E3 gene manipulations affect oncolytic adenovirus activity in immunocompetent tumor models

Yaohe Wang, Gunnel Hallden, Richard Hill, Arthi Anand, Ta Chiang Liu, Jennelle Francis, Gabriel Brooks, Nick Lemoine, David Kirn

Research output: Contribution to journalArticle

113 Scopus citations

Abstract

Oncolytic replication-selective adenoviruses constitute a rapidly growing therapeutic platform for cancer. However, the role of the host immune response and the E3 immunoregulatory genes of the human adenovirus were unknown until now. We identified four mouse carcinoma lines of variable permissivity for adenoviral gene expression, cytopathic effects and/or burst size. To determine E3 gene effects in immunocompetent tumor-bearing hosts, we injected tumors with one of three adenoviruses: Ad5 (E3 wild type), d/309 (del. E3 10.4/14.5, 14.7 kDa) or d/704 (del. E3 gp19 kDa). Compared with Ad5 and d/704, d/309 was cleared much more rapidly and/or its activity was lower in all four models. Intratumoral injection with d/309 resulted in markedly greater macrophage infiltration and expression of both tumor necrosis factor and interferon-γ. Adenovirus replication, CD8+ lymphocyte infiltration and efficacy were similar upon intratumoral injection with either d/704 or Ad5. E3-dependent differences were not evident in athymic mice. These findings have important implications for the design of oncolytic adenoviruses and may explain the rapid clearance of E3-10.4/14.5,14.7-deleted adenoviruses in patients.

Original languageEnglish
Pages (from-to)1328-1335
Number of pages8
JournalNature Biotechnology
Volume21
Issue number11
DOIs
StatePublished - Nov 1 2003
Externally publishedYes

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    Wang, Y., Hallden, G., Hill, R., Anand, A., Liu, T. C., Francis, J., Brooks, G., Lemoine, N., & Kirn, D. (2003). E3 gene manipulations affect oncolytic adenovirus activity in immunocompetent tumor models. Nature Biotechnology, 21(11), 1328-1335. https://doi.org/10.1038/nbt887