Systemic Delivery of Oncolytic Viruses: Hopes and Hurdles

Table 1

Completed clinical trials using systemically delivered oncolytic viruses for the treatment of solid tumours.

Viral agent	Virus species	Modifications	Cancer type	Pt no.	Treatment regime	Toxicity	Results	References
ONYX-015	Adenovirus	E1B-55 kD-ve	Advanced carcinoma with lung metastasis	10	Phase I, dose-escalation study	No dose-limiting toxicity was observed. Grade 2-3 toxicities were common (fever, rigors and fatigue).	IV administration was well tolerated up to 2×10^13 particles. Not designed for objective tumour responses.	Nemunaitis et al., 2001 [10]
ONYX-015	Adenovirus	E1B-55 kD-ve	Liver metastases from gastrointestinal carcinoma	11	Phase I, dose-escalation study hepatic artery infusion	No dose-limiting toxicity. Commonly mild to moderate fever, rigors and fatigue.	Objective response with chemotherapy + virus in a patient who was refractory to both 5-FU and ONYX-015 as single agents. 2 high dose patients had stable disease on combination therapy lasting from 7 to 17 months.	Reid et al., 2001 [11]
Onyx-015	Adenovirus	E1B-55 kD-ve	Metastatic liver deposits from gastrointestinal primaries	27	Phase II, hepatic artery infusion in combination with 5 FU and leucovorin	2 patients had reversible grade 3/4 hyperbilirubinemia and 1 patient had a reversible severe systemic inflammatory response.	3 patients with partial responses, 4 with minimal responses, 9 with stable disease, and 11 with progressive disease. Unclear from this study whether observed responses were due to viral treatment or chemotherapy or combination.	Reid et al., 2002 [12]
ONYX-015	Adenovirus	E1B-55 kD-ve	Metastatic colorectal cancer refractory to conventional therapy	24	Phase I/II, hepatic artery infusion	No dose-limiting toxicity was observed.	Overall median survival was 10.7 months. 2 patients had partial responses (tumur vol reductions of 66% and 72%). 11 patients had stable disease after viral treatment and median survival in this group was 19 months.	Reid et al., 2005 [13]
CG7870	Adenovirus	E1A under control of the rat probasin promoter E1B under control of the PSA promoter-enhancer	Hormone-refractory metastatic prostate cancer	23	Phase I, single intravenous infusion	Mostly grade 1 or 2 flulike symptoms were observed. There were 8 grade 3 events (fever or fatigue). At higher doses, asymptomatic grade 1 or 2 transaminitis were reported.	No partial or complete tumour responses were observed. 5 patients had a decrease in serum PSA of 25% to 49% following a single treatment.	Small et al., 2006 [14]
PV701	Newcastle disease virus	Naturally attenuated	Advanced or metastatic solid cancers that were refractory to standard treatment	79	Patients were recruited into 4 different IV dosing regimes.	Grade 3 fever in 11% flu-like symptoms	62 patients assessed for response, 2 major responses, 14 had no disease progression for 4–30 months.	Pecora et al., 2002 [15]
PV701	Newcastle disease virus	Naturally attenuated	Pallitive solid tumors	16	Phase 1	No dose-limiting toxicities. Mild flu-like symptoms were common.	Four patients had stable disease for ≥6 months.	Laurie et al., 2006 [16]
NDV-HUJ	Newcastle disease virus	Naturally attenuated	Recurrent glioblastoma multiforme	14	Phase I/II	5 patients had grade I/II constitutional fever.	One patient achieved a complete response.	Freeman et al., 2006 [17]
PV701	Newcastle disease virus	Naturally attenuated	Advanced chemorefractory cancer	18	Phase 1	Mild or moderate in severity, and self-limiting	Not design for assessment of response but 4 major and 2 minor tumour responses were observed.	Hotte et al., 2007 [18]
NV1020	Herpes simplex virus type 1	ICP0 & ICP4-ve Only 1 copy of γ134.5 Transgene inserted HSV-1 TK gene (α4)	Hepatic colorectal metastases refractory to first-line chemotherapy	12	Phase I, dose-escalation study, hepatic artery infusion	Mild or moderate in severity, and self-limiting	Tumour response assessed at 28 days after viral delivery. 7 patients had stable disease. 2 patients had a partial response (tumour vol reductions of 39% and 20%). Median survival for this group was 25 months.	Kemeny et al., 2006 [19]; Fong et al., 2009 [20]
NV1020	Herpes simplex virus type 1	ICP0 & ICP4-ve Only 1 copy of γ134.5 Transgene inserted HSV-1 TK gene (α4)	Advanced metastatic colorectal	Phase 1 = 13, Phase 2 = 19	Phase I/II study, hepatic artery infusion treatment followed by two or more cycles of conventional chemotherapy	Mild-to-moderate febrile reactions after each NV1020 infusion. Grade 3/4 transient lymphopenia in two patients	After completion of NV1020 administration, 50% showed stable disease. Best overall tumor control rate after completion of combined therapy was 68% (1 partial response, 14 stable disease). Median time to progression was 6.4 months. Median overall survival was 11.8 months. One-year survival was 47.2%.	Geevarghese et al., 2010 [21]
JX-594	Vaccinia—Wyeth	TK-ve Transgene inserted in TK region hGM-CSF (pE/L) and Lac-Z (p7.5)	Unresectable primary hepatocellular carcinoma	9	Phase 2, pilot safety study IV then IT injection followed by sorafenib treatment	They assert viral treatment was well tolerated and sorafenib side effects were consistent with previously reported.	7 out of 9 were able to be assessed for response. Of these, 6 achieved necrotic responses. 5 had stable disease and 1 had a partial response.	http://www.clinicaltrials.gov/ Jennerex Biotherapeutics, Inc. NCT01171651 http://www.jennerex.com/pr_091310.html
JX-594	Vaccinia—Wyeth	TK-ve Transgene inserted in TK region hGM-CSF (pE/L) and Lac-Z (p7.5)	Metastatic solid tumour disease which is refractory to conventional therapy specifically: Melanoma, Lung Cancer, Renal cell cancer, SCC of head and neck	23	Phase I, Dose Escalation Study	No dose-limiting toxicities. Mild flu-like symptoms were common.	Demonstrated that at the higher doses used (1×10^7 to 3×10^7 PFU/kg) JX-594 can selectively infect, replicate and express transgene products in target tumour tissue whilst sparing normal tissue. Although not designed for efficacy, one patient had partial response.	http://www.clinicaltrials.gov/ Jennerex Biotherapeutics, Inc. NCT00625456; Breitbach et al., 2011 [22]
Reolysin	Reovirus—type 3 Dearing	Wild-type	Advanced or metastatic solid cancers that were refractory to standard treatment	33	Phase 1, Dose Escalation study	No dose-limiting toxicity was observed. Grade 1-2 toxicities were common (fever, fatigue and headache).	Antitumor activity was observed radiologically and by tumor markers.	Vidal et al., 2008 [23]