Table 1.
Combination therapy of armed oncolytic viruses and immune modulators.
| Transgene | Virus | Tumor | Additive immunologic effects | Toxicity |
|---|---|---|---|---|
|
Cytokines | ||||
| GM-CSF | HSV [[22], [48], [121]] | Adenocarcinoma [33], Metastised (phase I)a [[22], [34]] Breast cancer [121], Melanoma (phase I)a [[121], [122]] | Improved peripheral blood mononuclear cell response [124] | Grade 1 and 2 [[22], [34]], |
| AdV [[34], [110], [122]] | CD3+ T cell infiltration [33] | |||
| MV [33] | Long-term immunity against rechallenge with tumor cells [33] | |||
| VSV [123] | ||||
| NDV [124] | ||||
| IL-12 | AdV [108] | Neuroblastoma [45], Glioma [43], Prostate [48], Squamous Cell Carcinoma [[46], [47]], Melanoma [108] | Infiltration of macrophages, T helper, CTL and NK cells [[43], [45], [47], [48]] | No signs [[44], [46], [47]] |
| HSV [[30], [43], [44], [45], [47], [48]] | Improved survival [108] and protective against rechallenge [47] | |||
| VSV [46] | ||||
| IL-2 | NDV [[52], [53], [54], [55], [56]] | Melanoma [[54], [55]], Hepatoma [[52], [53]], Squamous Cell Carcinoma [51] | Infiltration of T helper and CTL [[51], [52], [53], [54], [55], [56]] | No signs [[53], [54]] |
| HSV [51] | Immunity against rechallenge with tumor cells [[51], [52], [53], [54]] | |||
| IL-15 | VSV [57] | Colon carcinoma [57], Melanoma [[58], [127]] | Increase in tumor specific CTLs in the blood [57] | IL-15 only detectable in tumor [58] |
| NDV [58] | Infiltration of T helper and CTL [58], [126] | |||
| IAV [125] | Immunity against rechallenge with tumor cells [58] | |||
| HSV [126] | Increases survival in mouse model [[58], [127]] | |||
| IAV [127] | ||||
| IFN-β | MV [61] | Non-small cell lung cancer [128], [129], | Improved survival mouse model [61] | Not reported |
| VV [128] | Mesothelioma [61], Pancreatic adenocarcinoma [59] | |||
| VSV [129] | ||||
| NDV [59] | ||||
| IFN-γ | NDV [55] | Melanoma [55], Mammary and colon carcinoma[62] | Increased cytokine expression and improved DC maturation [62] | Not Reported |
| VSV [62] | Increased T cell infiltration [55] | |||
| Others: IL-18[30], [108], IL-17[130], TNF[55], MIP1a[131], FLT3L[131] | NDV [55] | Improved T cell responses | Not reported | |
| VSV [130] | ||||
| AdV [108] | ||||
| HSV [30] | ||||
| Chemokines: CCL5[65], CCL2[67], CCL19[132], CXCL11[64], [133] | VV [[65], [66], [122], [123]] | Colon carcinoma | Improved DC maturation [65] | Not reported |
| HSV [67] | Improved infiltration T helper cells and CTLs [64], [65], [132], [133] | |||
| Induces a Th2 response, but reverts to a Th1 response in combination with DC vaccination [65] | ||||
|
Co-stimulatory ligands | ||||
| B7.1/CD80 | HSV [84] | Neuroblastoma[84], Melanoma (patients)a [86] | Immunity against rechallenge with tumor cells [84] | Low grade [86] |
| VV [86] | Response in 3/11 patients [86] | |||
| 4-1BBL/CD137L | VV [89] | Melanoma | No difference in DC maturation | Not reported |
| Infiltration of CTL | ||||
| CD40L | AdV [92] | Melanoma[93], | More Th1 cytokines [92] | No signs [92] |
| AdVdd [90] | Solid tumor (patients)a[92] | Infiltration of T helper, CTL, NK, DC, MDSC [93] | ||
| VV [93] | Improved survival, but not with armed VSV [90] | |||
| VSV [90] | ||||
| OX-40L | AdV [95] | Melanoma, lung carcinoma | Infiltration of T helper and CTL | Not reported |
| GITRL | AdV [31] | Melanoma | Infiltration of T helper and CTL | No signs |
| LIGHT | AdV [99] | Prostate | Recruitment of effector T cells Reduced Treg suppression |
Not reported |
| CD70 | VV [98] | Colon adenocarcinoma | Reduced tumor growth | Not reported |
|
Checkpoint inhibitors | ||||
| anti-CTLA4 | MV [75] | Melanoma | Infiltration of T helper and CTL [75], [108] | No signs [75], [108] |
| AdV [[74], [108]] | Decreased infiltration of Tregs [75] | |||
| anti-PD1 or PD-L1 | MV [75] | Melanoma | Infiltration of T helper and CTL [75], [83] | No signs [75] |
| VV [83] | Decreased infiltration of Tregs [75], [83] | |||
| MYXV [81] | Improved survival [81] | |||
|
Combinations | ||||
| GM-CSF+IL-12 | AdV [[104], [105]] | Melanoma | Secreted cytokine profile shifted from Th2 to Th2 response [105] | Not reported |
| Infiltration of T helper, CTL, NK and DC [104], [105] | ||||
| Immunity against rechallenge with tumor cells [105] | ||||
| IL-12 + IL-18 | AdV [106] | Melanoma | Infiltration of T helper, CTL, NK | Not reported |
| IL-12 + CCL2 | HSV [67] | Neuroblastoma | Reduced tumor growth | Not reported |
| B7.1 + IL-12 | AdV [41] | Melanoma | Infiltration of T helper, CTL and DC | Not reported |
| B7.1 + IL-18 | HSV [132] | Neuroblastoma, Prostate | Reduced tumor growth No significant difference in survival |
Not reported |
| B7.1 + GM-CSF | AdV [85] | Melanoma | Infiltration of T helper, CTL and DC Immunity against rechallenge with tumor cell | Not reported |
| 4-1BBL + IL-12 | AdV [42] | Melanoma | Infiltration DC, T helper and CTL | No signs |
|
Others | ||||
| HPGD | VV [100] | Several tumor models | Expression of Th1 cytokines, CXCL10/11, CCL5 | Not reported |
| Decreased infiltration MDSC | ||||
| More DCs secreting IL-12 in LN | ||||
| TRIF | VV [100] | Renal cell carcinoma | Increased immune stimulatory cytokine response | Not reported |
| Improved survival | ||||
| DAI | VV [103] | Melanoma | Improved CD8+ cell infiltration | Not reported |
| Reduced tumor growth | ||||
a
indicates patient studies, whereas other studies were performed in mouse models.