A Novel Assay to Assess Primary Human Cancer Infectibility by Replication-Selective Oncolytic Adenoviruses

Author:

Wang Yaohe1,Thorne Stephen2,Hannock Joseph3,Francis Jennelle1,Au Tina2,Reid Tony2,Lemoine Nick1,Kirn David45,Halldén Gunnel1

Affiliation:

1. 1Cancer Research UK Molecular Oncology Unit, Imperial School of Medicine and

2. 3Veterans Affairs Palo Alto Health Care System and Stanford University School of Medicine, Palo Alto, California;

3. 2Department of Obstetrics and Gynaecology, Hammersmith Hospital, London, United Kingdom;

4. 4Department of Clinical Pharmacology, Oxford University Medical School, Oxford, United Kingdom; and

5. 5Jennerex Biotherapeutics, Mill Valley, California

Abstract

Abstract Purpose: Replication-selective oncolytic adenoviruses hold promise for cancer treatment, but the predictive use of cell lines, dissociated tumor tissue, and animal models for efficacy against primary cancers are unclear. To further evaluate cytotoxicity and the potential for efficacy of replication-competent adenoviruses we therefore developed a novel methodology using primary human cancer specimens ex vivo; ovarian, colon, rectal, and breast carcinomas were included. Experimental Design: Tissue culture conditions were developed to maintain viability of adenocarcinomas ex vivo for 48 hours postsurgery. Explants were infected by replication-competent (wild type 5 and E1A mutant dl922-947) and replication-defective (dl312) adenoviruses; early (E1A) and late (hexon) viral gene expression, αv integrins, coxsackievirus and adenovirus receptor (CAR) and tissue viability were assessed by immunohistochemistry and histopathology. Viral replication was verified by replication assays on selected samples. Results: Viral gene expression varied dramatically among cancer specimens (n = 41). With Ad5, hexon expression was high in 8 of 11 tested specimens, whereas E1A levels were detectable in 16 of 27 tumor explants. Viral gene expression, distribution, and cytopathic effects were greater postinfection with dl922-947. Specimens that supported early gene expression (E1A) also supported viral replication in 13 of 14 tested cases, determined by recovery of infectious units. As predicted, the replication-defective adenovirus dl312 was not associated with viral gene expression. Conclusions: Primary human tumor tissue remained viable when cultured ex vivo enabling evaluation of viral mutants in tissue with intact morphology. This assay may have great use in determining treatment-sensitive cancers and assess specific oncolytic mutants in individual cases.

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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