Table 2.
Clinical experience of virotherapy in liver cancers
| Virus | Route/ phase | Cancer type/patient number | Doses/schedule (vp: viral particles; pfu: plaque-forming units; other therapies in italics) | AE (G3/G4 episodes; DLT; most freq. AE) | Antitumoural response† | PD | Viral end-points: gene expression, replication, shedding, and pharma-cokinetics | Immune response | References |
|---|---|---|---|---|---|---|---|---|---|
| Ad-d/1520 (Onyx-015; AE1B-55K, AE3B) | I (IT) | GI liver mets/ 19 | 2 × 109 to 2 × 1012 vp/ days 1, 29, 57 | No DLT; fever, asthenia, chills | n.a. | n.a. | n.a. | n.a. | [7] |
| I (HAI) | CRC liver mets/11 | 2 × 108 to 2 × 1012 vp/ days 1, 8, 22, 50, 78; 5-FU 425 mg/m2 iv days 22, 50, 78, Leucovorin 20 mg/m2 iv days 22,50, 78 | No DLT; 30 G3/G4 AE; fever, chills, transaminitis | n.a. (2 PR at high doses) | n.a. | Q-PCR + (blood, d 4) >2 × 1011 vp; 1-5 × 106 genome/ml (d 4) | All Ab (50%+ at baseline) | [26] | |
| II (HAI) | CRC liver mets/27 | 2 × 1012 vp/ days 1, 8, 22, 50, 78; 5-FU 425 mg/m2 iv days 22,50, 78, Leucovorin 20 mg/m2 iv days 22,50, 78 | 27 G3/G4 AE; fever, chills, ALP ↑ | 3/27 (11%) chemo-refractory: 2/24 (8%) | 11/27 (41%) | 6/8 Q-PCR + (blood); 5/7 viremia (genome copies) on d 4 | All Ab (50%+ at baseline); TNF, IFN-γ, IL-1, IL-6, IL-10 induction | [27] | |
| I/ II (IT, HAI, IV) | Liver/ 16 | 1.5 × 108- 1.5 × 1010 vp7days 1,2,15,16,29,30 (IT); days 1-5 (HAI, IV); 5-FU 300 mg/m2 qd x 3m, oxaleplatin 85 mg/m2 q3w (extra-hepatic cases) | No DLT; fever, chills | 0 (3/6 CEA ↓ >50%) | 1/7 (14%) | ISH, EM, HE + (Bx) | n.a. | [24] | |
| II (IV then IT) | HCC/ 5 | 1.5 × 109 vpVday 1 (IV); days 2, 15, 16, 29, 30 (IT) | 3 G3/G4 AE; fever, chills | 1/5 (1/5 AFP ↓) | 4/5 (80%) | HE, EM + (Bx); serum PCR + (disappeared after 4 hrs) | All Ab (100%+ at baseline) | [25] | |
| I/ II (IT, IP) | Hepatobiliary / 19 | 3 × 108 to 5 × 108 vp* (IT) up to 1.5 × 109vp* total; 5 × 108 vp* (IP) for ascites | 6 G3/G4 AE; fever, myalgia, abd pain | 1/19 (8 others have AFP↓ > 50%) | 6/19 (32%) | 0 CPE (urine); 2/2 bile stent PCR +; 4/4 ascites PCR + (d 1-9) | All Ab (100%+ at baseline) | [22] | |
| HSV-NV 1020 (Δ1 copy ICP34.5, ΔUL24, ΔUL56) | I (HAI) | CRC liver mets/ 12 | 3 × 106 to 1 × 108 pfu | No DLT; fever, nausea, headache | Reduced CEA in some patients | n.a. | 1 PCR + (serum, saliva) | n.a. | [29] |
| II (HAI) | CRC liver mets/ 21 | 1 × 108 pfu x 4 | No significant toxicity | 0 (single agent); 3/11 PR (after C/T) | 11/21 | n.a. | n.a. | [30] | |
| VV-JX-594 (ATK, GM-CSF-express-ing) | I (IT) | Primary and secondary liver tumours | 1 × 108 to 3 × 109 pfu | Fever, chills; DLT: transient hyper-bilirubinemia | 70% (Choi); 30% (RECIST) | 1/10 (10%) | All Q-PCR+ (serum) | All ↑ Ab (21%+ at baseline); TNF, IFN-γ induction | [17], [18] |
Abbreviations: AE: adverse effect; DLT: dose-limiting toxicity; HCC: hepatocellular carcinoma; CRC: colorectal carcinoma; IT: intratumoural; IP: intraperitoneal; IV: intravenous; HAI: hepatic arterial infusion; EM: electron microscopy; EUS: endoscopic ultrasound; R/T: radiotherapy; C/T: chemotherapy; n.a.: non-available; ND: not done; bx: biopsy; IHC: immunohistochemistry; PCR: polychain reaction; PD: progressive disease; PR: partial response; Q-PCR: quantitative PCR; ISH: in situ hybridization; ALP: alkine phosphate; vp: viral particle and pfu: plaque-forming unit.
*
Estimated based on particle-to-pfu ratio of 20.
†
Antitumoural response = complete remission + PR.