Table 4 The clinic trials of OVs

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 × 10^9–10 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, 10^6–11 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]