Combination therapies in trans restoring or activating immune cell functions
| Target | Virus (species) | Antibody form | Effect ex vivo/in vivo | Delivery route (frequency) | Ref. |
| PD-1/PD-L1 | vvDD (VV) | Anti-PD-1 IgG | Fibrosarcoma/ s.c. in C57BL/6 mice: ↓tumor mass; ↑survival | OV: i.t. (2; 0, 3 dpi) Ab: i.v. (3; 0, 3, 6 dpi) | 14 |
| PD-1/PD-L1 | MV vaccine strain | Anti-PD-L1 IgG | Melanoma/ s.c. in C57BL/6 ↑survival; ↓tumor mass | OV: i.t. (4; 4 consecutive days) Ab: i.p. (4; every third day) | 16 |
| PD-1/PD-L1 | Pelareorep (Reo serotype 3-Dearing strain) | Anti-PD-1 IgG | Melanoma/ s.c. in C57BL/6 mice: ↓ tumor mass; ↑ survival; ↑ IFN-γ (ELISA); ↓ Treg activity | OV: i.t. (3; day 0, 3, 5 dpi) Ab: i.v. (8; 7, 9, 11, 13, 15, 17, 19, 21 dpi) | 29 |
| PD-1/PD-L1 | VSV-mIFN-β-NIS (VSV Indiana strain; encode IFN-β, NIS) | Anti-PD-L1 IgG | AML s.c./ in C57/B6 mice: ↓tumor mass in blood, bone marrow, spleen; ↑survival; ↑IFN-γ+CD8+ T cell (FC; 7 dpi) | OV: i.v. (1) Ab i.p. (3; 3, 6, 9 dpi) | 32 |
| PD-1/PD-L1 | MV-EGFR (MV vaccine strain; redirect viral entry via EGFR) | Anti-PD-1-IgG | Giloma o.t./ in C57BL/6 mice: ↓tumor mass in blood, bone marrow, spleen ↑survival; ↑intratumoral T cell (FC, MRI, 6 dpi); ↑ granzyme B+CD8+ T cell, CD8+/Treg ratio (FC, 6 dpi) | OV: i.t. (4; day 0, 3, 7, 10) Ab: i.p. (3; day 1, 3, 9) | 31 |
| PD-1/PD-L1 | GM-CSF/Reo/VSV-ASMEL (GM-CSF/REO for prime-boost; VSV expresses cDNA library of melanoma antigens) | Anti PD-1 IgG | Melanoma s.c./ in C57BL/6 mice: ↑ survival; ↑ IFN-γ, IL-17 (ELISA); ↑Th1, Th17 response | GM-CSF/REO: i.p./i.v. (2 cycle; −14 to –7 dpi) VSV-ASMEL: i.v. (3; day 0, 2, 4 dpi) Ab: i.v. (6; 0, 2. 4, 7, 9, 11 dpi) | 117 |
| PD-1/PD-L1 | vvDD-IL-2-RG (VV; encodes IL-2) | Anti-PD-1 IgG; Anti-PD-L1 | Colon cancer/ i.p. in C57BL/6 mice: ↑ survival; ↑ abscopal effect; ↓ s.c. distant tumor mass | OV: i.p. (1) Ab: i.p. (0; 0, 2, 4, 6 dpi) | 118 |
| PD-1/PD-L1 | vvDD-CXCL11 (VV; encodes CXCL11) | Anti-PD-L1 IgG | Colon cancer/ i.p. in C57BL/6 mice: ↓ tumor mass; ↑ survival ; ↓ PD-L1 in intratumoral TAM, MDSC, DC, ↑ CD8+ T cell activation, CD8+/Treg ratio; ↓ LAG3+PD-1+CD8+ T cells (FC, 5 dpi); ↓ s.c. rechallenged tumor; ↑ systemic antitumor immunity | OV: i.t. (1) Ab: i.p. (4; 0, 2, 4, 6 dpi) | 30 |
| PD-1/PD-L1 | Ad5-CMV-mIL-2 and Ad5-CMV-mTNF α(2 Ad clones expressing IL-2 and TNF-α) | Anti-PD-1 IgG | Melanoma/ s.c. in C57BL/6JOlaHsd mice: ↓tumor mass; ↑survival; ↑ intratumoral CD4+, CD8+ T cells Melanoma/ s.c. in C57BL/6JOlaHsd mice: ↓tumor mass; ↑survival; ↑ intratumoral CD8+/ CD4+ T-cell ratio | OV: i.t. (1) Ab: i.p. (4; 0, 3, 6, 9 dpi) OV: i.t. (4; 0, 1, 3, 6 dpi) Ab: i.p. (4; 0, 1, 3, 6 dpi) | 119 120 |
| PD-1/PD-L1 | TILT-123 (Ad; encodes TNF-α and IL-2) | Anti-PD-1 IgG | PDAC/ s.c. in Syrian golden hamsters: ↓tumor mass; ↑survival Urological tumor biopsies: ↑ IFN-γ, granzyme B, CXCL10 | OV: i.t. (8; 0, 3, 6, 9, 12, 15, 18, 21 dpi) Ab: i.p. (8; 0, 3, 6, 9, 12, 15, 18, 21 dpi) OV: (1) Ab: (1) | 33 120 |
| PD-1/PD-L1 | DP-TRP2-PeptiCRAd (Ad; coated with MHC-II–restricted Diphtheria–Pertussis peptides and MHC-I–restricted TRP2 peptides) | Anti-PD-1 IgG | Melanoma/ s.c. in C57BL/6 mice: ↓tumor mass; ↓ naive T cells in lymph nodes; ↑ CD4+ memory T cells in lymph nodes | OV: i.t. (4; 0, 2, 4, 6 dpi) Ab: i.p. (3; 0, 4, 8 dpi) | 121 |
| CTLA-4 | MV vaccine strain | Anti-CTLA-4 IgG | Melanoma/ s.c. in C57BL/6 mice: ↓tumor mass; ↑survival | OV: i.t. (four consecutive days) Ab: i.p. (4; every third day) | 16 |
| CTLA-4 | NDV LaSota strain | Anti-CTLA-4 IgG | Melanoma/ i.d. in C57BL/6 mice: ↓ local, distant tumor mass; ↑ survival; ↑ distant CD45+ cells, CD8+/Treg ratio, granzyme B+CD8, Ki67+CD8 T cell (FC, 8 dpi) ↑ systemic antitumor immunity | OV: i.t. (4; 0, 3, 7, 9 dpi) Ab: i.p.: (4; 0, 3, 7, 9 dpi) | 36 |
| PD-1/PD-L1; CTLA-4 | VVWR/TK−RR−/FCU1 (WR; TK, RR deletion) | Anti-PD-1 IgG; Anti-CTLA-4 | Fibrosarcoma/ s.c. in C57BL/6 mice: ↓ local, distant tumor mass; ↑ survival; ↑ abscopal effect | OV: i.t. (2; 0, 3 dpi) Ab: i.p. (3; 6, 9, 12 dpi) | 37 |
| PD-1/PD-L1, CTLA-4 | VSV-HIF2α+VSV-SOX-10+VSV-c-Myc (3 VSV clones expressing HIF2α, SOX-10, c-Myc) | Anti-PD-1 IgG, anti-CTLA-4 IgG (co-use) | Glioma/ i.c. in C57BL/6 mice: ↑ survival; ↑ IFN-γ, IL-17 (ELISA); ↑Th1, Th17 response | OV: i.v. (6; 0, 2, 4, 7, 9, 11 dpi) Ab: i.v. (3; 7, 9, 11 dpi) | 122 |
| PD-1/PD-L1, CTLA-4 | G47Δ-mIL12 (HSV; encodes IL-12) | Anti-PD-1 IgG, anti CTLA4 IgG (co-use) | Giloma i.c./ in C57BL/6 mice: ↑ survival; ↑ intratumoral CD11b+CD45hi peripheral macrophage, CD8+/Treg ratio (FC, 7 dpi); ↑ T-cell activation (IHC, CD3, Ki67, 7 dpi); ↑ M1-like macrophage repolarization (IHC, CD68, pSTAT1, 7 dpi) | OV: i.t. (1) Ab: i.p.: (3; day 0, 3, 6 dpi) | 38 |
| PD-1/PD-L1, CTLA-4 | rAd.GM (Ad; encodes GM-CSF) | Soluble TGF-βRII-Fc (E1B promoter), anti-PD-1 IgG, anti-CTLA-4 IgG (co-use) | Breast cancer o.t./ in BALB/c mice: ↓ tumor mass; ↑ survival; ↑ intratumoral CD8+ T, memory T cells, ↓Treg; ↑ M1-like macrophage repolarization (IHC, 17 dpi); ↑ Th1 cytokine genes (qPCR, 17 dpi) | OV: i.t. (2; 0. 3 dpi) Ab: i.p.: (3; day 1, 4, 7 dpi) | 123 |
| PD-1/PD-L1, CTLA-4, TGF-β/ TGF-βR | rAd.sT (Ad; encodes soluble TGF-βRII-Fc) | Soluble TGF-βRII-Fc (TERT promoter), anti-PD-1 IgG, anti-CTLA-4 IgG (co-use) | Breast, colon cancer/ s.c. in BALB/c mice: ↓ tumor mass, metastasis | OV: i.t. (2; (0, 2 dpi) Ab: i.p. (4; day 1, 3, 5, 9 dpi) | 124 |
| 4-1BB | vvDD (VV) | Anti-4-1BB IgG | Breast cancer/ s.c. B6 mice: ↓ tumor mass, metastasis; ↑ intratumoral CD11b+, CD11c+ myeloid cells, CD8+ T cells, CD11b+Ly6G+ neutrophils (nine dpi) | OV: i.t. (2; 0, 2 dpi) Ab: i.p. (2; 4, 6 dpi) | 39 |
| GITR | HF-10 (HSV) | Anti-GITR IgG | Colon cancer, fibrosarcoma/ s.c. in BALB/c mice: ↓ tumor mass; ↓ intratumoral Tregs (FC, 5 dpi); ↑ IFN-γ (FC, 7 dpi); ↑ antiviral CD8+ T cell | OV: i.t. (3; 0, 1, 2 dpi) Ab: i.t. (1; two dpi) | 40 |
Ab, antibody; Ad, adenovirus; AML, acute myeloid leukemia; CMV, cytomegalovirus; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; dpi, day post-infection; FC, flow cytometry; FRβ, folate receptor-beta; GITR, glucocorticoid-induced tumor necrosis factor receptor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HER2, human epidermal growth factor receptor 2; HIF2α, hypoxia-inducible factor-2 alpha; HSV, herpes simplex virus; i.c., intracranially; i.d., intradermally; IFN-γ, interferon-γ; IgG, immunoglobulin G; IHC, immunohistochemistry; IL-2, interleukin 2; i.p., intraperitoneal; i.t., intraturmoral; i.v., intravenous; IVA, influenza A virus; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; MV, Measles virus; NDV, Newcastle disease virus; o.t., orthotopic; OV, oncolytic virus; PD-1, programmed cell death protein-1; PDAC, pancreatic ductal adenocarcinoma; PD-L1, programmed cell death ligand-1; Ref, reference; Reo, reovirus; RR, ribonucleotide reductase; Sox10, Sry-related HMg-Box gene 10; TAM, tissue-associated macrophage; TGF-β, transforming growth factor beta receptor II; TGF-βRII, transforming growth factor beta receptor; TK, thymidine kinase; Treg, regulatory T cell; Treg, regulatory T cell; VEGFA, vascular endothelial growth factor A; VEGFR, vascular endothelial growth factor receptor; VSV, vesicular stomatitis virus; VV, vaccinia virus; vvDD, vaccinia virus Western Reserve strain.