Construction of Targeted and Armed Oncolytic Adenoviruses
Oncolytic (replication-competent) adenoviruses (Ads) represent the most advanced platform for cancer gene therapy. These viral vectors ablate tumors by killing tumor cells in the process of virus replication. As progeny virions are released, they infect r
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duction Adenoviruses (Ads) belong to the family Adenoviridae. Ads have icosahedral protein capsids without a lipid envelope; their genome is a double-stranded DNA of approximately 30–40 kilobase pairs (kbp). There are 51 serotypes of Ads divided into groups A–F. Ad type 5 (Ad5) from group C has been used for the past three decades as a vector for gene transfer. Historically, replication-competent Ad5 vectors were initially described. Later, with the development of complementing cell lines expressing some of Ad5 proteins in trans, it became possible to construct replication-deficient vectors (1). Replication-deficient Ad5 vectors have been used in numerous gene therapy studies aimed to replace defective genes with correct
David H. Kirn et al. (eds.), Oncolytic Viruses: Methods and Protocols, Methods in Molecular Biology, vol. 797, DOI 10.1007/978-1-61779-340-0_3, © Springer Science+Business Media, LLC 2012
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K. Doronin and D.M. Shayakhmetov
ones (replacement gene therapy). It was found, however, that the transient nature of expression from these vectors is a major limitation. In cancer gene therapy, however, transient expression does not represent an obstacle since the goal in this case is to kill infected cancer cells. As replication-deficient vectors have higher cloning capacities and are generally considered a safer alternative, these vectors were used in gene therapy studies initially for delivery of therapeutic genes to cancer cells in tumors. It was soon realized that replication-competent Ad vectors might have advantages over replication-deficient vectors in the context of cancer gene therapy because these vectors are self-amplifying within tumors and they can reinfect tumor cells that were not infected upon initial transduction. Repeating cycles of reinfection result in elimination of tumors. This envisaged scenario led to expectations that oncolytic (replication-competent) Ad can be used for systemic (intravascular) treatment rather than the intratumoral injection route that has been used in the majority of clinical trials. Wild-type Ads of various serotypes were used in clinical trials as early as 1956 and were found to lack significant anticancer activity (2). A first-generation cancerspecific vector ONYX-015 with a deletion of E1B-55K was believed at that time to confer selectivity of replication in p53 negative (cancer) versus p53 positive (normal) cells. This vector was evaluated in clinical trials in the 1990s and was found to lack activity as a single agent although some activity was found in combination with chemotherapy (3). More recently, a vector similar to ONYX-015 but lacking the E3 region (Oncorine, H101) was approved for clinical use in China against head and neck cancers using intratumoral injection in combination with chemotherapy. The approval of Oncorine was an important milestone for the field of cancer gene therapy and oncolytic viruses; however, more efficacious oncolytic Ads need to be developed to win regulatory approval in other countries. In addition, for commercial success, oncolyt
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