The Hitchhiker's Guide to Virotherapy

1 In contrast to most other cancer therapies, early research with oncolytic viruses (OV) tended to use direct or intratumoural routes of administration, initially motivated by concerns that the major limitation of intravenous delivery would be immune attack against the viruses, whether by complement, cytokine or most critically neutralising antibodies. Even in the absence of preformed circulating neutralising antibodies, antiviral immunity develops rapidly over the course of multiple viral administrations [1]. Preclinically ex vivo cell preparations have been used to load virus onto or into assorted cells, including white blood cells (often called 'hitchhiking'), but such manoeuvres would be difficult to implement clinically. Given these perceived limitations, many have chosen direct administration to maximise intratumoural delivery: H101 (an oncolytic adenovirus with selectivity against p53-defective tumour cells) is approved in China and is given intratumourally for head and neck cancers. Several viruses have been administered into the tumour bed perioperatively for glioma. Measles has been administered intraperitoneally in ovarian cancer. One of the field-leading products is T-Vec (aka OncoVex), an engineered herpes virus. Its recent acquisition by Amgen was a fillip for those in the OV field, and was based on promising phase II data in melanoma where the virus was injected intratumourally into all accessible lesions [2]; a phase III study has closed to recruitment and results are keenly awaited. However these direct delivery routes are unpleasant for patients, unpopular with clinicians and unachievable for many deep-seated tumours [3]. We previously recovered replication-competent reovirus from tumour following intravenous infusion in three patients with head and neck cancer, [4] a finding recently replicated by Breitbach and colleagues using JX-594, an engineered vaccinia derivative [5]. Following intravenous injection JX594 was detected in whole blood by quantitative polymerase chain reaction (qPCR) for at least four hours after infusion. Patients underwent tumour biopsies 8-10 days after viral administration, and these biopsies were examined by PCR and by immunohistochemistry (IHC) for native viral protein and expression of the engineered marker gene. Amongst the eight subjects treated in the higher dose cohorts, all eight had at least one positive viral marker; four were positive across all three assays. These vital observations that two different viruses, administered intravenously, reach tumour tissues strongly support the further development of OV for systemic use in metastatic disease. However, neither of these studies completely addressed the issue of how a systemically administered virus might successfully run the gauntlet of anti-viral immunity. …