Table 3.
The therapeutic efficacy mechanisms of OVs
| Efficacy mechanism | Virus | Gene | Gene function | Mechanism or target protein | Comment, advantage | Unresolved issue, problem or disadvantage | Refs |
|---|---|---|---|---|---|---|---|
| NAb evasion | Ad | Ad5; Ad5-RGD; Ad5/3 | Avoid NAbs | Fiber knob modification | Avoid the NAb response in human cancer patients | NAb is not the only anti-viral defense system | [88] |
| NAb evasion | MV | TRMV ectodomain | Avoid NAbs | The MV F cytoplasmic tail and a TPMV H protein with a truncated cytoplasmic tail | Avoid the MV-neutralization | Lost some fusion function | [76] |
| NAb evasion | VSV | LCMV-GP | To abrogate neurotoxicity, circumvent humoral immunity | rVSV (GP) escapes humoral immunity |
The neurovirulence of VSV is mitigated Avoid the inactivation by complement and NAbs |
Not occur naturally, preclinical safety assessments must be extensive and thorough | [58] |
| Complement evasion | NDV | CD46, CD55 in the viral envelope | To enhance complement evasion | Regulators of complement activity (RCA) | To enable the NDV to resist the complement | Homologous restriction | [89] |
| Complement evasion | VV | Pexa-Vec; complement inhibitor, CP40 | CP40 inhibits the function of complement | The complement dependence of anti-vaccinia antibody | CP40 enhance the delivery efficacy of virus | No AE was not observed | [90] |
| Cancer cell and CAF interaction | VV, VSV∆51, Maraba MG1 virus | FGF2 | To prevent the ability of malignant cells to detect and respond to virus | TGF-β produced by tumor cells reprogrammed CAFs. CAFs produced FGF2 to reduced retinoic acid-inducible gene I (RIG-I) in cancer cells | OV encoded to produce FGF2 is safe in tumor-bearing mice and show improved therapeutic efficacy | The specific molecular mechanism remains to be elucidated | [121] |
| Cell carriers | MV | MSC | MSC transferred MV infection to target cells | The protection from anti-measles antibodies, preferentially accumulate at tumor sites | Cell carriages protect MV from the effect of neutralizing antibody | MV infected MSC did not produce a significant amount of progeny virus | [79] |
| Cell carriers | HSV | MSC | MSC in sECM, then used for the tumor lesions | Killing of GBMs in vitro and in vivo by oHSV infection and tumor destruction | sECM-encapsulated MSC-oHSVs result in statistically significantly increased anti-GBM efficacy | The conventional GBM cell lines used here | [115] |
| Cell carrier | HSV | MSC | Intra-arterial delivery of MSC-oHSV can effectively tracks and kill metastatic tumors | Effectively metastatic melanoma cells in the brain, and that combination therapy with an immune checkpoint blocker boosts the efficacy | Overcomes the hurdles of systemic delivery | Need MSCs | [72] |
| Cell carrier | Ad | BM-hMSCs | Intraarterial delivery effectively eradicated human gliomas | Delta-24-RGD infects and replicates in PD-BM-hMSCs, that PD-BM-hMSCs effectively deliver Delta-24-RGD to the tumors | Overcomes the hurdles of systemic delivery | Need BM-hMSCs | [81] |
| BiTA | VV | EphA2-TEA-VV | Redirecting T cells to tumors | Killing of viral infected and noninfected tumor cells, “bystander killing” | Improved antitumor T-cell responses | The complete clinical responses rarely observed | [47] |
| BiTA | Ad | EnAdenotucirev (EnAd) EpCAM-CD3 | BiTA to EpCAM | BiTA leads to clustering and activation of both CD4 and CD8 T cells; BiTA under the virus major late promoter | Activation of endogenous T cells to kill endogenous tumor cells despite the immunosuppressive environment | Limited to EpCAM-positive tumors | [101] |
| BiTA | Ad | ICO15K-cBiTA. E2F binding sites and an RGDK motif | cBiTAs to EGFR + cells | Increased the persistence and accumulation of tumor-infiltrating T cells in vivo | Robust T-cell activation, proliferation, and bystander cell-mediated cytotoxicity. Shown favorable toxicity profiles | The oncolytic properties reduced twofold compared with the nonmodified virus; Limited to EGFR-positive tumors | [43] |
| Immune stimulation | HSV | GM-CSF | Stimulates the production and maturity of immunocytes | HSV can inhabit the growth of pancreatic carcinoma | The agent was highly attenuated | [98] | |
| Immune stimulation | HSV-1 | GM-CSF | Local and systemic anti-tumor response | A rapid eradication of malignant cells and Enrichment in cytotoxic T cells and a decrease of regulatory T cells in injected and noninjected lesions | Interferon pathway activation and early influx of natural killer cells, monocytes, and dendritic cells | T-VEC HSV proteins in FNA and immunohistochemistry needed. Functional viral replication in nonmalignant cells needed | [112] |
| Immune stimulation | HSV-2 | Deletion of ICP34.5 and ICP47 | ICP34.5 is a neurovirulence gene; ICP47 blocks antigen presentation | The oncolytic activity of HSV-2 is like HSV-1 and can be improved by the sequential use of doxorubicin | Physical barriers restrict the initial distribution and subsequent spread of viruses | [55] | |
| Immune stimulation | HSV | G47Δ-mIL12 | IFNγ and T cell killing inducers | Induces M1-like polarization (iNOS + and pSTAT1 +) in TAMs | The synergistic interaction between G47Δ-mIL12 and two checkpoint inhibitors (anti-CTLA-4 and anti-PD-1) in curing glioblastoma and inducing immune memory | Multiple distinct immunotherapeutic strategies will likely be required | [32] |
| Immune stimulation | HSV | Ruxolitinib (RUX). Δγ34.5 | Constitutively activate STAT signaling | Ruxolitinib improved viral replication and immune response | Increased CD8 + T-cell activation in the tumor microenvironment | [31] | |
| Immune stimulation | VSV | lipopolysaccharide (LPS) | LPS, a TLR-4 agonist, activating innate immune response | LPS can enhance the local therapy effects induced by IT treatment of VSV | [87] | ||
| Immune stimulation | Ad5 | Helicobacter pylori neutrophil-activating protein (HP-NAP) | HP-NAP can recruit neutrophils and induce Th-1 type differentiation | HP-NAP improves the anti-tumor effect through the activation of innate immune system | The systemic level of HP-NAP cannot be measured | [120] | |
| Immune stimulation | VV | HPGD | HPGD is a prostaglandin 2 (PGE2) inactivating enzyme | Reduce MDSC, re-sensitize resistant tumors, enhancing systemic attraction of T cells | HPGD targets PGE2 and depletes G-MDSC; Alters chemokine profiles and immune cell infiltrate | Inducing inflammation, unable to prime adaptive immunity | [173] |
| Immune stimulation | NDV | NDV-ICOSL | ICOS ligand targets ICOS-positive tumor | Enhanced infiltration with activated T cells, and effiency together with systemic CTLA-4 blockade | Combination therapy leads to the expansion of activated TILs | The optimal pathways not known; Limited to a subset of patients | [108] |
| Immune stimulation | poliovirus/rhinovirus chimera | PV receptor CD155 | CD155 is a ligand for CD226, TIGIT, and CD96 with roles in immune response modulation | Stimulates canonical innate anti-pathogen inflammatory responses within the TME that culminate in dendritic cell and T cell infiltration | In addition to lytic damage to malignant cells, noncytotoxic infection of APCs/DCs involved | The use of murine models and in vitro systems, not in patients | [111] |
| Immune stimulation | CD28 | CD28 provide co-stimulatory signals, which are required for T cell activation | Highlight intratumoral CD28 co-stimulation by myeloid-antigen-presenting cells for activation of PD-1 + tumor-infiltrating T lymphocytes during PD-1 blockade in HGSOC | Optimal tumor-specific T cells required for immunotherapy | Not address the immunologically ‘‘cold’’HGSOCs. Some of these tumors completely lack recognition of TAAs by T cells, whereas others simply exclude the tumor-specific T cells from TME | [113] | |
| Apoptosis | HSV-2 | Her2-COL-sFasL | sFasL-containing molecules induce cell apoptosis | Secretable and self-multimerizing sFasL improved the potency | The bystander effect through the tumor cell apoptosis | Cause the death of normal cells | [17] |
| Apoptosis | HSV | oHSV-TRAIL | Alters cell proliferation, death and DDR pathways | Inactivate MEK/ERK and Chk1 signaling pathways, which underlies the anti-GSC activity of oHSV-TRAIL | Potent therapeutic efficacy of an apoptotic variant in glioblastoma models that recapitulate chemo-resistance and recurrence | [158] | |
| Transductional targeting | Ad | Ad-hTERT, CARsc-pSia | Highly polySia-selective retargeting | A bispecific adapter comprising the coxsackievirus/adenovirus receptor ectodomain and a polySia-recognizing scab | Elicits an effective tumor-directed T-cell response after systemic virus delivery and facilitates therapy of disseminated lung cancer | Limited to CAR-deficient, polySia-positive cancer | [41] |
| Transductional targeting | HSV | oHSV-scFv-HER2 (R-LM113) or HSV-scFv-oHER2-mIL-12 (R-115) |
IL-12 to elicit a local immune response scFv to HER2 |
R-115 unleashed the immunosuppressive tumor microenvironment | A reduction in the growth of the primary and distant tumor | Limited to HER2-positive cancer | [174] |
| Transcriptional targeting | HSV-1 | ICP6 defective. γ134.5 under B-myb promoter | γ134.5 protein can circumvent the consequences of PKR activation | Myb34.5 replicates to high level in human PDAC cell lines and is associated with cell death by apoptosis | Virus replicate to high level selectively in PDAC cells | Limited to B-myb present | [13] |
| DARPins | MV | DARPins | Targeted both to HER2/neu and EpCAM | Simultaneously targeted to tumor marker HER2/neu and CSC marker EpCAM | High in vivo efficacy with the potential to handle IT variation of antigen expression | The CSC targeting remains to be elucidated | [48] |
| PARPi | HSV | PARPi | Targeting DDR in cancer with HR repair deficiencies | Increased sensitivity to PARPi due to oHSV-induced Rad51 loss | Overcomes the clinical barriers of PARPi resistance and DNA repair proficiency | The large diversity between different patient GSCs genomically | [33] |
| NIS | MV | Thyroidal sodium-iodide symporter (NIS) | Monitoring by noninvasive imaging of radioiodine | CD46, which is the cellular receptor for MV-NIS, mediating both virus entry and subsequent cell killing through cell–cell fusion | MV-NIS can replicate before being cleared by the immune system. Monitored non-invasively | The small sample size of patients treated in phase II trial | [150] |
| Prodrug activation | Reovirus-3 | RT3D. Drug: cyclophosphamide | Improve viral delivery by immune suppression | Cyclophosphamide may improve tumor delivery | Administration with the association of PBMCs may enhance effiency | Cyclophosphamide is ineffective in this clinical trial | [85] |
| TGF-βR inhibitor | HSV | TGF-βR inhibitor | TGF-β drives, invasion/migration, angiogenesis, immune-suppression | Synergistic in killing recurrent GSCs through, JNK-MAPK blockade and increase in oHSV replication | A novel synergistic interaction of oHSV therapy and TGF-β signaling blockade | 1) treatment at an early time-point, 2) the use of a nodular GBM model | [156] |
| Immune checkpoint inhibitor | VV | PD-1/PD-L1 blockade | Enhances virus-specific CD8+ T-cell responses and reduced viral load | Dual therapy elicited systemic and potent anti-tumor immunity。 | Eliminated immunosuppressive cells (including MDSC, TAM, Treg and exhausted CD8 + T cells), and elicit more anti-tumor immunity | The toxicity; VV elicited a host antiviral immune response, and immune suppressor cells recruitment | [175] |
| Virus stability | HSV | ATN-224 | ATN-224 can form chelate with copper ion | ATN-224 increased serum stability of oHSV and enhanced the efficacy of systemic delivery | Greatly enhanced its replication and antitumor efficacy | The specific mechanism needs further study | [86] |
| Chemokine | HSV-2 | FusOn-H2. Deletion of ICP10 protein kinase domain | Viruses attract T cells to the infected tumor cells | Improve the therapeutic effect through the high level of chemokines in the tumor lesion | Combined with adoptive T-cell therapy | The specific mechanism has not been clarified | [176] |
| Immune evasion | HSV | BAI1, and its N-terminal cleavage fragment (Vstat120) | Vstat120 inhibits TNFα production by blocking BAI1-mediated macrophage response | Reduced macrophage/microglial infiltration, activation and TNFα production | Shields from inflammatory macrophage antiviral response without reducing safety | How Vstat120 might block the function of BAI1 is currently unclear | [39] |
| CDH1 | HSV | CDH1 | E-cadherin, a ligand for KLRG1, an inhibitory receptor on NK cells | E-cadherin enhanced the spread of oHSV-CDH1 by facilitating cell-to-cell infection and viral entry and reduced viral clearance from NK cells | Simultaneously blocks cytolytic NK cell activity and promotes viral infectivity | Just blocks NK cells | [177] |
| RNA interference | HSV-1 | Bcl-2 and Survivin RNAi sequences | The knockdown of Bcl-2 and Survivin genes | Improves the antitumor effect of OVs in high PKR phosphorylation tumor cells | Dual silencing of Bcl-2 and Survivin improved the antitumor effect of oncolytic HSV-1 in vitro and in vivo | In the low PKR phosphorylation tumor cells, the antitumor effect is restricted | [118] |