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Oncolytic viruses are in advanced clinical development showing excellent safety, but suboptimal potency due to limited virus spread within tumors. Here, by developing an immunoRNase\u2010encoding oncolytic adenovirus, we combine viral oncolysis with intratumoral genetic delivery of a small antibody\u2010fusion protein for targeted bystander killing of tumor cells (viro\u2010antibody therapy). Specifically, we explore genetic delivery of a small immunoRNase consisting of an EGFR\u2010binding scFv antibody fragment fused to the RNase Onconase (ONC<jats:sub>EGFR<\/jats:sub>) that induces tumor cell death by RNA degradation after cellular internalization. Onconase is a frog RNase that combines lack of immunogenicity and excellent safety in patients with high tumor killing potency due to its resistance to the human cytosolic RNase inhibitor. We show that ONC<jats:sub>EGFR<\/jats:sub> expression by oncolytic adenoviruses is feasible with an optimized, replication\u2010dependent gene expression strategy. Virus\u2010encoded ONC<jats:sub>EGFR<\/jats:sub> induces potent and EGFR\u2010dependent bystander killing of tumor cells. Importantly, the ONC<jats:sub>EGFR<\/jats:sub>\u2010encoding oncolytic adenovirus showed dramatically increased cytotoxicity specifically to EGFR\u2010positive tumor cells <jats:italic>in vitro<\/jats:italic> and significantly enhanced therapeutic activity in a mouse xenograft tumor model. The latter demonstrates that ONC<jats:sub>EGFR<\/jats:sub> is expressed at levels sufficient to trigger tumor cell killing <jats:italic>in vivo<\/jats:italic>. The established ONC<jats:sub>EGFR<\/jats:sub>\u2010encoding oncolytic adenovirus represents a novel agent for treatment of EGFR\u2010positive tumors. This viro\u2010antibody therapy platform can be further developed for targeted\/personalized cancer therapy by exploiting antibody diversity to target further established or emerging tumor markers or combinations thereof.<\/jats:p>","DOI":"10.1002\/ijc.29258","type":"journal-article","created":{"date-parts":[[2014,10,10]],"date-time":"2014-10-10T08:28:40Z","timestamp":1412929720000},"page":"2228-2240","source":"Crossref","is-referenced-by-count":14,"title":["Genetic delivery of an immuno<scp>RN<\/scp>ase by an oncolytic adenovirus enhances anticancer activity"],"prefix":"10.1002","volume":"136","author":[{"given":"In\u00e9s","family":"Fern\u00e1ndez\u2010Ulibarri","sequence":"first","affiliation":[{"name":"Oncolytic Adenovirus Group German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Hammer","sequence":"additional","affiliation":[{"name":"Oncolytic Adenovirus Group 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