seen. Long term surveillance of exposed monkeys as well as the patients 
enrolled in the various clinical protocols will be necessary to better 
understand the actual frequency and severity of the risks associated with 
this procedure. 
2.2 Clinical Experience 
2.2.1 In protocol 92-1-248, 12 HIV seropositive identical twins have received 
between 1 and 4 infusions of activated, expanded, unfractionated 
lymphocytes from their seronegative twin. The infusions have generally 
been well-tolerated. Some of the infusions have been associated with 
fevers, chills, headaches, myalgias, fatigue, and/or hypotension requiring 
intravenous fluids within 24-48 hours, currently thought to represent a type 
III hypersensitivity reaction to bovine proteins in previously sensitized 
individuals, as the cells are cultured in media supplemented with fetal calf 
serum. Transient increases in CD4 counts have appeared in most recipients 
within 2 weeks post-transfer. These increases have generally waned 
during the subsequent few weeks prior to the next cell transfer. Several 
recipients have demonstrated evidence of viral activation immediately post- 
transfer, but this has not been universal. 
2.2.2 In Vivo Human Experiments in SCID with Autologous PBLs Transduced 
with the ADA Gene 
Two patients with severe combined immunodeficiency due to adenosine 
deaminase deficiency have been treated with infusions of autologous 
lymphocytes transduced with the ADA gene via a retroviral vector (protocol 
#90-C-195). To date, no significant side effects have occurred and 
immunologic benefit has been observed. Specifically, reversal of 
lymphopenia, defective T cell cytolytic activity, skin test anergy, and 
deficient antibody production have been achieved in these patients 
associated with gene/T cell therapy. Continuous circulation of modified 
cells during 21 months of observation has been seen in the first patient 
enrolled on the protocol, including during a 7 month period when this 
patient received no additional infusions of cells. ADA levels in the 
circulating T cells have increased from initially undetectable levels to 10% 
to 50% of that measured in the carrier parents. 
The studies of these children with SCID demonstrate that significant 
reconstitution of T cell function can be achieved in immunodeficient 
patients with infusions of autologous polyclonal T cells activated for short 
term (<2 weeks) growth in culture. 
2.2.3 In Vivo Human Experiments with TIL Transduced with the LNL6 Vector 
The human gene transfer N2/TIL clinical protocol (86-C-183c) was 
approved in 1989. In this study, 10 patients with advanced malignant 
melanoma received tumor infiltrating lymphocytes (TIL) that have been 
marked with the safety-modified N2 vector called LNL6. Extensive safety 
studies on the retroviral supernatant prior to transduction of human TIL, 
the transduced TIL before infusion into the patient, and the patients who 
received the gene marked TIL were performed. 
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