Selectivity of oncolytic viral replication prevents antiviral immune response and toxicity, but does not improve antitumoral immunity.
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.
Gürlevik
Engin
E
Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
Woller
Norman
N
Strüver
Nina
N
Schache
Peter
P
Kloos
Arnold
A
Manns
Michael P
MP
Zender
Lars
L
Kühnel
Florian
F
Kubicka
Stefan
S
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
D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D019098:Telomerase