4.3.5 Potential for Malignancy: Could the vector transform respiratory cells and cause 
malignancy? The risk of AvlCF2 induced malignancy after in vivo administration is expected 
to be extremely low for several reasons. First, there has never been an association of 
adenovirus infection with malignancy in humans. Despite the high prevalence of infection of 
the general population by adenovirus there has been no proven association between adenoviral 
infection of any serotype and any form of human malignancy (Horwitz, 1990, Straus, 1984). 
Second, clinical administration of wild type adenovirus to an estimated > 5 million military 
recruits as part of a vaccination protocol has never resulted in an association with malignancy 
(Chanock et.al., 1966; Couch et.al., 1963; Top et.al., 1971a, Top et.al., 1971c). Third, 
serotype 5 adenovirus from which AvlCF2 was derived, one of the more common serotypes, 
is classified as subgroup C, a class that has a lower transforming potential and is non- 
tumorigenic in rodents (Ginsburg, 1984). Fourth, the transforming genes (El) have been 
removed from the vector thus eliminating its transforming potential. Fifth, although one 
potential mechanism for the induction of host malignancy could occur on the basis of insertional 
mutagenesis, adenovirus is known to integrate at very low frequencies (Karlsson et.al., 1985, 
1986). Therefore, it seems that the risk of malignancy associated with AvlCF2 is very low. 
4.4. Risk of Horizontal Transmission of AvlCF2 Vectors From the Treated Patient to 
Other Individuals: Will the adenovirus vector become infectious? (See also discussion above 
4.3.2 Replication of AE1 Recombinant Vectors) Once in the epithelial cells of patients, the AE1 
recombinant adenoviral vector AvlCF2 should not be transmitted to other individuals unless it 
replicates. It is known that AE1 adenoviral vectors can be complemented with respected to 
replication by El genes in trans by wild type adenovirus (Figure 32) or cells that contain and 
express adenoviral Ela gene products (e.g. 293 cells which are used to produce AE1 adeno- 
viruses) and also by Ela-like cellular factors. Thus, at least theoretically, the possibility exists 
for person-to-person transmission if the patient developed an intercurrent infection with wild-type 
virus after treatment with AvlCF2. While such complementation might provide the factors for 
generating infectious virus which could lead to transmission, this could only occur if 1) sufficient 
viral genomic replication occurs, 2) replicated viral genomes are packaged, 3) intracellular- 
packaged virions are released, and if the extracellular virus survives the hostile milieu present 
within the CF respiratory tract such that surviving virus is excreted in quantities sufficient to 
result in secondary infections. Failure of any of these steps would break down the ability for 
interpersonal spread of the recombinant vector. Thus, while the potential for interpersonal 
spread is unknown, it is not likely to be an important practical issue with AE1 adenoviral 
vectors. 
To insure that complementation by wild virus does not occur, subjects will be screened for 
the presence of adenovirus infection on admission for this study. Then they will be isolated 
during the study to prevent adenovirus infection. 
Although Ad5 can complement Avl series AE1 adenoviral vectors when co-infected in the 
same cell, as previously observed for El + , AE3 vectors (Berkner and Sharp et.al., 1983), 
AE1,AE3 vectors appear to inhibit replication of co-infecting wild-type adenovirus (Figure 32), 
albeit by an unknown mechanism. Thus, if an individual treated with AvlCF2 were to become 
infected with wild-type adenovirus, complementation of the El defect of the vector might occur. 
However, it is also possible that the vector may actually limit the wild-type infection. 
Therefore, it is possible that continued presence of AvlCF2 Ad5 might actually be beneficial, 
producing a longer duration of effective treatment. Nevertheless, extensive steps will be taken 
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