Genetic delivery of an immunoRNase by an oncolytic adenovirus enhances anticancer activity
Inés Fernández-Ulibarri
Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
Search for more papers by this authorKatharina Hammer
Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
Search for more papers by this authorMichaela A.E. Arndt
Department of Translational Medicine, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 560, 69120 Heidelberg, Germany
Search for more papers by this authorJohanna K. Kaufmann
Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
Search for more papers by this authorDominik Dorer
Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
Search for more papers by this authorSarah Engelhardt
Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
Search for more papers by this authorRoland E. Kontermann
Institut für Zellbiologie und Immunologie, Stuttgart University, Allmandring 31, 70569 Stuttgart, Germany
Search for more papers by this authorJochen Hess
Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany
Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Search for more papers by this authorHeike Allgayer
Clinical Cooperation Unit Molecular Oncology of Solid Tumors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Department of Experimental Surgery, Medical Faculty Mannheim, University Heidelberg, Theodor-Kutzer-Ufer 1 – 3, 68167 Mannheim, Germany
Search for more papers by this authorJürgen Krauss
Department of Translational Medicine, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 560, 69120 Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Dirk M. Nettelbeck
Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
Correspondence to: Dirk M. Nettelbeck, Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany, Tel.: +49 (0) 6221 424450, Fax: +49 (0) 6221 421659, E-mail: [email protected]Search for more papers by this authorInés Fernández-Ulibarri
Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
Search for more papers by this authorKatharina Hammer
Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
Search for more papers by this authorMichaela A.E. Arndt
Department of Translational Medicine, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 560, 69120 Heidelberg, Germany
Search for more papers by this authorJohanna K. Kaufmann
Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
Search for more papers by this authorDominik Dorer
Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
Search for more papers by this authorSarah Engelhardt
Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
Search for more papers by this authorRoland E. Kontermann
Institut für Zellbiologie und Immunologie, Stuttgart University, Allmandring 31, 70569 Stuttgart, Germany
Search for more papers by this authorJochen Hess
Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany
Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Search for more papers by this authorHeike Allgayer
Clinical Cooperation Unit Molecular Oncology of Solid Tumors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Department of Experimental Surgery, Medical Faculty Mannheim, University Heidelberg, Theodor-Kutzer-Ufer 1 – 3, 68167 Mannheim, Germany
Search for more papers by this authorJürgen Krauss
Department of Translational Medicine, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 560, 69120 Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Dirk M. Nettelbeck
Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
Correspondence to: Dirk M. Nettelbeck, Oncolytic Adenovirus Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany, Tel.: +49 (0) 6221 424450, Fax: +49 (0) 6221 421659, E-mail: [email protected]Search for more papers by this authorAbstract
Antibody therapy of solid cancers is well established, but suffers from unsatisfactory tumor penetration of large immunoglobulins or from low serum retention of antibody fragments. 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-encoding oncolytic adenovirus, we combine viral oncolysis with intratumoral genetic delivery of a small antibody-fusion protein for targeted bystander killing of tumor cells (viro-antibody therapy). Specifically, we explore genetic delivery of a small immunoRNase consisting of an EGFR-binding scFv antibody fragment fused to the RNase Onconase (ONCEGFR) 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 ONCEGFR expression by oncolytic adenoviruses is feasible with an optimized, replication-dependent gene expression strategy. Virus-encoded ONCEGFR induces potent and EGFR-dependent bystander killing of tumor cells. Importantly, the ONCEGFR-encoding oncolytic adenovirus showed dramatically increased cytotoxicity specifically to EGFR-positive tumor cells in vitro and significantly enhanced therapeutic activity in a mouse xenograft tumor model. The latter demonstrates that ONCEGFR is expressed at levels sufficient to trigger tumor cell killing in vivo. The established ONCEGFR-encoding oncolytic adenovirus represents a novel agent for treatment of EGFR-positive tumors. This viro-antibody 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.
Abstract
What's new?
Antibody therapy of solid cancers is well established, but suffers from unsatisfactory tumor penetration of large immunoglobulins or from low serum retention of antibody fragments. Oncolytic viruses are emerging anti-cancer agents that show suboptimal potency due to limited virus spread within tumors. This study establishes an oncolytic virus that genetically delivers a small antibody-based biotherapeutic—an immunoRNase—to tumors. The combined approach addresses barriers to both viral spread and antibody penetration through the expression of small antibody-derivatives inside the tumor that leads to targeted bystander killing and enhanced therapy. Such viro-antibody therapy platform offers interesting opportunities for personalized cancer therapy or targeting of heterologous tumors.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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