, not necessarily efficacy. Another study 
would have to be proposed later to determine actual efficacy. He 
said the HGTS approved this protocol on the condition that final 
IBC and IRB approval be granted as well as minor revisions to the 
informed consent document. 
Dr. Clewell said the proposal is a clinical study and the results 
will be of great interest from the standpoint of efficacy of TNF 
in tumor control, as well as the potential for this type of gene 
therapy. He noted that Dr. Rosenberg and his colleagues have a 
great deal of experience in developing and testing 
immunotherapeutic approaches to the treatment of various 
malignancies. This study is a natural and reasonable outgrowth 
of their previous studies with TIL cells. 
Dr. Clewell said the retroviral vector system is based on ongoing 
TIL studies, with the main difference being the addition of a 
segment of recombinant cDNA coding for human TNF. He noted that 
the investigators had proved the vector could be successfully 
established by both G418 resistance testing and Southern blot 
analysis. Western blot analysis indicated production of 
additional TNF by transduced cells. Supernatants have been 
tested and shown not to contain active virus, and transduced TILs 
were shown in PCR studies to be free of viral envelope antigens. 
Furthermore, transduced TILs were shown to be dependent on IL-2 
for growth and survival. 
Dr. Clewell said several questions were raised by the NIH IRBs 
and the IBC, and that these committees had asked for: 
1. Primate toxicity studies; 
2. Studies using murine neutralizing antibody to human TNF 
in mouse experiments; and 
Recombinant DNA Research, Volume 14 
[123] 
