titer and three of the four showed transient vector expression post transplant. 
Tests for replicating virus in serum, peripheral blood mononuclear cells, and 
bone marrow cells, performed two and three years post transplant have been 
negative. PCR performed on peripheral blood and bone marrow cells for the 
viral envelope region (sensitivity of detection 1 in 100,000 cells) were negative 
in all four animals. To date no animal has shown any clinical illness as a 
result of virus exposure. 
4.4 Insertional Mutagenesis 
The intact Moloney murine leukemia virus (MoMLV), the parent retrovirus 
of LNL-6, can cause neoplasia in mice. There is no evidence that this will be 
a problem in non>human primates or in humans. In 21 monkeys undergoing 
a retroviral-mediated gene transfer/autologous bone marrow transplantation 
protocol there has been no evidence of neoplasia (mean follow-up of 2.5 to 
4.5 years). There are also no known examples of transformation of primate 
cells by a murine retrovirus either in vitro or in vivo. Although clinical 
experience is limited, there has been no toxicity or pathology after 
approximately 72 patient-months in the TIL cell study. 
In fact, the mechanism by which the Moloney virus causes leukemia in mice 
is unlikely to be operative in man. The murine T-cell lymphoma associated 
with MoMLV is not due directly to MoMLV but is caused by a recombinant 
virus called a mink focus forming virus which, results from recombination 
between MoMLV and endogenous murine leukemia virus sequences. These 
murine endogenous virus sequences are not present in humans. Moreover, 
adult mice do not develop lymphomas after MoMLV; it is only newborn mice 
that are susceptible, suggesting some step in T-cell development might be 
important in cellular transformation. Lastly, the tropism (i.e., specificity of 
MoMLV for the T-cell) and the strain dependence of MoMLV are not 
detectably shared with any human cell. 
Nevertheless, it is theoretically possible for a retrovirus to insert into a 
protooncogene or tumor suppressor gene leading to cellular transformation. 
The complex virus-oncogene tropism in the murine system, the presence of 
two copies of each tumor suppressor gene in most cells, and the multistep 
process of malignant transformation suggest that the probability of RMGT 
leading to malignancy in primates is exceedingly low. 
4.5 Recombination with Human Endogenous Retroviral Sequences 
Another theoretical concern is recombination of the retroviral vector with 
human endogenous retroviral sequences, leading to the production of a 
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