There have been many clinical trials of a variety of OVs delivered systemically, as summarised in . Oncolytic adenovirus was one of the first oncolytic viruses to be developed and licensed for treatment of cancer [8
]. The first generation of oncolytic adenovirus, ONYX-015 (also known as dl
1520, H101 in China), is a genetically modified adenovirus with deletion of the 55 kD gene in the E1B region. Nemunaitis et al. [10
] in 2001 performed a dose escalation study using this agent in patients with advanced carcinoma with lung metastases. They demonstrated that ONYX-015 was safe to deliver systemically with no toxicity up to doses of 2 × 1013
particles, but the study was not designed for objective tumour responses. Also commencing in 2001, a succession of studies delivered ONYX-015 via hepatic artery infusion for the treatment of metastatic colorectal carcinoma with liver deposits [11
]. In the first of these trials, a phase I dose escalation study, one patient (9%) responded after combination therapy with conventional chemotherapy and two patients (18%) had stable disease lasting several months [11
]. In a larger phase II follow-up trial, three patients (11%) had partial responses, nine (33%) had stable disease, and eleven (41%) patients had progressive disease [12
]. A final phase II trial by this group demonstrated similar results to the previous studies with overall median survival of 10.7 months with two patients (8%) having a partial response and a further eleven (46%) having stable disease [13
]. Of those with stable disease the median survival was prolonged to nineteen months. In a different study, Small et al. [14
] treated patients with hormone-refractory metastatic prostate cancer using a single intravenous infusion. Unlike ONYX-015, the adenovirus (CG7870) in this trial was modified so that E1A was under the control of the rat probasin promoter and E1B was under the control of the PSA promoter-enhancer, thus making it prostate specific. Results from this trial were disappointing with no complete nor partial responses, although five patients (22%) did have a 25% to 49% reduction in their serum PSA values.
Completed clinical trials using systemically delivered oncolytic viruses for the treatment of solid tumours.
PV701 is a naturally attenuated Newcastle disease virus, which has been used systemically in a number of clinical trials between 2002 and 2007 [15
]. Three of these trials were phase I studies in patients with a variety of advanced/metastatic solid tumours [15
]. In the Pecora et al. [15
] study in 2002, 62 patients were assessed for a tumour response and two patients (3%) had a major response and 14 patients (23%) had stable disease for 4–30 months. Hotte et al. [18
] performed a small phase I study and although not designed to assess efficacy, four major (22%) and two minor (11%) responses to the treatment were observed. A similarly sized trial by Laurie et al. [16
] in 2006 reported stable disease in four patients (25%) for greater than six months. Freeman et al. [17
] investigated the safety of using Newcastle disease virus in patients with recurrent glioblastoma multiforme and as with the other studies the treatment was well tolerated but the efficacy was again disappointing with only one patient (7%) having a complete response.
NV1020 is a Herpes Simplex virus type 1 with deletions of the latency factors ICPO and ICP4, and only one copy of its virulence factor y134.5. Another element of safety is the insertion of the α
4 promoter to control the HSV-1 TK gene expression, which sensitises the virus to antiviral drugs such as acyclovir. One phase I trial [19
] delivering NV1020 via hepatic artery infusion in patients with hepatic metastases from colorectal primaries refractory to first-line treatment reported seven patients (58%) with stable disease and two patients showing a partial response. Median survival in this group was 25 months. Another trial by Geevarghese et al. [21
] in 2010 again delivered NV1020 by hepatic artery infusion in patients with advanced metastatic colorectal carcinoma but this time followed by conventional chemotherapy. After completion of the combined approach, there was a 68% response rate, with one patient with a partial response and fourteen patients with stable disease. Median survival in this study was 11.8 months.
Reolysin is a type 3 Dearing Reovirus in its wild-type form. Vidal et al. [23
] completed the only trial using systemic delivery in 2008. They performed a phase I dose escalation study assessing the safety of a variety of doses. As such they observed no dose-limiting toxicity, and they further comment that antitumour activity was observed both radiologically and by tumour markers. However, no objective radiologic responses were observed in terms of Response Evaluation Criteria in Solid Tumours. Despite this they did report that eight patients showed disease stabilisation. There are also two phase II trials and one phase III trial that have been registered (NCT01166542, NCT01199263, NCT01280058). The phase III trial is in patients with metastatic or recurrent squamous cell carcinoma of the head and neck, whereas the two phase II trials are in recurrent ovarian/fallopian tube cancer and recurrent pancreatic cancer, respectively. All these trials are still recruiting ().
Ongoing or pending clinical trials using systemically delivered oncolytic viruses for the treatment of solid tumours.
JX-594 is a Vaccinia virus based on the Wyeth strain with a thymidine kinase (TK) deletion and the insertion of human granulocyte macrophage colony stimulating factor (hGM-CSF) gene and Lac-Z into the TK-deleted region. These transgenes are under the control of pE/L and p7.5 promoters, respectively. Jennerex Biotherapeutics Inc. has reported the results of one trial using this agent systemically in patients with unresectable primary hepatocellular carcinoma. They performed a phase I safety study delivering JX-594 initially systemically then intratumourally with subsequent sorafenib treatment. Seven out of nine of their patients were suitable to be assessed: in six patients (67%), the tumours necrosed, and of these five patients (56%) had stable disease and one patient (11%) had a partial response. They have recently reported the results of another dose escalation study using JX-594 in patients with metastatic solid tumour disease, which was refractory to conventional therapy. The treatment was well tolerated and at higher doses of virus (1 × 107
to 3 × 107
PFU/kg), and they demonstrated that JX-594 can selectively infect, replicate, and express transgene products in target tumour tissue whilst sparing normal tissue. Although the study was not designed for efficacy, one patient had partial response [22
]. Jennerex Biotherapeutics Inc. has two trials pending with respect to this agent, the details of which are illustrated in .
In general these clinical trials have shown that oncolytic viruses can be delivered systemically with limited toxicity and latency. However, what they have not shown, and indeed were not powered to show, is that these agents are efficacious at treating either the primary tumour or metastatic disease. There is a complete lack of appropriately powered phase IIb or phase III trials using OVs delivered systemically, although there are a few pending for Reovirus. The data that are available demonstrate that systemically delivered oncolytic viruses offer only modest improvements, if at all, over and above conventional second-line therapy. Clearly if intravenously delivered OVs are to play a part in the future treatment of advanced cancer, there needs to be dramatic improvement.