title: Selectivity of oncolytic viral replication prevents antiviral immune response and toxicity, but does not improve antitumoral immunity.
abstract: Oncolytic infection elicits antitumoral immunity, but the impact of tumor-selective replication on the balance between antiviral and antitumoral immune responses has not yet been investigated. To address this question, we constructed the highly tumor-selective adenovirus Ad-p53T whose replication in target tumor cells is governed by aberrant telomerase activity and transcriptional p53 dysfunction. Telomerase-dependent or nonselective adenoviruses were constructed as isogenic controls. Following infection of mice with the nonselective adenovirus, viral DNA and mRNA levels correlated with strong stimulation of innate immune response genes and severe liver toxicity, whereas telomerase-/p53-specific replication did not trigger innate immunity and prevented liver damage. Compared to telomerase-dependent or unselective viral replication, telomerase-/p53-specific virotherapy significantly decreased antiviral CD8-specific immune responses and antiviral cytotoxicity in vivo. Consistent with our hypothesis, telomerase-selective replication led to intermediate results in these experiments. Remarkably, all viruses efficiently lysed tumors and induced a therapeutically effective tumor-directed CD8 cytotoxicity. In immunocompetent mice with extended lung metastases burden, treatment of subcutaneous primary tumors with Ad-p53T significantly prolonged survival by inhibition of lung metastases, whereas unselective viral replication resulted in death by liver failure. In summary, the degree of tumor selectivity of viral replication marginally influences antitumoral immune responses, but is a major determinant of antivector immunity and systemic toxicity.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
authors.forename: Engin
authors.initials: E
authors.lastname: Gürlevik
authors.forename: Norman
authors.initials: N
authors.lastname: Woller
authors.forename: Nina
authors.initials: N
authors.lastname: Strüver
authors.forename: Peter
authors.initials: P
authors.lastname: Schache
authors.forename: Arnold
authors.initials: A
authors.lastname: Kloos
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.forename: Florian
authors.initials: F
authors.lastname: Kühnel
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicka
mesh_terms: D000256:Adenoviridae / Q000502:physiology*; D000257:Adenoviridae Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D006801:Humans; D007124:Immunoenzyme Techniques; D008107:Liver Diseases / Q000276:immunology* / Q000628:therapy / Q000821:virology; D008175:Lung Neoplasms / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D050504:Oncolytic Viruses / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D014779:Virus Replication / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D019098:Telomerase