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Persistent Replication of the Modified Chimeric Adenovirus ONYX-015 in both Tumor and Stromal Cells from a Patient with Gall Bladder Carcinoma Implants¹

Division of Hematology/Oncology, Departments of Medicine [S. W., B. Y., M. H.] and Pathology [J-Y. T., E. H.], Weill Medical College of Cornell University, New York, New York 10021, and the Departments of Surgery [R. K.], Radiology [A. R.], Medicine [D. M.], Pathology [M. E.] and Microbiology-Immunology [M. H.], Albert Einstein College of Medicine and the Albert Einstein Cancer Center, Bronx, New York 10463

Purpose: ONYX-015 is a chimeric, E1B-deleted adenovirus designed to replicatepreferentially in p53-deficient tumor cells; however, little is understood about its actual replication potential in human tumors. We hypothesized that replication of a late viral gene, hexon, would demonstrate replication of virus in human tissues.

Experimental Design: In the course of a clinical trial, a patient with paired abdominal wall implants from a primary gall bladder carcinoma was injected with ONYX-015, 1 x 10¹⁰ viral particles/lesion, followed by sequential excision of the lesions at 37 h and 7 days. Tissue sections were analyzed for evidence of viral replication.

Results: In situ Reverse transcription-PCR was used to measure expression of hexon. Strong signals were obtained in gland-forming tumor cells both at 37 h and at 7 days. Signal was predominantly observed in the cytoplasm. The signal was also observed in adjacent normal stromal cells. Analysis of p53 status of the tumor by immunohistochemistry and Affymetrix Genechip demonstrated an inactivating mutation in p53. Routine H&E staining of the tumor sections revealed no evidence of necrosis at 37 h or 7 days after injection of virus. Presence of viral protein at both 37 h and 7 days was confirmed by immunohistochemistry using antibodies directed against hexon, penton, and fiber proteins.

Conclusions: Evidence for replication of hexon confirms that ONYX-015 is not only present but capable of replicating in tumor cells up to 1 week after intralesional injection and that replication is not confined to p53-mutated tumor cells.

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