Table 2 Tumor specificity mechanisms of OVs

Transcriptional targeting

HSV-1

oHSV1-SS1, Signal-Smart 1 (SS1). ICP4 expression under ELK

ICP4, a viral protein necessary for replication

oHSV1-SS1 infects only host cells with overactivation of the Ras/ERK/ELK pathway

SS1 virus preferentially infects prostate cancer cells and induces changes in viability, invasiveness and necrosis

ELK signaling may not reflect the situation in tumor tissues

[165]

Transcriptional targeting

HSV-1

HCC-specific gene promoters

Specific promoters drive selective viral gene expression

Transfer therapeutic genes; target, multiply in, and eradicate hepatoma cells via their lytic cycle

Some HCC-specific gene promoters were identified and can be used for virotherapy

The viral replication relies on the overexpression of B-myb in tumor cells

[11]

Transcriptional targeting

HSV-1

KTR27. The tetR gene controlled by the ICP0 promoter at the ICP0 locus and the essential ICP27 gene under the control of the tetO-bearing ICP27 promoter

ICP0 is required for viral gene expression, replication at low MOI and reactivation; ICP27 is an essential IE protein that modifies and transports viral transcripts to the cytoplasm

Repression of the tetO-bearing ICP27 promoter by tetR would greatly impair the ability of the virus to initiate productive infection in the absence of tetracycline

KTR27 can limit its replication to the targeted TME with localized tetracycline delivery, thus minimizing unwanted viral replication in distant tissues following local virotherapy

Whether KTR27 would be equally effective against small-cell lung cancer or NSCLC xenografts remains to be determined

[166]

Transcriptional targeting

Ad

HYPR-Ad-mIL4, The Ad E1A viral replication and IL-4 genes under the hypoxia/HIF-responsive promoter

Ad E1A makes cells more susceptible to virus replication

Bidirectional tumor-restrictive hypoxia/HIF promoter to drive viral E1A gene expression

Hypoxia-dependent IL-4 expression, viral replication, and conditional cytolysis of hypoxic cells

Limited to tumors that develop hypoxia/HIF activation

[167]

Transcriptional targeting

Ad

Telomelysin (OBP-301); hTERT promoter; combined with chemotherapy drugs: cisplatin and paclitaxel

hTERT promoter to express the viral gene; chemotherapy drugs

Drive the expression of E1A and E1B genes linked with an IRES, induces selective E1 expression, and selectively kills human cancer cells

Most cancer cells express Telomerase transcription factor

These findings need further research in vivo and in different tumor type to determine its validity

[122]

Transcriptional targeting

VV

rVACV is based on the tet operon of transposon Tn10

Tet operon can be activated tetracycline derivatives such as doxycycline

Exogenous control of gene expression levels by administration of a nontoxic inducer

The control of viral gene expression can benefit the safety of virotherapy

Induction rates need increase and the background expression need decrease

[123]

Transductional targeting

VSV

Replication-defective VSV, deleted its glycoprotein gene, VSVΔG, pseudotyped with MV-F and MV-H displaying scFv specific for EGFR, FR or PSMA

VSV G gene encoding VSV-G protein, for cell entry

The retargeted VSV (VSVΔG pseudotypes) infected only cells that expressed the targeted receptors (EGFR, FR, or PSMA)

Pseudotyped VSV infects only cells expressing the corresponding receptor both in vitro and in vivo

The prevalence of preexisting anti-measles antibodies in the patient population could neutralize the systemically administered virus

[168]

Transductional targeting

HSV

scFv-HER2-gH

gH/gL and gB constitute the conserved fusion apparatus

Engineering in gH of scFv directed to the cancer-specific HER2 receptor

Entry of viruses in the absence of gD or upon deletion of key residues in gD for the nectin1/HVEM binding

It can only be used for the tumor cells with HER2 receptor

[14]

Transductional targeting

HSV

gB-scFv-HER2

gB contributes to determine the virus tropism

Engineering in gB of scFv directed to the cancer-specific HER2

Activation of the chimeric gB-HER2 did not require the activation of the gD and gH/gL

Re-targeted to the HER2-positive cancer cells

[169]

Transductional targeting

HSV

gD-GCN4R and gD-HER2

Determine the virus tropism

Simultaneous insertion of both the GCN4 peptide and the Her2 scFv in gD

Re-targeted to the HER2 and GCN4R positive cells

Restricted to HER2 and GCN4R positive cells

[54]

Transductional targeting

HSV

gB-GCN4R and gD-HER2

Determine the virus tropism

Insertion of the GCN4 peptide in gB and detargeting plus HER2-retargeting via gD

Optimize the retargeted oncolytic HSVs to the translational phase

Restricted to the HER2 and GCN4R positive cells

[53]

Transductional targeting

SVV

Wild type virus

Anthrax toxin receptor 1 (ANTXR1)

SVV interacts directly and specifically with ANTXR1

ANTXR1 as the high-affinity cellular receptor for SVV

Non-modified virus

[170, 171]

Immune evasion

HSV-2

Δ ICP47 and ΔICP34.5

ICP34.5, a neurovirulence gene; ICP47 blocks MHC I function in infected cells

Δ ICP34.5 restricts oHSV replication to tumor cells and Δ ICP47 to promote virus oncolytic activity by up-regulating US11 and TAA presentation

Treatment with DOX followed by the oHSV2 was significantly more beneficial than treatment with either agent alone

The extracellular matrix restricts the initial distribution and subsequent spread of viruses in the tumor mass

[55]

Immune evasion

ZIKV

ZIKV-E218A,

NS5 (E218A)

NS5 (E218A) has 2'-O methyltransferase activity

ZIKV-E218A sensitizes the virus to translational inhibition by type I IFN and IFIT1

Lysis of glioblastoma stem cells (GSCs) with less toxicity to normal neural cells

The anti-tumor effect remains to be determined n patient-derived GSCs in vivo

[172]

Immune stimulation

NDV

NDV-expressing ICOS ligand (NDV-ICOSL)

Enhance systemic immune checkpoint blockade

NDV-ICOSL enhances tumor control, TIL infiltration, the efficacy of CTLA-4 blockades

Potentially avoiding additional systemic toxicity

ICOSL could have additional interaction partners

[108]

Immune stimulation

Ad

a 24-base-pair deletion in the E1A gene (Ad5D24)

E1A makes cells more susceptible to virus replication

Ad coated with MHC-I tumor epitopes (the modified poly-K-SIINFEKL, PeptiCRAd)

significantly improve the response rate to checkpoint blocking antibodies

[78]

Post-transcriptional targeting

Ad

Insertion of CPE regulatory sequences in the 3’-UTR of the E1A gene (AdCPE)

E1A makes cells more susceptible to virus replication

CPEB4 bind to CPEs in the 3’-UTR of E1A confers E1A expression post-transcriptionally, resulted in tumour-specific oHSV

CPEB-dependent regulation can be exploited to attenuate viral toxicity, by preventing the spread of the virus in normal tissues

Rely on the cellular transcription machinery, but not for viruses that use virally encoded polymerases in the cytoplasm, such as the MV and VV

[56]

miRNA targeting

VSV

4 tandem copies of a neuronal miRNA125 target sequence inserted in the 3’-untranslated region of the viral polymerase (L) gene

Polymerase L gene coding for RNA-dependent RNA polymerase

miRNA125 targets engineered into VSV to ameliorate its neuropathogenicity by restricting viral replication in specific tissues

Compared to picornaviruses and adenoviruses, the VSVs were relatively resistant to miRNA-mediated inhibition, but neurotoxicity was ameliorated significantly

Mutation and selection of viruses containing altered miRNA target sequences could be a potential pitfall, with mutations in the miRT sequence reducing the efficiency

[57]

miRNA targeting

HSV

apoE-AAT promoter linking with gH and miR-122a complimentary sequence at 3’UTR of gH (LCSOV)

gH is needed for virus assembly and cell entry

Viral gene are replicatible in HCC owning to absent of miR-122a

LCSOV is a safe oHSV that can precisely target HCC both in vivo and in vitro

The strategy depends heavily on promoter activity in the targeted tumor cells

[12]

Translational targeting

HSV-1

ICP6 expression is defective, and expression of the HSV-1 γ1 34.5 gene is regulated by the cellular B-myb promoter (Myb34.5)

The UL39 gene encodes ICP6, an ICP6 mutant HSV that can only replicate in dividing cells

oHSV γ1 34.5 kills tumor cells by PKR-induced inhibition of cell proliferation and tumor growth; ICP6 defective oHSV efficiently replicates and kills dividing cells

HSV-1-based selective Myb.34.5 virus effectively replicates and kills PDAC-derived cells both in vitro and in vivo

The viral replication relies on the overexpression of B-myb in tumor

[13]