Table 1.
Human clinical studies of virotherapy for malignant pleural mesothelioma (MPM).
| Strain | Modification(s) | Study design | Results |
|---|---|---|---|
| Adenovirus | |||
| Ad.HSVtk (replication incompetent) | Insertion of thymidine kinase suicide gene | 21 patients in single-arm, dose-escalation study received single intrapleural dose followed by ganciclovir (89) | Gene transfer documented in 11 patients, minimal toxicity, no tumor responses |
| 5 patients given high-dose vector in same method as above study, with addition of systemic steroids (90) | Decreased inflammatory response but no improvement in gene transfer | ||
| Long-term follow-up of 21 patients who received high-dose vector (41) | Good safety profile, two patients lived >6.5 years | ||
| Ad.IFNβ (replication incompetent) | Insertion of interferon (IFN)β gene | Phase I dose-escalation study, 7 patients given single intrapleural dose (91) | Clinical response in three patients at 60 days, IFNβ detectable in fluid of eight patients |
| Follow-up phase I study, 10 patients given 2 intrapleural doses (92) | Repeated dosing safe, response by CT scan at 60 days in two patients | ||
| Adenovirus expressing IFNα2b (replication incompetent) | Insertion of IFNα2b gene | Pilot and feasibility study with 9 patients given 2 intrapleural doses of vector (93) | Five patients with stable disease or tumor regression at 60 days, gene transfer augmented by second dose |
| Phase II trial of two intrapleural doses of vector combined with chemotherapy in 40 patients (94) | Partial response in 25%, stable disease in 62.5%, median survival 13 months, six patients lived >2 years | ||
| Ad5-D24-GM-CSF (replication competent) | Partial deletion of E1A, insertion of granulocyte macrophage colony-stimulating factor (GM-CSF) gene | 20 patients with advanced solid tumors (2 with MPM) given 1 intratumoral dose (64) | 47% overall clinical benefit rate, one MPM patient with stable disease |
| ONCOS-102 (Ad5/3-D24-GM-CSF) | Insertion of Ad3 fiber knob, partial deletion of E1A, insertion of GM-CSF | 12 patients with advanced solid tumors (2 with MPM) given multiple intratumoral injections combined with oral cyclophosphamide (95) | Clinical response rate 40% at 3 months, one MPM patient with stable disease, increased PD-L1 in both MPM patients |
| Ad5/3-D24-GM-CSF | 21 patients with advanced tumors (1 with MPM) given one intratumoral and one IV dose, with oral cyclophosphamide (96) | Evidence of efficacy in 13 of 21 patients, MPM patient with stable disease, no grade 4/5 adverse events | |
| Herpes simplex virus type 1 (HSV-1) | |||
| HSV-1716 (replication competent) | Deletion of γ134.5 gene | Phase I/IIa study of inoperable MPM with single or multiple intrapleural doses (97) | Pending, expected completion in 2016 (NCT01721018) |
| Vaccinia virus | |||
| VV–IL-2 (replication competent) | Insertion of interleukin-2 gene, deletion of thymidine kinase gene | Small pilot study with six patients receiving multiple intratumoral injections (98) | Well-tolerated, viral gene expression detected for up to 3 weeks after administration, no tumor responses |
| JX-594 (replication competent) | Deletion of thymidine kinase gene, insertion of GM-CSF gene | Phase I trial, 23 patients with metastatic solid tumors (1 MPM patient), given single IV dose (99) | No dose-limiting toxicities, MPM patient with partial response for >10 weeks |
| Measles | |||
| Measles virus (MV)–NIS (replication competent) | Edmonston strain with insertion of NIS gene | Phase I trial enrolling patients with MPM confined to single pleural cavity, given q28 days for up to six cycles (100) | Pending, currently enrolling patients (NCT01503177) |
| Newcastle disease virus | |||
| PV701 (replication competent) | Naturally attenuated, non-recombinant | Phase I trail of 79 patients with advanced solid malignancies (2 with mesothelioma), virus given intravenously at various doses and intervals (101) | 9 patients with objective responses, 1 peritoneal mesothelioma patient with 35% tumor reduction and received 30 total doses, 1 MPM patient with progressive disease |
| Reovirus | |||
| Type 3 Dearing strain (replication competent) | Wild-type, non-recombinant | Phase 1 trial in 25 patients with advanced malignancy (1 MPM patient), given IV q3 weeks at escalating doses, combined with docetaxel (102) | Disease control rate 88%, MPM patient with minor response |