Abstract
Cancer gene therapy consists of numerous approaches where the common denominator is utilization of vectors for achieving therapeutic effect. A particularly potent embodiment of the approach is virotherapy, in which the replication potential of an oncolytic virus is directed towards tumor cells to cause lysis, while normal cells are spared. Importantly, the therapeutic effect of the initial viral load is amplified through viral replication cycles and production of progeny virions. All cancer gene therapy approaches rely on a sufficient level of delivery of the anticancer agent into target cells. Thus, enhancement of delivery to target cells, and reduction of delivery to non-target cells, in an approach called transductional targeting, is attractive. Both genetic and non-genetic retargeting strategies have been utilized. However, in the context of oncolytic viruses, it is beneficial to have the specific modification included in progeny virions and hence genetic modification may be preferable. Serotype chimerism utilizes serotype specific differences in receptor usage, liver tropism and seroprevalence in order to gain enhanced infection of target tissue. This review will focus on serotype chimeric adenoviruses for cancer gene therapy applications.
Highlights
Significant reductions in cancer mortality have been achieved by improving cancer prevention, early diagnosis and treatments
There are over 50 different serotypes of adenoviruses that were originally classified depending on their ability to neutralize serum to cross-block them
Binding and reduced hepatic tropism, and, importantly, favorable tumor-to-liver transduction ratios in murine models of renal cancer when compared to Ad5 even though it featured intact Ad5 hexon. These results suggest that the role of Ad5 fiber in liver tropism should not be overlooked
Summary
Significant reductions in cancer mortality have been achieved by improving cancer prevention, early diagnosis and treatments. Cancer gene therapy has aimed at transferring a gene for correction of the disease phenotype or to express therapeutic molecules inside or near the target cell. The success of cancer gene therapy is dependent on the ability of the vector to deliver the therapeutic gene (or viral genome in the case of oncolytic viruses) into the target tissue. There are various factors that prevent systemically delivered viruses from reaching their target, and extensive research efforts have focused on improving the delivery of adenoviral vectors. In the context of oncolytic virotherapy, genetic engineering is the only feasible means to modify viruses for tropism alteration or expansion, as the whole approach depends on the production of progeny virions which should display the qualities the injected virus displays. Important goals include de-targeting of the liver and avoidance of pre-existing neutralizing antibodies
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