Clinical trials of combining oncolytic viruses and antibodies in cis and trans
| Virus | Antibody | Tumor | Phase/ no. of pts/route | Clinical outcomes | Cellular outcomes | Trial ID | Ref |
| Cis combination | |||||||
| NG-350A (Ad) | Agonist anti-CD40 IgG (cis) | Advanced epithelial tumors | 1a/16/i.v. | SD: 50% | ↑ IL-12, IFN-γ and IL-17a; ↑ T-cell clone in PBMC | NCT03852511 | 22 |
| RP2 (HSV) | Anti-CTLA-4 antibody-like molecule (cis) | Advanced solid tumors | 1/9/ i.t. | ORR: 33.3% | ↑ intratumoral T cell; ↑ inflammation gene signature (interim) | NCT04336241 | 23 107 |
| ONCR-177 (HSV) | Anti-PD-1 antibody, anti-CTLA-4 antibody (cis) | Advanced solid tumors | 1/14/ i.t. | n.a. | ↑ intratumoral T cell; ↑ IFN-γ, Ki67+ T cells in plasma | NCT04348916 | 24 |
| Cis/trans combination | |||||||
| RP2 (HSV) | Anti-CTLA-4 antibody-like molecule (cis); nivolumab (trans) | Advanced solid tumors | 1/27/OV: i.t., Ab: i.v. | Anti-PD-1 failed cutaneous melanoma—PR: 40%; uveal melanoma—PR: 33%; SCCHN: PR: 33% | ↑ intratumoral T-cell infiltration; ↑ inflammation signature; ↑ existing T-cell clone; ↑ new T-cell clone (interim) | NCT04336241 | 23 |
| Trans combination | |||||||
| ONCOS-102 (Ad) | Pembrolizumab (trans) | Melanoma | 1/2/12/OV: i.t., Ab: i.v. | ORR: 33% | ↑ abscopal antitumor response | NCT03003676 | 42 |
| RP1 (HSV) | Nivolumab (trans) | Melanoma, NMSC | 1/2/67/OV: i.t., Ab: i.v. | Melanoma—PR: 36.1% NMSC—CR: 61.3% | ↑ intratumoral T cell; ↑ inflammation gene signature (interim) | NCT03767348 | 41 |
| T-VEC (HSV) | Pembrolizumab (trans) | Melanoma stage IIIB–IV | Ib/ 21/OV: i.t., Ab: i.v. | CR: 33.3%; ORR: 61.9%; DCR: 76%; 18-month PFS: 67%. 18-month OS: 90%. | ↑ intratumoral CD8+ T cell, GrB+ cell, CD45RO+memory T cell, Teff/Treg ratio ; ↑ proliferating CD8+ T cell in PBMC | NCT02263508 | 78 |
| T-VEC (HSV) | Ipilimumab (trans) | Melanoma stage IIIB–IV | Ib/ II/ 18/OV: i.t., Ab: i.v. | ORR: 50% ; DRR: 44%; DCR: 72%; 18-month PFS: 50%. 18-month OS: 67%. | ↑ total and activated CD8+, ICOS+CD4 T cell in PBMC | NCT01740297 | 108 |
| T-VEC (HSV) | Ipilimumab (trans) | Melanoma stage IIIB–IV | II/ 98/OV: i.t., Ab: i.v. | ORR: 39% (vs 18% without OV); median PFS: 8.2 months (vs 6.4 months without OV) | n.a. | NCT01740297 | 102 |
| HF-10 (HSV) | Ipilimumab (trans) | Melanoma stage IIIB–IV | II/ 46/OV: i.t., Ab: i.v. | BORR (24 weeks): 41%; DSR: 68%; median PFS: 19 months; median OS: 26 months | ↑ intratumoral CD8+ T cell; ↓ CD4+ T cell | NCT02272855 | 43 |
| HF-10 (HSV) | Ipilimumab (trans) | Melanoma stage IIIB–IV | II/ 28/11OV: i.t., Ab: i.v. | DCR: 100%, median OS: 342 days with persistent infection (vs 33%, 251 days without persistent infection) | ↑ ICOS on CD4+ T cell; ↓ PD-L1 on monocyte in responders’ PBMC | NCT03153085 | 109 |
| V937 (Coxsackievirus A21) | Pembrolizumab (trans) | Melanoma stage IIIV–IV | Ib/ 36/OV: i.t., Ab: i.v. | CR: 22%; PR: 25%; PFS: 11.9 months; OS: 30.9 months | n.a. (Interim) | NCT02565992 | 110 |
| V937 (Coxsackievirus A21) | Ipilimumab (trans) | Melanoma stage IIIB/C–IV | Ib/ 50/OV: i.t., Ab: i.v. | ORR: 30%; PFS: 6.2 months; OS: 45.1 months | ↑ CD4+, CD8+, memory T cell in PBMC | NCT02307149 | 44 111 |
| Pelareorep (Reo) | Pembrolizumab+chemotherapy: (i) gemcitabine or (ii) irinotecan or (iii) leucovorin with 5-fluorouracil (trans) | Relapsed metastatic PDAC | Ib/ 10/OV: i.v., Ab: i.v. | PR: 10%; SD: 20%; median PFS: 2 months; median OS: 3.1 months | ↑ intratumoral CD8+ T cell; ↑T cell clonality responders’ PBMC; ↑ CXCL9, CXCL10, CXCL11 in PBMC | NCT02620423 | 112 |
| Pelareorep (Reo) | leucovorin/5-fluorouracil/ oxaliplatin/ bevacizumab (trans) | Advanced RAS-activated CRC | II/ 51/OV: i.v., Ab: i.v. | ORR: 53%; DCR: 86%; median PFS: 7 months; median duration response of ORR: 5 months (vs 35%; 83%; 9 months; 9 months without OV) | n.a. | NCT01622543 | 113 |
Ab, antibody; Ad, adenovirus; BORR, best overall response rate; CR, complete response; CRC, colorectal cancer; CXCL9, C-X-C motif chemokine ligand 9; CXCL10, C-X-C motif chemokine ligand 10; CXCL11, C-X-C motif chemokine ligand 11; DCR, disease control rate; DRR, durable response rate (response lasting for ≥6 months); DSR, disease stability rate; Grb, granzyme B; HSV, herpes simplex virus; ICOS, inducible costimulatory; IFN, interferon; IL, interleukin; i.t., intratumoral; i.v., intravenous; NMSC, non-melanoma skin cancer; ORR, objective response rate; OS, overall survival; OV, oncolytic virus; PBMC, peripheral blood mononuclear cell; PDAC, pancreatic ductal adenocarcinoma; PD-L1, programmed cell death ligand-1; PFS, progression-free survival; Pts, patients; Ras, rat sarcoma; Ref, reference; Reo, reovirus; SCCHN, squamous cell carcinoma of head and neck; SD, stable disease; Teff, effector T cell; Treg, regulatory T cell; T-VEC, talimogene laherparepvec.