Viral oncolysis is an exciting area of research with applications to tumours throughout the body. Understanding the background and development of viral oncolytic therapy is important for future applications. For the interventional radiology community, intra-arterial viral oncolysis holds promise as a new treatment for primary and metastatic liver cancer. It may soon become an additional tool for the practicing interventional oncologist, writes Omar Zurkiya.
Viral oncolysis broadly refers to the use of modified viruses to infect and subsequently lyse tumour cells. This concept arises from the observation that viral replication is itself effective in destroying tumour cells. This effect is then amplified by reinfection of adjacent tumour cells by the progeny virion released from lysed tumour cells.
Herpes simplex virus 1 (HSV-1) has been the primary focus of current efforts in viral oncolysis. It is a double-stranded DNA virus that is a ubiquitous pathogen transmitted by direct mucosal contact. Infection with HSV-1 is common, reported to be 66% to 84% in the USA. Skin or mucosal infection with HSV-1 is typically followed by transmission via sensory nerves to the trigeminal ganglia where lifelong latent infection occurs. Reactivation from ganglionic neurons may occur resulting in an epithelial ulcer (eg “cold sore”) with viral shedding into the oral cavity or epithelia in the trigeminal distribution.
HSV-1 possesses several features well suited to viral oncolytic therapy. It does not integrate into the cellular genome, has a large transgene capacity of up to 50kb, and is already highly prevalent in the general population. Additionally, effective anti-herpetic agents are available to stop unwanted viral replication.
HSV-1 mutants that preferentially replicate in neoplastic cells rather than normal cells have been characterised, and several variants of replication deficient HSV-1 mutants have been created and studied. They follow a common theme in that their replication is significantly attenuated in normal cells, while activated in cancer cells. Studies have been performed in various strains including those known as G207, NV1020, OncoVEXGM-CSF and rRp450. Each of these mutants is attenuated relative to wildtype HSV-1.
Where we are now
G207 is an HSV-1 mutant under development by MediGene (Frankfurt, Germany) in which both copies of the γ134.5 gene, implicated in viral replication have been deleted, and the UL39 gene is inactivated. In a phase I trial establishing safety in subjects with brain tumours, no toxicity or serious adverse events were attributed to G207. Additionally, there was no difference in side-effects between patients who had previously been exposed to HSV-1 versus those not previously exposed. In a phase I trial from the University of Alabama, published in May of 2014, G207 was administered stereotactically into glioblastoma tumours in conjunction with radiation. Six of the nine patients in the trial demonstrated stable disease or partial response for at least one of the time points in the study with three demonstrating marked radiographic response.
NV1020 is an HSV-1 mutant in which the internal repeat is deleted and replaced by a fragment of the HSV-2 genome. In a study of interest to the interventional radiology community, a phase I, open-label, dose-escalating trial in patients with metastatic colorectal carcinoma to liver has been performed. Patients received a single 10-minute hepatic arterial infusion of NV1020. Adverse events were either mild or moderate in severity, and self-limiting. Only three serious adverse events (one transient rise in serum g-glutamyltransferase, one diarrhoea, and one leukocytosis) experienced by three patients were considered to be possibly or probably related to NV1020. There was no evidence of disseminated herpes infection.
A multicentre phase I/II study published in September 2010 from Vanderbilt University evaluated 32 patients with advanced metastatic colorectal cancer (mCRC) to the liver. Patients received four weekly intra-arterial NV1020 doses, followed by two or more cycles of conventional chemotherapy. An optimum biological dose of 1×108 plaque forming units per dose was established. Of the 22 patients receiving this dose, 11 (50%) initially showed stable disease.
OncoVEXGM-CSF is an HSV-1 mutant expressing granulocyte macrophage colony stimulating factor (GM-CSF). In a phase II study OncoVEXGM-CSF was injected intratumourally into patients with stage IIIC or IV melanoma. Patients received an initial injection into 1–10 accessible tumours followed by three-week interval, then continued two-weekly injections for a total of up to 24 injections. Both patients previously exposed and not previously exposed to HSV-1were included in the study. Response rates were similar in these two groups. The overall response rate by RECIST was 26% (eight with complete response and five with partial response). Overall survival was 58% at one year and 52% at 24 months.
At our institution rRp450 is under investigation for viral oncolysis. It is a genetically engineered HSV-1 mutant of laboratory strain KOS. The viral gene (UL39) encoding infected cell protein 6 (ICP6) has been removed and substituted with the coding sequence of another gene, rat cyp2B1 cytochrome p450 gene. rRp450 is therefore defective in expression of ICP6 (large subunit of viral ribonucleotide reductase), markedly attenuating its replication in normal cells. Its replication in cancer cells is significantly more robust, as these transformed cells provide nucleotide precursors to complement the absence of viral ribonucleotide reductase.
Preclinical studies demonstrated that following administration into portal venous system, viral replication occurs preferentially in liver tumour cells versus normal liver. The cytotoxicity associated with the viral replication results in a marked reduction in tumour burden and prolongation of animal survival. Importantly, rRp450 retains its thymidine kinase gene, thereby rendering the virus susceptible to treatment with acyclovir and its analogues to terminate any unwanted viral replication.
A phase I clinical trial to determine the safety of rRp450 and the highest dose of this agent that can be given safely is currently underway at Massachusetts General Hospital. This involves intra-arterial injection of rRp450 for treatment of primary liver tumours as well as metastatic tumours to the liver. Additional study goals include how the agent is absorbed by the liver cancers, how quickly it is eliminated, and evaluation of tumour response.
For the interventional radiology community, intra-arterial viral oncolysis holds promise as a new treatment for primary and metastatic liver cancer. It may soon become an additional tool for the practicing interventional oncologist
Omar Zurkiya is with the division of Interventional Radiology, Department of Radiology, Massachusetts General Hospital, USA. He has reported no disclosures pertaining to the article
