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P05

Normothermically perfused human liver lobes containing tumours as a model to profile viral therapeutics.

D S Johnson(1) B Nicholls(1) E Page(1) K RJ Friesen(1) F Caviezel(1) E J Jacobus(1) L W Seymour(1) K D Fisher(1) C C Coussios(1) A N Gordon-Weeks(1) R C CARLISLE(1)

1:University of Oxford

Liver lobes with resident tumours are commonly resected from cancer patients. We show these lobes can now be attached to a clinically approved liver transplantation device (metra®, OrganOx, Oxford), creating a unique testing platform to match the scale, physiology, vasculature, and immune composition of tumours in a human patient, whilst allowing dosing, testing and sampling regimens which would not be permitted in a patient on a clinical trial. Three hemi-liver lobes containing either cholangiocarcinoma or metastatic colorectal tumours retrieved in theatre were connected to the  metra® to mimic physiological conditions. The lobes were dosed with 1e¹² copies of an Ad11-based "traffic light" virus with UnaG green protein expression under an early viral promoter to show uptake and red fluorescent protein expression under a late viral promoter to indicate replication. Health of the lobes were maintained for up to 60 hours post-dosing, after which raised hydrodynamic vascular resistance and lactate levels signalled a loss of function. Throughout the perfusion, metrics of liver health were recorded, and blood samples were taken to profile viral clearance using QPCR and infectivity tests. Normal liver and tumour tissue samples were taken at the conclusion for QPCR, flow cytometry, ex vivo out-growth, and immunohistochemistry. Clearance of the virus showed good alignment with clinical data. Active virus was present in out-grown ex vivo sample slices with green and red fluorescence evident in tumour tissue. This model could provide useful insights into the pharmacokinetics and distribution of virus-based therapies in human liver containing tumours.

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