die. More threatening is the possibility that insertion may initiate oncogenic transformation of 
the cell. The magnitude of the risk that gene transfer poses to a patient can not be accurately 
stated at present, but such a risk should be low. The data in primates accumulated so far 
indicates that the risk (at worse) should be considerably less than that associated with the 
conditioning cytoablation/immunosuppression regimens used for haploidentical bone marrow 
transplantation. In our 70 months of cumulative patient observation in the human gene 
transfer clinical protocol and the 32 years of cumulative observation of primates (some 
severely immunosuppressed) intentionally exposed to large amounts of infectious replication 
competent retrovirus, j]q untoward effects of retroviral exposure or retroviral-mediated gene 
transfer have been observed. The risk factors to consider are detailed in the review "Safety 
Factors Related to Retroviral Mediated Gene Transfer in Humans”, copies of which have been 
made available to the Committee. Long-term surveillance of our exposed monkeys as well as the 
TIL patients will be necessary in order to obtain a better understanding of the actual frequency 
and severity of the risks associated with this procedure. 
1.6 Summary and Rationale for Proposed Protocol 
ADA(-)SCID is a profound dual system immunodeficiency disease (63). SCID is one of several 
genetic diseases which can be effectively treated by bone marrow transplantation (64). 
Children with SCID due to ADA deficiency can be cured by HLA-matched sibling donor bone 
marrow transplantation, probably the treatment of choice for this disease even though there can 
be morbidity and mortality associated with this procedure. Treatment for those children who do 
not have a suitable matched sibling donor is not as satisfactory. Alternative transplantation 
strategies as well as enzyme replacement techniques are being tested in this patient population. 
ADA(-)SCID patients may unfortunately not reconstitute with haploidentical marrow cells, may 
not be candidates for cytoablation due to antecedent lung or liver disease, or may have a milder 
phenotype that does not justify the risk of haploidentical bone marrow transplantation with 
preparative cytoablation. PEG-ADA therapy has resulted in some improvement in growth, a 
variable increase in the number of T-lymphocytes in the peripheral blood and a decrease in the 
incidence of severe infections. 
Another approach to the treatment of severe genetic disease is the use of gene therapy (65,66). 
For the past 3 years, we have conducted experiments in vitro and in vivo that have documented 
that T-lymphocytes are suitable vehicles for gene transfer. The use of T-lymphocytes as gene 
therapy vehicles is especially significant in ADA deficient patients where the engraftment of T- 
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Recombinant DNA Research, Volume 14 
