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DOI: 10.1055/s-0032-1323875
Onkolytische Sendai-Viren als neuartiger Ansatz zur virotherapeutischen Behandlung des HCC
Introduction: Hepatocellular carcinoma (HCC) is one of the most common cancers. Virotherapy provides an alternative new mechanistic treatment approach, based on a selective viral replication in tumor cells, inducing cellular destruction. To reach a broad range of different tumors and select an ideal vector system for each disease entity, including tumors of hepatobiliary origin, it is challenging to develop new oncolytic viruses with attractive properties. Murine parainfluenza virus type I (Sendai virus, SeV) is a murine pathogen that infects human cell types in a highly efficient manner. SeV has entered clinical trials recently; however, infectious progeny viruses are not constitutively produced in host cells, which mean an immediate abrogation of viral replication in cancer cells.
Aim: Development and evaluation of genetically modified SeV vectors, which enable a tumor-selective replication, followed by widespread oncolysis.
Methods: By mutagenesis and reverse genetics, six novel recombinant SeV-variants (rSeV Fmut) with different knockouts of immune modulating accessory proteins could be successfully rescued. These were evaluated in detail in terms of viral spread, quantification of progeny viruses as well as for death induction capabilities in HCC cell lines and primary human hepatocytes (PHH) or fibroblasts (MRC-5). Viral spread was additionally investigated in a xenograft model in vivo.
Results: All new rSeV Fmut-variants replicated well in human HCC cells (up to 3.2×108 TCID50/105 cells). In contrast, virus release from untransformed MRC-5 fibroblasts or PHH was reduced by about three log steps, and even more pronounced for two SeV-knockout variants (<5×103 TCID50). Even at low virus-to-cell ratios (MOIs of 0.01 or 0.1) a highly sufficient oncolysis could be observed. Furthermore, a tumor-restricted spread could be confirmed in vivo in a PLC/PRF/5 hepatoma-xenograft mouse model.
Conclusion: Novel recombinant oncolytic SeV vectors exhibit a selective and effective replication in human HCC tumor cells in vitro as well as in vivo in a hepatoma xenograft. As SeV vectors already entered clinical trials, these novel oncolytic particles can be used to build up a new vector platform providing innovative treatment options for primary liver tumors.
Neue therapeutische und diagnostische Perspektiven beim hepatozellulären Karzinom (HCC)
Donnerstag, 20. September 2012/10:30–12:00/Saal D