Human Gene Therapy Subcommittee - 11/21-22/91 
Dr. Walters called on Dr. Economou to respond to the reviewers comments and 
questions. Dr. Economou presented a report on eight melanoma patients receiving TIL 
therapy at the UCLA. The first patient had metastatic melanoma at multiple 
subcutaneous sites and in the lung. Several subcutaneous sites were harvested and 
expanded in interleukin 2 (IL-2). Analysis revealed a 98 % pure population of CD8(+) 
TIL. These cells exhibited autologous tumor-specific cytotoxicity that was major 
histocompatibility complex (MHC)-restricted. Cytotoxicity was not observed against 
allogeneic cells. No clinical response was observed following administration of maximum 
tolerated doses of TIL and IU2. Experiments on another melanoma patient with only 
one subcutaneous nodule and two large liver metastases generated few TIL cells with a 
mixed phenotype and non-specific tumor cell cytoxicity. A computerized tomography 
(CT) scan showed dramatic reduction in the size of the patient's liver metastases 
following the administration of homeopathic doses of TILs. Dr. Economou stated that 
he has not been able to identify in vitro correlates for biological behavior in vivo. 
A third case was presented in which a patient had metastatic melanoma to the axilla to 
several subcutaneous sites. Also, the patient had two metastases, one in the brain and 
the other in the kidney. The axilla mass was resected and TIL were expanded. 
Following administration of these expanded TIL, the subcutaneous mass disappeared and 
another was reduced in size by 50%. Resection of the subcutaneous metastasis revealed 
necrotic tumor. The kidney metastasis was unaffected by treatment. Following a radical 
nephrectomy of this patient, the kidney tumor was identified as primary renal cell cancer. 
Therefore, this one patient was internally controlled; melanoma TIL effected regression 
of the melanoma tumor but had no effect against the renal cell cancer. It has not been 
possible to determine which properties are responsible for these clinical results. 
In response to the earlier question asking if the cytotoxic effect of TILs could be 
enhanced, Dr. Economou said that an increase in tumor specificity could be tested in 
vitro. TILs exhibit increased cytokine production but it is unclear which ones are 
necessary for improved specificity: tumor necrosis factor (TNF), IL-7, or granulocyte- 
macrophage colony stimulating factor (GM-CSF). Dr. Economou hypothesized that TIL 
will preferentially traffic to tumor, but not to muscle, skin, or other organs or tissues. 
This protocol will permit an unambiguous and clear testing of the in vivo behavior of 
TIL. 
Dr. Economou presented a brief overview of the protocol. TIL and PBL will be isolated 
from the patient and transduced with two very closely related (but PCR-distinguishable) 
retroviral vectors. These transduced cells will be expanded in IL-2 then infused into the 
patient. Bulk TIL and PBL, CD8( + ) TIL and PBL, and CD4( + ) TIL and PBL 
populations will be isolated and compared. The melanoma patients will be supported 
with continuous infusion of IL-2 and intramuscular injection of a-Interferon (IFN). 
Renal cell patients will receive continuous infusion of a -IFN in addition to IL-2. 
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Recombinant DNA Research, Volume 15 
