Table 1 –

Studies evaluating the use of oncolytic viruses in the treatment of melanoma

Oncolytic Virus	Genome	Family	Phase of development	Study design	Target accrual	Outcomes	Trial ID (status)
T-VEC (Imlygic™)	DNA	HSV	FDA approved in 2015 for the treatment of advanced melanoma.	Phase I study evaluating escalating doses (106-108 pfu/mL) of intratumoral TVEC injection as either a single-dose or multi-dose regimen in malignant melanoma and other solid tumors	30	Most commonly reported AEs were injection reactions (dose limiting local reactions occurred at 107 pfu/mL in HSV sero-negative patients) and flu-like symptoms (fever (any grade) occurred in 4/13 patients in single-dose and 11/17 patients in multi-dose regimen). The recommended phase II dose was 106 pfu/mL (independent of HSV serology status), followed 3 weeks later by 108 pfu/mL administered every 2 weeks.	Unavailable (completed)1
				Single-arm phase II trial in unresectable, injectable IIIc-IV melanoma	50	ORR = 26%, 8 CR, 5 PR, OS = 58% at 1 year & 52% at 2 years. Responses were observed in injected and distant lesions.	NCT00289016 (completed)
				Randomized, parallel assignment of intralesional T-VEC or GM-CSF, Phase III (OPTiM trial) in unresectable, injectable IIB-IV melanoma	437	Significantly higher DRR observed in the TVEC-treated group compared to GM-CSF-treated group (16.3% vs 2.1%; odds ratio, 8.9; P<0.001). 15% of uninjected visceral metastasis had a response. OS (TVEC treated group) = 23.3 months vs GM-CSF group = 19.9 months; HR, 0.79; P=0.051).	NCT00769704 (completed)
HF-10	DNA	HSV	Clinical trials	Single group assignment phase I in superficial and refractory cancers including malignant melanoma.	28	Chills, nausea, fatigue and weight loss were observed in 12.5% of patients with 87.5% of all patients experiencing tumor emergent adverse events.	NCT01017185 (completed)
Reovirus Serotype 3 - Dearing Strain (Reolysin®))	RNA	Reoviridae	Clinical trials	Open label, single arm, phase I, dose escalation trial of IV Reolysin in solid tumors	18	Overall clinical benefit of 45% with few G1–2 toxicities and no dose-limiting toxicities.	Unavailable2
				Single group assignments, phase I, dose escalation trial of daily IV Reolysin for 5 days every 4 weeks in advanced solid tumors	33	Radiologic evidence of stable disease in 25% of patients. Common G1–2 toxicities included fever, fatigue, headache, and flu-like symptoms, with few episodes of G3–4 hematologic toxicities. No dose-limiting toxicities were observed.	Unavailable3
				Open label, phase I, dose escalation trial of percutaneous intralesional Reolysin in various advanced solid tumors.	19	Local tumor response in 37% of patients with limited G1–2 toxicities, including local erythema and flu-like symptoms and few episodes of G3–4 lymphopenia, headache.	Unavailable4
				IV administration, open-label, single group assignment phase II in metastatic melanoma	23	No objective response was observed when given intravenously. Few G3–4 toxicities were observed including fatigue, lymphocytopenia, and hyponatremia. G1–2 toxicities were common.	NCT00651157 (completed)
ECHO-7 virus (Rigvir ®)	RNA	Picornaviridae	Clinical trials	Retrospective study in IB-IIC melanoma	79	Treatment with Rigvir resulted in a statistically significant increase in overall survival compared to observation (HR 6.27, 95% CI 1.75–22.43), without significant toxicity.	N/A5
				Case report in stage IVM1c melanoma	1	Prolonged survival	N/A6
Vaccinia virus	DNA	Poxvirus	Clinical trials	2-dose-escalation phase I trial of intralesional injections of rV-B7.1 in metastatic melanoma	12	25% clinical response with limited, G1–2 toxicities, including fever, fatigue, and myalgias.	NCT00004148 (complete)
				Dose escalation phase I trial of intralesional injection of vaccinia virus expressing the B7.1 (CD80) costimulatory molecule in melanoma lesions	12	53% objective clinical response with limited, G1–2 toxicities including fatigue, pain, nausea, and anorexia.	NCT00022568 (not recruiting)
				Phase I/II trial of intradermal injection in stage III and IV melanoma	20	Objective clinical response rates of 41% with limited G1–2 toxicities including leukopenia, flu-like symptoms, nausea, fever, and skin rash, and one episode of G3 leukopenia.	Unavailable7
				Phase I/II trial of intranodal injection of vaccinia virus encoding antigenic epitopes and costimulatory molecules in stage III and IV melanoma	16	Objective clinical response rates 50% with limited G1–2 toxicities including fever, skin rashes, pruritus, and leukopenia, and one high-grade toxicity of atrioventricular block, unrelated to study drug.	NCT00116597 (complete)
Coxsackie virus A21	RNA	Picornaviridae	Clinical trials	Single-arm study Phase I ipilimumab combination trial in IIIB/C and IV melanoma that have progressed on prior single agent anti-PD-1 therapy	59	Recruiting, preliminary results available, ORR = 50%8	NCT02307149 (recruiting)
				Single-arm study Phase I pembrolizumab combination trial in IIIB/C and IV melanoma	9	Recruiting	NCT02565992 (recruiting)
				Single-arm study Phase II in IIIC and IV melanoma.	57	ORR = 28%, 8 CR, 8 PR, OS = 75.4% at 1 year	NCT01227551 (completed)
				Single-arm study Phase II extended dosing trial in IIIC and IV melanoma	16	Study completed in 2016, data analysis ongoing.	NCT01636882 (completed)
Adenovirus	DNA	Adenoviridae	Clinical trials	Treatment with Ad5/3-D24-GMCSF in 9 patients with melanoma refractory to chemotherapy	9	Objective clinical response rate of 33% with limited, low-grade toxicities including constitutiona symptoms, nausea, and pain, few high-grade toxicities od fatigue, dyspnea, and pericardial/pleural fluid caused by disease progression.	N/A9
				Phase I: intratumoral injection of unresectable stage III/IV melanoma12	14	Clinical activity observed in 71% of patients receiving the two highest dose levels with low-grade toxicities including fever, chills, nausea, and fatigue, as well as one death unrelated to study drug.	NCT01397708 (complete)

^1. Jennifer C.C. Hu, Robert S. Coffin et al. A Phase I Study of OncoVEX^GM-CSF, a Second-Generation Oncolytic Herpes Simplex Virus Expressing Granulocyte Macrophage Colony-Stimulating Factor. Clin Cancer Res November 15 2006 (12) (22) 6737–6747

^2.Gollumadi R, Ghalib MH, Desai KK, et al (2010) Intravenous administration of Reolysin®, a live replication competent RNA virus is safe in patients with advanced solid tumors. Investigational New Drugs 28(5):641–649.

^3. Vidal L, Pandha HS, Yap TA, et al (2008) A Phase I Study of Intravenous Oncolytic Reovirus Type 3 Dearing in Patients with Advanced Cancer. Clinical Cancer Research 14(21):7127–7137.

^4. Morris DG, Feng X, DiFrancesco LM, et al (2013) REO-001: A phase I trial of percutaneous intralesional administration of reovirus type 3 dearing (Reolysin ®) in patients with advanced solid tumors. Investigational New Drugs 31:696–706.

^5. Donina S, Strele I, Proboka G, et al (2015) Adapted ECHO-7 virus Rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study. Melanoma Research 25(5):412–426.

^6. Alberts P, Olmane E, Brokane L, et al (2016) Long-term treatment with the oncolytic ECHO-7 virus Rigvir of a melanoma stage IV M1c patient, a small cell lung cancer stage IIIA patient, and a histiocytic sarcoma stage IV patient – three case reports. APIMS 124:896–904.

^7. Zajac P, Oertli D, Marti W, et al (2003) Phase I/II Clinical Trial of a Nonreplicative Vaccinia Virus Expressing Multiple HLA-A0201-Restricted Tumor-Associated Epitopes and Costimulatory Molecules in Metastatic Melanoma Patients. Human Gene Therapy 14:1497–1510.

^8. COX Curti B, Richards J, Hallmeyer S, et al. The MITCI (phase Ib) study: a novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients with or without previous immune checkpoint therapy treatment. Presented at the 2017 AACR Annual Meeting; April 2–5, Washington, DC. Abstract CT114.

^9. Bramante S, Kaufmann JK, Veckman V, et al (2001) Treatment of melanoma with serotype 5/3 chimeric oncolytic adenovirus coding for GM-CSF: Results in vitro, in rodents and in humans. Int J Cancer 137:1775–1783.