Table 4.

The clinic trials of OVs

Virus name	Oncolytic virus (short name)	Viral gene modification	Non-viral gene addition	Human Phases, (N)	Tumor type	Virus administration route, dose and times	Combination therapy	Safety	Efficacy, (n/N, CR, PR, SD, NR; Survival)	Novelty, advantages	Comments, disadvantages	Refs
HSV-1	T-VEC	ICP34.5 ICP47 deletion	GM-CSF	Phase Ib/II; 19	Melanoma	IT, week 1, 106 pfus/mL; week 4 and every 2 wks, 108 pfu /mL	Ipilimumab, IV, 3 mg/kg/3 wks 4x	Nausealipase amylase	18-month PF-SD, 50%; 18-month OS, 67%	A tolerable safety profile, and greater efficacy	AntigenspecificT cell not sure	[35]
HSV-1	Talimogene laherparepvec (T-VEC)	ICP34.5 ICP47 Deletion	GM-CSF	phase II,(198)	Melanoma, unresectable stages IIIB to IV	Wk 1, ≤ 4 mL × 106 pfu/mL; after 3 wks, ≤ 4 mL, 108 pfu/mL/2 wks	Ipilimumab, 3 mg/kg/3 wks 4x	Fatigue chills, diarrhea	Greater antitumor activity versus ipilimumab	This was the first randomized trial of an OV plus checkpoint inhibitor	Phase II only	[34]
HSV-1	T-VEC	ICP34.5 ICP47 deletion	GM-CSF	Phase III, 436	Melanoma, unresected stages IIIB-IV	IT; 2.8 ml, 2 times			Tumor decrease ≥ 50% in 64% injected, 15–34% uninjected	Response in injected and uninjected lesions	Mechanisms unclear	[99]
HSV-1	T-VEC	ICP34.5 ICP47 deletion	GM-CSF	41 patients	Melanoma unresected, stage IIIB-IVM1c	IT, 4 ml × 106 pfu/ml at day 1, 4 ml × 108 PFU/ml/2wks 21 days later		Vomiting, abdominal pain, chills, hyperhidrosis, pyrexia	ECOG performance of 0 (68%) or 1 (32%). Median treatment 13.1 wks (3.0–41.1)	A comparable safety profile	Study endpoints limited	[25]
HSV-1	T-VEC	ICP34.5 ICP47 del	GM-CSF	Phase 1, 27	Melanoma IIIB–IV	IT, 106 pfu/mL HSV-naïve, 108 3 wks later, every 2 weeks until DP/DLT	PD-1 inhibitor		Most only mild symptoms, fever and chills	Higher response rate than OPTiM, response associated with lesion size	Limited sample size	[134]
HSV-1	T-VEC	ICP34·5 ICP47 del	GM-CSF	Phase 2, 60	Melanoma advanced	IT, 106 PFU/mL, 108 21 d later and every 14 d thereafter		Chills, flu-like symptoms		Extensive on the intratumoral distribution and transmissibility		[131]
HSV-1	HSV1716	ICP34.5 (RL1), mutation		Phase I, 9	Extracranial cancers, Pediatric cancer	IT, 105–107 pfu 1–4 doses		Fever, chills, cytopenia systemic viremia		Tolerable safety	Virus persistence not clear	[178]
HSV-1	HSV1716	ICP34.5 Del	TK	Phase I/IIa,13	MPM	Intrapleural, 107 iu, 1, 2 or 4 times/wk	Cisplatin	Worst CTCAE, grade 1 for 46%; grade 2 for 46; grade 3, 8%	SD, 2/each, PD, 1–4	Future immune checkpoint inhibitor combination	Patients limited	[133]
HSV-1	HF10			Phase I, 12	Pancreatic cancer, unresectable locally advanced	IT, EUS 1/4wks, -4 × unless DLT appears	Erlotinib gemcitabine		3 PR, 4 SD, 2 PD	Safe treatment		[179]
HSV-1	Seprehvir HSV171	ICP34.5 /RL1 mutation		Phase I, 9	Solid tumors, non-CNS	IT, 5 × 104 -2 × 106 iu/kg or IV 2.5 × 105 -2 × 107 iu/kg		1, grade 3 hypotension, flu-like symptoms, 1, mild bleeding	Well tolerated, promising anti-cancer efficacy	First IV Seprehvir in Young Patients	Not clear IT or IV better	[132]
HSV-1	OrienX010		GM-CSF	Phase I, 12	unresectable stage IIIC–IV melanoma	10 mL of 8 × 107pfu/mL OrienX010 IT injections every 2 weeks		Only one patient experienced a grade ≥ 3 adverse event and no dose limiting toxicities were observed	The median progression-free survival was 2.9 months and overall survival was 19.2 months	safe and well tolerated with a positive trend of antitumor effects	A larger clinical trial is warranted to validate the results of this study	[180]
HSV-1	G47Δ	Deletion the α47 gene and overlapping US11 promoter, γ34.5 gene and ICP6 gene		Phase II, 19	residual or recurrent glioblastoma	IT, 1 × 109 p.f.u. per dose in 1 ml and repeatedly for up to six doses	radiation therapy, temozolomide, bevacizumab	fever (17 of 19) followed by vomiting, nausea, lymphocy topenia and leukopenia	The 1-yr survival rate of 84.2% and the median OS and PFS of 20.2 months and 4.7 months, respectively	the first oncolytic virus drug in Japan	The study population was rather small	[135]
HSV-1	G47Δ	Deletion the α47 gene and overlapping US11 promoter, γ34.5 gene and ICP6 gene		Phase I/II, 13	Progressive glioblastoma	IT, 3 × 108 pfu (low dose) or 1 × 109 pfu (set dose), twice to identical coordinates within 5–14 days	radiation and temozolomide therapies	fever, headache and vomiting	Median overall survival was 7.3 (95%CI 6.2–15.2) months and the 1-year survival rate was 38.5%	tumor cell destruction via viral replication and lymphocyteinfiltration towards tumor cells		[136]
Ad	Enadenotucirev	E2B substitution Ad3 to Ad11, E3 del, 25 bp del in E4orf4		Phase I, 17	CRC, NSCLC, UCC, RCC	IT (CRC) ≤ 3 × 1011 vp on d1; IV, 3 doses 1 × 1012 vp on d1/3/5		Asthenia, neutropenia, chills, pyrexia	High local CD8+ cell infiltration in 80% tumors	Safety, targeting, kinetic, immunology		[142]
Ad	Enadenotucirev	E2B Ad3 for Ad11; E3 del, E4orf4 25 bp del		Phase I, 61	Colorectal cancer	IV, 1 × 1010 vp/5 min on days 1, 3, and 5		Pyrexia, chills, hypoxia, lymphopen-ia, neutropenia		MDT tedermined	only limited information antitumor activity	[67]
Ad	Enadenotucirev	E2B Ad3 for Ad11; E3 del, E4orf4 25 bp del		Phase I, 30	Colorectal cancer, advanced	IV, 1–3 × 1012 vp, 3 × , wks 1–2, prior to chemoradiotherapy	Chemoradiation	No more than 30% probability of a DLT	Very high selectivity for colorectal cells	Administered systemically	Statistical support	[143]
Ad	DNX-2401 (Delta-24-RGD; tasadenoturev)	E1A 24-bp del	RGD-motif into the fiber H-loop	Phase I, 37	Glioma, malignant recurrent	Stereotactic IT via implanted catheter (107 -3 × 1010 vp)		No dose-limiting toxicities observed	OS, 3y, 20%	Direct oncolytic effect + antitumor immune response		[69]
Ad	DNX-2401	E1A 24-bp del	RGD-motif into the fiber H-loop	Phase I, 12	Glioma, diffuse intrinsic pontine	Cerebellar peduncle biopsy, IT 5 × 1010	Radiotherapy and chemotherapy	Grade III-IV, secondary to dose dense temozolomide				[68]
Ad	DNX-2401	E1A 24-bp del	RGD-motif into the fiber H-loop	Phase I, 12	Diffuse Intrinsic Pontine Gliomas	Cerebellar peduncle, 1 × 1010 or 5 × 1010 viral particles of DNX-2401,	radiotherapy	headache, nausea, vomiting, and fatigue; Hemiparesis and tetraparesis developed in 1 patient each	a reduction in tumor size, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients	Resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients	associated with adverse events	[181]
Ad	DNX-2401	E1A 24-bp del	RGD-motif into the fiber H-loop	Phase I, 20	recurrentglioblastoma	locally delivered by convection enhanced delivery, 107 to 1 × 1011 viral particles		In 14 patients, 17 serious AEs occurred, of which 8 were unrelated to the study treatment	Median PFS was 82 days, with a median OS of 129 days; One patient with complete regression and still alive after 8 years	The first to assess the local and locoregional responses upon infusion of an oncolytic virus into the tumor and surrounding brain by sequential sampling of brain interstitial fluid and cerebrospinal fluid		[182]
Ad	ICOVIR-5	E1A-Δ24 deletion	DM-1 insulator, E2F1 promoter, Kozak seq, RGD fiber	Phase I, 12	Melanoma	IV, 1a, 1 × 1011 vp, 2a, 3.3 × 1011, 3a, 1012, 4a, 3.3 × 1012, 5a, 1013 vp			Reached metastases but no tumor regression	the MTD determined	Necessary to arm the oAd	[139]
Ad	ICOVIR-5	E1A-Δ24 deletion,	DM-1 insulator, E2F-1 promoter, Kozak seq, RGD fiber	Phase I, 16	Solid tumors, relapsed or refractory	IV, weekly infusions 6 wks, 2 × 106 cells/kg children, 0.5–1 × 106 cells/kg adults, 2 × 104 vp/cell	MSC	In pediatric patients, grade 1 fever headache; In adult patients, grade 1 fever asthenia	Two patients showed SD	Safe	Antiviral immune response may limit the effects	[82]
Ad	Aglatimagene besadenovec (AdV-tk)		TK gene	Phase 1, 8	Glioma, malignant;recurrent ependymoma	IT, 1011 and 3 × 1011 vp	Valacyclovir; radiation therapy, temozolomide	Grade 1–2 fever, fatigue, and nausea/vomiting	3, survived 24 m; 2 PFD at 37.3 and 47.7 m	The first study of GMCI in pediatric CNS tumors	The study population was small	[141]
Ad	VCN-01	E1A-Δ24 deletion	E2F1 promoter	Phase I, 2	Retinoblastoma	Intravitreous inject., Twice 14d interval, 2 × 109–10 vp/eye, 1/10-100MFD		No systemic AV and viral genomes in blood	Have anti-tumor activity	provide a tumor- selective treatment option	Local vitreous inflammation	[140]
Ad	CG0070	E2F-1 promoter/E1A	GM-CSF	Phase II trial, 35	NMIBC, high-grade	2 h DDM pretreatment, 1012 Vp/100 mL saline/45–50 min/wk via a 100% silicone 3-way catheter, intravesical 6x		Bladder spasms, hematuria, dysuria, urgency, dysuria, hypotension	47% CR 50% CR for CIS	Tolerable safety, replication, GM-CSF expression	Relatively small sample size and short follow-up	[93]
Ad	NSC.CRAd-S-pk7		Survivin promotor, poly-L-lysine (pk7)	Phase I, 12	Glioma	6·25 × 1010 vp/5 × 107 NSCs, 1·25 × 1011 vp/108, or 1·87 × 1011 vp/1.5 × 108	NSCs	Grade 3 viral meningitis due to the inadvertent injection	PFS, 9·1 m; OS, 18·4 m	1·875 × 1011/1·50 × 108 NSCs for phase 2 trial	Replication conditional upon surviving	[65]
VV	GL-ONC1		Ruc-GFP, β-glucuronidase, and β-galactosidase	Phase I, 19	Head/neck carcinoma, locoregionally advanced unresected nonmetastatic	IV. Day 3, cohort 1, 3 × 108 pfu; cohort 2, 1 × 109 pfu; cohort 3, 3 × 109 pfu; cohort 4, 3 × 109 pfu, on d3, 8; 4 doses in cohort 5, d3, 8, 15, 22	Cisplatin Radiotherapy	Grade 1–2 rigors, fever, fatigue, and rash. Grade 3 hypotension, mucositis, nausea, vomiting	1y (2y) PFS and OS were 74.4% (64.1%) and 84.6% (69.2%), respectively	This is the first clinical trial for head and neck cancer	Limited benefit of repeated administrations of virus	[148]
VV	GL-ONC1		Ruc-GFP, β-glucuronidase, β-galactosidase	Phase I, 9	PC or PM	IP, 107–109 pfu/4 wks, 4x, dose escalation		Transient flu-like symptoms, abdominal pain		First-in-man intraperitoneal (IP)	Infection limited to treatment cycle 1	[149]
VV	TG4023 (MVA-FCU1)		Yeast FCU1	Phase I, 16	Liver tumors	IT, 107, 108, or 4.108 pfu, a DLT-driven 3 + 3 dose-escalating	5-FC	Pyrexia, asthenia, vomiting, decreased appetite	5FU = 1.9 ± 2.6 ng/ml/sera, 56 ± 30 ng/g/tumor. FCU1 found	Safe, MTD = 4 × 108 pfu, high 5-FU in tumors		[147]
VV	ACAM2000		tk-positive oVV	Phase I, 26	AML, stage III or IV	Incubated VV with SVF for 15–60 min	Adipose stromal vascular fraction cells	Self-limiting skin rashes	Well tolerated	First-in-human study		[80]
VV	Olvi-Vec			Phase 1b,12	PRROC	Intraperitoneal, 3 × 109 (n = 6), 1 × 1010 (n = 5), and 2.5 × 1010 (n = 1) PFU/day on two consecutive days		There were no Grade 4 TRAEs, no dose relationship to TRAEs, and no deaths attributed to Olvi-Vec	Median PFS was 15.7 weeks	safety, clinical activities, and immune activation		[183]
VV	JX‑594		GM-CSF	Phase II,20	Advancedsoft‑tissue sarcoma	Intra-venously at the dose 1.109 every 2 weeks for the first 3 injections and then every 3 weeks	Cyclophosphamide	The two most frequent toxicities were grade 1 fatigue and fever and grade 2 fatigue and grade 2 lymphopenia in arms 1 and 2, respectively	One patient out 4 assessable for efficacy was progression-free at 6 months in arm 2	Cyclophosphamide and JX-594 could have a synergistic antitumor, and immuno-stimulating activity	The first stage of the Simon’s design was not satisfied	[95]
MV	MV-NIS		NIS	Phase I, 32	MM	Infusion in 250 ml saline/60 min	Cyclophosphamide	Neutropenia, leukocyte down, thrombocytopenia, anemia	CR (1); serum FLCs drops; MV-NIS replicated	Safe and novel approach for relapsed and refractory disease	Small sample size	[150]
MV (Edmonston strain)	MV-NIS		NIS	Phase I, 32	Melanoma metastatic	IV, 106–11 iu/patient		MTD was not reached	Increased T-cell responses against MAGE-C1 MAGE-A3	Future combination with immune checkpoint inhibitor		[92]
MV	MV			phase I, 10	GBM	IT, on day 1 and 5 via a catheter				Prediction algorithm for oncolytic treatment	Validation limited	[184]
Parvovirus	ParvOryx			Phase II, 7	Pancreatic cancer, metastatic	IV, 40% dose in 4 days, 60% IV, 1, hepatic m	Gemcitabine, nab-paclitaxel		Pronounced anti-tumor effects	Further crucial information		[153]
Parvovirus	H-1 Parvovirus,ParvOryx01			Phase I/IIa, (18)	GBM, recurrent	Escalating dose, IT or IV injection at 1 and 9 days			Median survival extended	Safety, tolerability, virus pharmacokinetics, shedding, MTD	Necrosis induction needs further study	[152]
Reovirus (type 3 dearing)	Pelareorep (REOLYSIN ®)			Phase II,14	Melanoma, metastatic	1 h intravenous infusion at a dose of 3 × 1010 TCID50	Paclitaxel carboplatin	Pyrexia, grade 3 febrile neutropenia (1)	SD = 85%, PFS and OS = 5.2 and 10.9 m, 1-year OS 43%	Safe and potentially efficacious		[126]
Reovirus	Pelareorep			Phase II,74	Breast cancer, metastatic	IV, 3 × 1010 TCID50/4 wks on days 1, 2, 8, 9, 15, and 16	Paclitaxel	fever fatigue diarrhoea chills nausea “flu-like”	PFS increase from 4 to 7.5 m in 67	The first randomized phase II trial	The trial did not demonstrate a benefit	[185]
Reovirus	Pelareorep			Phase I,11	PDAC	4.5 × 1010 TCID50 IV on days 1 + 2 after chemotherapy	Pembrolizumab, 2 mg/kg IV on day 8	Grade 3 or 4 TRAEs neutropenia/leukopenia /myalgias/fever/chills	PFS = 2 m OS = 3.1 m 1/2-year survival = 35%/23%	Not add significant toxicity, encouraging efficacy	Small sample size	[129]
Coxsackievirus	Coxsackievirus A21 (V937)			Phase II, 57	unresectable stage IIIC or IV melanoma	3 × 108 TCID50 in a maximum 4.0-mL volume by intratumoral injection		No treatment-related grade ≥ 3 adverse events occurred	6-month PFS rate per irRECIST, was 38.6%	V937 was well tolerated	combination with immune checkpoint inhibitors are ongoing	[186]