Next Article in Journal
Impact of Tumor Site and Adjuvant Radiotherapy on Survival of Patients with Adenoid Cystic Carcinoma: A SEER Database Analysis
Next Article in Special Issue
Personalizing Oncolytic Virotherapy for Glioblastoma: In Search of Biomarkers for Response
Previous Article in Journal
Risk of Nonmelanoma Skin Cancers and Parkinson’s Disease—Meta-Analysis and Systematic Review
Previous Article in Special Issue
Measles Virus as an Oncolytic Immunotherapy
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 13
Issue 4
10.3390/cancers13040588
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Oncolytic Virotherapy in Solid Tumors: The Challenges and Achievements

by
Ke-Tao Jin
1,†,
Wen-Lin Du
2,3,†,
Yu-Yao Liu
1,
Huan-Rong Lan
4,
Jing-Xing Si
3,* and
Xiao-Zhou Mou
3,*
1
Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, Zhejiang, China
2
Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
3
Clinical Research Institute, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
4
Department of Breast and Thyroid Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua 321000, Zhejiang, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2021, 13(4), 588; https://doi.org/10.3390/cancers13040588
Submission received: 31 December 2020 / Revised: 26 January 2021 / Accepted: 30 January 2021 / Published: 3 February 2021
(This article belongs to the Special Issue Oncolytic Virus Immunotherapy)
Browse Figure
Versions Notes

Abstract

:

Simple Summary

Oncolytic virotherapy (OVT) is a promising approach in cancer immunotherapy. Oncolytic viruses (OVs) could be applied in cancer immunotherapy without in-depth knowledge of tumor antigens. Improving efficacy, employing immunostimulatory elements, changing the immunosuppressive tumor microenvironment (TME) to inflammatory TME, optimizing their delivery system, and increasing the safety are the main areas of OVs manipulations. Recently, the reciprocal interaction of OVs and TME has become a hot topic for investigators to enhance the efficacy of OVT with less off-target adverse events. Current investigations suggest that the main application of OVT is to provoke the antitumor immune response in the TME, which synergize the effects of other immunotherapies such as immune-checkpoint blockers and adoptive cell therapy. In this review, we focused on the effects of OVs on the TME and antitumor immune responses. Furthermore, OVT challenges, including its moderate efficiency, safety concerns, and delivery strategies, along with recent achievements to overcome challenges, are thoroughly discussed.

Abstract

Oncolytic virotherapy (OVT) is a promising approach in cancer immunotherapy. Oncolytic viruses (OVs) could be applied in cancer immunotherapy without in-depth knowledge of tumor antigens. The capability of genetic modification makes OVs exciting therapeutic tools with a high potential for manipulation. Improving efficacy, employing immunostimulatory elements, changing the immunosuppressive tumor microenvironment (TME) to inflammatory TME, optimizing their delivery system, and increasing the safety are the main areas of OVs manipulations. Recently, the reciprocal interaction of OVs and TME has become a hot topic for investigators to enhance the efficacy of OVT with less off-target adverse events. Current investigations suggest that the main application of OVT is to provoke the antitumor immune response in the TME, which synergize the effects of other immunotherapies such as immune-checkpoint blockers and adoptive cell therapy. In this review, we focused on the effects of OVs on the TME and antitumor immune responses. Furthermore, OVT challenges, including its moderate efficiency, safety concerns, and delivery strategies, along with recent achievements to overcome challenges, are thoroughly discussed.

1. Introduction

The first hints of the possible anticancer effects of viruses occurred during the early 20th century, with evidence of tumor regression in patients with simultaneous viral infections [1]. Such reports persisted until the 1950s, when the primary clinical studies on the tumor-killing ability of viruses that form the cornerstone of today’s achievements were carried-out [2]. Since then, various preclinical and clinical studies have attempted to optimize the viruses for increasing specificity, efficiency, and reducing adverse events (AEs), which led to the introduction of oncolytic virotherapy (OVT) as emerging immunotherapy of cancers [3]. Oncolytic virus (OVs) or cancer-killing viruses are defined as natural or genetically modified viruses that are able to selectively proliferate in tumor cells without damaging normal cells [4]. This natural tropism of some viruses to tumors is due to an increase in some receptors (such as CD54) on the surfaces of tumor cells or defects of tumor cells to induce innate immunity against viruses [5]. So far, various DNA and RNA OVs have been used to treat cancer [6]. The majority of DNA viruses are double-stranded, while RNA viruses are predominantly single-stranded. The advantages of double-stranded DNA viruses are their large genomes which enable them to carry large eukaryotic transgenes and high fidelity DNA polymerase, maintaining the virus genome integrity during replication [7]. Regarding their relatively small size, RNA viruses cannot encode large transgenes. However, they are better candidates in the delivery system due to less induction of immune responses [8]. Several RNA viruses and DNA viruses, including reovirus (RV), Seneca Valley virus (SVV), poliovirus (PoV), parvovirus (PV), vaccinia virus (VACV), and herpes simplex virus (HSV) have the ability to cross the blood-brain barrier (BBB) enabling their use in brain tumors [9,10,11,12,13,14]. OVT started with wild-type viruses such as Newcastle disease virus (NDV), myxoma virus (MYXV), SVV, PV, coxsackievirus (CV), and RV [3]. However, genetic modification was a revolutionary achievement in the OVT providing greater specificity and efficacy against tumors with higher safety for healthy cells [15]. Genetically modified OVs (GMOVs) mainly include PoV, measles virus (MeV), adenovirus (AdV), VACV, HSV, and vesicular stomatitis virus (VSV) [3]. The first GMOV was HSV-1, introduced in 1991 [16]. So far, three OV-based drugs have been approved for cancer treatment, the first of which was an unmodified ECHO-7 virus called Rigavirus which was approved in 2004 in Lativa under the brand name Rigvir for melanoma [17]. However, the approval was withdrawn in 2019 due to its low efficacy. The two other approved OVs are GMOVs include Oncorine (H101 adenovirus), which obtained approval for head and neck cancer in China in 2005 [3], and T-VEC or Imlygic (HSV-1), which was approved in 2015 in the United States and Europe for non-surgical melanoma [18]. The efficacy of OVs on many cancers, such as melanoma, glioblastoma, triple-negative breast cancer (TNBC), head and neck cancers, and colorectal cancers has been elucidated [19,20,21,22,23], and a large number of clinical trials are currently evaluating the wild-type and GMOVs efficiency and safety in various cancers which are listed in Table 1. Along with the therapeutic approaches, GMOVs expressing reporter genes can be applied in the diagnosis of various cancers by positron emission tomography or single-photon emission computed tomography [24].
OVs can kill the tumor cells in the following main ways: 1. OVs infect and replicate specifically in tumor cells leading to direct lysis of tumor cells. Malignant cells have defects in antiviral responses allowing OVs to replicate and lyse malignant cells [7]; 2. OVs can induce different types of immunogenic cell death (ICD), including necrosis, necroptosis, immunologic apoptosis, pyroptosis, and autophagy. Tumor cell death or lysis causes the release of tumor-associated antigens (TAA) and neoantigens (TAN) and damage-associated molecular patterns (DAMPs), which increase inflammation and improve the efficacy of immunotherapy [25,26]; 3. OVs, especially GMOVs, can enhance tumor antigen presentation and prime the immune response in the tumor microenvironment (TME) by induction of antiviral responses, inflammation, cytokine production, and expression of costimulatory molecules [26,27]; 4. The infection of vascular endothelial cells (vECs) by OVs destroys tumor vasculature, resulting in tumor necrosis and the infiltration of immune cells into the TME [28].
Accordingly, a considerable part of OVT effects on tumors is achieved by changing the TME from an immunosuppressive to the immunostimulatory microenvironment and affecting the tumor vasculature and matrix. Moreover, the success of OVT in solid tumors largely depends on the OV access to the tumor. Here, we review the effects of OVs on the TME and antitumor immune responses. Furthermore, OVT challenges, including its moderate efficiency and safety concerns, along with recent achievements to overcome challenges, are thoroughly discussed. Regarding the critical role of OV delivery strategy in the efficacy of OVT, recent approaches enhancing OV delivery into the TME are also provided.

2. Oncolytic Virus Effects on TME

The long-term effects of immunotherapy in solid tumors are mostly unsatisfactory, partly due to the immunosuppressive condition of TME and low infiltration of immune cells. TME consists of tumor cells, tumor-associated fibroblasts (TAF), vEC, mesenchymal cells, myeloid-derived suppressor cells (MDSCs), and tumor-infiltrating leukocytes (TILs), such as T cells, B cells, dendritic cells (DCs), natural killer (NK) cells, macrophages, and neutrophils [90]. The presence of exhausted cytotoxic T lymphocytes (CTLs), helper T-cells (THs), and NK cells, as well as a large number of regulatory T-cells (Tregs), tolerogenic DCs, MDSC, and M2-macrophages, induce immunosuppressive milieu in the TME through inhibitory ligands and secretion of inhibitory cytokines such as interleukin (IL)-10, tumor growth factor (TGF)-β, IL-35, and IL-27 [91]. OVs can change the paradigm in the TME and convert cold tumors to hot ones by various mechanisms.

2.1. OV-Mediated Lysis of Tumor

Direct oncolysis activity of OVs is the first stimulus of the immune response in the TME [92]. Overexpression of surface receptors such as CD46, CD54, CD155, CD55, and integrins enhances OVs’ preferable entry to tumor cells [93,94,95,96,97]. In normal cells, viral components known as pathogen-associated molecular patterns (PAMPs) are sensed by pattern recognition receptors (PRRs) and induce the production of interferon (IFN)-I through the Janus kinase signal transducer and activator of transcription (JAK-STAT) and Nuclear Factor (NF)-kB signaling pathways. IFN-I activates the protein kinase RNA-activated (PKR) signaling pathway leading to protein synthesis blockade and viral clearance [98]. Tumor cells have defects in antiviral pathways such as IFN-I, PKR, and JAK-STAT, resulting in the survival and proliferation of OVs, specifically in tumor cells [99,100,101]. Lysis of OV-infected cells releases a very diverse TAAs that prime immune cells to induce a local and systemic vaccination against the released TAAs [92]. While many cancer immunotherapies depend on identifying and targeting TAAs (one or several limited TAAs), OVT can vaccinate patients against the entire TAA and TAN treasure of cancer through a phenomenon called antigen/epitope spreading. Hence, OVT could be considered a kind of personalized immunotherapy. Interestingly enough, recent studies have reported the increase of TAA- and TAN-specific T cells in the blood of patients with melanoma and ovarian cancer treated with OVs, suggesting that the in situ OV injection might enhance the systemic antitumor response [102,103,104]. This finding raises hopes for the anti-metastatic effects of OVT. TANs are assumed to be derived from high mutational burden of tumor cells [105,106]. These immunogenic TANs are capable of eliciting tumor-specific immune responses and serve as ideal targets in immunotherapy [105,106,107]. However, TAN-specific T cells are not activated enough in cancer patients due to the poor presentation of TANs, lack of costimulatory signals, and abundance of inhibitory immune checkpoints in the TME [107]. OVs, especially armed OVs, have been shown to activate the TANs-specific T cells by increasing the access of APCs to the TANs (epitope spreading), enhancing the TANs processing and presentation by APCs, and providing costimulatory signals [107,108,109]. Accordingly, Wang et al. demonstrated that VACV armed with PD-L1 inhibitor and GM-CSF enhanced TANs presentation and activated systemic T cell responses against dominant and subdominant (cryptic) neoantigens [107], so OVT could potentiate the antitumor immune responses by activating the TANs-specific T cells.

2.2. Induction of Immunologic Cell Death

Apart from the direct lysis of cancer cells, OVs can induce various ICDs in virus-infected cells through induction of endoplasmic reticulum (ER) stress [110]. Infection of tumor cells with AdV, CV-B3, MeV, VACV, HSV, and H1-PV has been shown to induce ICD and autophagy in cancer cells [111,112]. ICD is characterized by the expression and release of DAMPs such as ATP, uric acid, heat shock proteins, ecto-calreticulin, and HMGB1, as well as extracellular proinflammatory cytokines [113]. Extracellular ATP acts as a danger signal which attracts and activates DCs [114]. HMGB1 and calreticulin can activate DCs via toll-like receptor (TLR)-4 signaling [115]. In addition, calreticulin neutralizes CD47 receptors on the tumor cell surface, and thereby, increases the tumor cell engulfment by macrophages [116]. OV-mediated ICD, along with other ICD-inducing methods such as chemotherapy and radiotherapy, break immune tolerance against the tumor and increase lymphocyte and neutrophil infiltration, leading to antitumor response and more survival in preclinical models [111].

2.3. Stimulation of Antitumor Immune Response

Besides the release of DAMPs, cancer cell death also causes the release of viral PAMPs in the TME. These PAMPs mainly include DNA, ssRNA, dsRNA, proteins, and capsid contents that activate innate immune cells through stimulating PRRs such as retinoic acid-inducible gene (RIG)-1, cyclic GMP-AMP synthase (cGAS), and stimulator of interferon genes (STING) [113]. DCs, as a bridge between the innate and adaptive immune systems, play a critical role in generating the antitumor response. DCs elicit a specific response against TAA-expressing tumor cells by engulfing OV-infected cells and cross-presentation of TAAs to CD8+ T and CD4+ T cells [117]. On the other hand, the OVs-derived PAMPs cause maturation of myeloid and plasmacytoid DCs, leading to the production of proinflammatory cytokines such as IFN-α, IFN-γ, IL-12, IL-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α [90,118,119]. These functional DCs, mainly CD103+ and BATF3+, prime CD8+ T cells against tumors [120]. Innate immune signaling, such as the cGAS-STING pathway, plays a pivotal role in the recruitment of lymphocytes to the TME through the expression of CXCL9 and CXCL10 [121]. Parallel to DCs, innate lymphoid cells (ILCs) also respond to the released PAMPs leading to higher inflammation and antitumor responses [18]. As an example, arenavirus-infected melanoma cells produce a high level of CCL5, leading to recruitment of NK cells and melanoma regression [122]. Interestingly, in situ antitumor responses following OVT are mainly mediated by IFN-I, whereas OVT-mediated systemic antitumor responses appear to be mediated by IFN-II excreted from TILs [123]. In general, the innate immune response to OVs increases lymphocyte infiltration, antigen presentation, and activation of the antitumor adaptive immune response through an IFN-mediated mechanism [18]. T cell activation requires at least three consecutive signals (peptide-MHC, CD28-B7, and stimulatory cytokines), all of which are defected in TME to escape adaptive immune responses. OVs, as potent immunogens, induce all three signals needed to activate T cells [18]. OVT increases the expression of B7-1/2 and CD40 on the surface of DCs and induces the expression of MHC-peptide on the surface of tumor cells leading to optimal activation of T cells [124]. Conversion of the TME phenotype from immunologically inert to immunologically active status can augment the effectiveness of the immunotherapeutic modalities.

2.4. Effect of OV on Tumor Vasculature

Some OVs, such as HSVs and VACVs, can target tumor stromal cells, such as TAFs, vECs, and pericytes, thereby destroy the tumor’s complex structure [26]. TGF-β secreted by tumor cells makes TAFs susceptible to OV infection [125]. OVs also reduce the fibrosis in the TME. VSV has been shown to infect hepatic stellate cells (HSCs), leading to tumor fibrosis reduction [126]. OVs affect the tumors vasculature by replicating in the tumor vECs. Vascular endothelial growth factor (VEGF) secreted from tumor vECs suppresses the antiviral response and allows the replication of OVs in endothelial cells through ERK1/2 and STAT3 pathways [127]. Following infection and replication, the OVs reduce VEGF production from the infected cell resulting in angiogenesis prevention in the tumor. OVs’ antiangiogenic properties further limit tumor growth by decreasing the oxygen and nutrition supplies [6]. VACV is shown to replicate in the tumor vEC and cause vascular destruction and ischemia [28]. Neutrophil infiltration into the TME seems essential for OVT-mediated ischemia through the induction of thrombosis in small tumor vessels [28]. It has been shown that the administration of JX-594 in hepatocellular carcinoma destroyed tumor vasculature without affecting patients’ normal vessels [28]. Thus, targeting of stromal cells by OVs increases the infiltration of immune cells into the TME, and converts immuno-deserted or immune-excluded tumors (with low TILs) into immune-infiltrated tumors [18]. OVT-mediated changes in the TME, including lymphocyte infiltration into the tumor, enhancement of TAAs/TANs presentation, and heating the TME can improve other immunotherapies such as adoptive cell therapy (ACT) and immune checkpoint inhibitors (ICIs) [90].

3. OVT Challenges and Achievements

3.1. Tumor Targeting

Although OVs have tumor tropism based on some overexpressed receptors and adhesion molecules on the tumor cells, the tumor tropism of wild OVs is not enough. GMOVs can express receptors with a high affinity for TAAs. For instance, insertion of single-chain antibodies (scAb) against human epidermal growth factor receptor (HER)-2, epithelial cell adhesion molecule (EpCAM), and carcinoembryonic antigen (CEA) increases the specificity of OVs to tumors [128,129,130]. Insertion of sequences such as the arginine-glycine-aspartate (RGD) motif or specific domain from AdV3 and AdV35 to AdV5, makes AdV5 specific for integrins, desmoglein-2, and CD46, which are overexpressed in tumors [131,132]. VSV expressing HIV-derived glycoprotein (gp)-160 is a specific VSV against leukemia and T lymphomas [133].
Defects in the IFN-I antiviral response, lack of tumor suppressor genes such as the retinoblastoma (Rb), and increased Ras signaling in tumor cells lead to the specific proliferation of OVs in tumor cells [134]. Insertion of tumor-specific promoters such as prostate-specific antigen (PSA) and human telomerase reverse transcriptase (hTERT) promoters, which are highly expressed in tumor cells, causes specific expression of viral genes in tumor cells [135,136]. Some micro-RNAs (miRNAs) are overexpressed in healthy cells while they are at negligible levels in tumor cells. Hence, targeting these miRNAs by miRNA-targeting sequences (miRNA-TS) destroys viral RNA in normal cells. Low expression of miRNA-TS targets in tumor cells causes viral RNAs to remain and replicate in tumor cells [137].

3.2. Improving Antitumor Efficacy

Genetic modifications of OVs to increase the expression of cytokines, chemokines, costimulatory molecules, tumor extracellular matrix (ECM)-degrading enzymes, and antiangiogenic molecules can enhance their antitumor effects (Figure 1). Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-bearing OVs such as T-VEC, Pexa-Vec, and CG0070 recruit antigen-presenting cells (APCs) and CTLs, resulting in a better TAA presentation with minimal antiviral response induction [6]. GMOVs expressing proinflammatory cytokines showed enhanced antitumor efficacy. Despite the considerable antitumor response, IL-2-secreting OVs cause systemic toxicity. The design of VACV expressing membranous IL-2 rather than secretory form increases local antitumor response with significantly reduced toxicity [138]. The use of IL-12, IL-15, IL-18, TNF-α, IL-24, and IFN-γ genes in OVs also enhances antitumor effects with much lower toxicity than IL-2 [6,139,140,141]. Interestingly, the application of the non-secretory form of these cytokines causes local effects rather than systemic AEs [142]. Expression of specific chemokines such as CCL5, CCL19, CCL20, CCL21 by engineered OVs (mainly VACV) increases the infiltration of naïve and memory T lymphocytes and DCs into the TME [143,144,145,146]. Simultaneously, employment of one or multiple costimulatory ligands, including CD40L, 4-1BBL, OX40L, and B7-1 in OVs such as LOAd703 (the combination of CD40L and 4-1BBL) increases antigen presentation and T cell priming [6,26,96]. Besides, insertion of TLR ligands such as CpG-rich regions in the OVs genome stimulates TLRs and further activates innate and acquired immunity [138].
Another way to enhance the immune responses in the TME is the elimination of immunosuppressive cells. GMOVs that express the hydroxyprostaglandin dehydrogenase (HPGD) enzyme inactivate PGE2 and reduce the presence of MDSCs in the TME [147]. Soluble CXCR4 expressed by GMOVs binds to CXCL12 secreted by tumor cells as a decoy receptor and inhibits the effects of CXCL12 on angiogenesis, metastasis, and recruitment of MDSCs [148].
Although OVT can release TAAs through various mechanisms, the expression of TAAs by GMOVs or coating the TAA-derived peptides on the surface of OVs increases T cell response and improves OVT. A large number of TAAs and peptides have been studied so far [26]. The advantage of peptide coating over peptide expression is the convenience, speed, lower cost, and the possibility of personalization for each patient in the peptide coating method [26].
OVs can be engineered to express proapoptotic proteins such as TNF-related apoptosis-inducing ligand (TRAIL) and apoptin that can induce specific apoptosis in tumor cells [149,150]. Insertion of the oncogene suppressor small interfering RNAs (siRNAs) in OVs could also suppress oncogene expression and inhibit tumor growth [151,152].
The host antiviral response ensures that OVs disappear after a while and prevents the AEs of their long presence. However, the host antiviral response might cause rapid clearance of OVs before fulfilling their antitumor activity [153]. Expression of IFN-I antagonists by OVs or some non-pathogenic bacteria reduces the innate immune response against OV and delays their clearance [154]. Also, the use of stem cells, polymers, and liposomes as OV carriers reduces the immunogenicity of OVs, shields them from neutralizing antibodies (nAbs), and improves their transmission to the TME, which is listed in Table 2. An interesting way to optimize cytokine production with minimal antiviral responses is to insert inducible promoters or regulatory genes so that the cytokine expression is exogenously induced after sufficient replication of OVs in tumor cells [155].

3.3. Tumor ECM and Vasculature Degradation

Tumor ECM is a barrier to access tumor cells. Co-administration of ECM-degrading enzymes such as relaxin [234], matrix metalloproteinase (MMP)-1, -8, -9 [131,226], chondroitinase [235], and hyaluronidase [226] with OVT, or induction of their genes expression in GLV-1h255 (VACV) and VCN-01 (OAdV) can increase OV spread into the TME and improved OVT efficiency in cancers such as retinoblastoma and pancreatic carcinoma [236,237]. Cellular tight junctions are also accounted as barriers for OV distribution. GMOVs can trigger the production of proteins such as penton-dodecahedra and junction opener-1, which open the cellular junction through binding to desmoglein-2 [226]. However, there are concerns about increasing the likelihood of metastasis in this method that needs further investigation.
On the other hand, the insertion of endostatin and thrombospondin-1 genes in HSV-Endo and T-TSP-1 (both are HSV) destroys tumor vasculature. It suppresses angiogenesis in lung and gastric cancer by inhibiting migration and enhancing apoptosis in vECs [238,239]. Also, the expression of anti-VEGF sc-Ab by VACV increases antiangiogenic and antitumor properties [240].

3.4. Biosafety of OVT

Besides tumor cells, some OVs might replicate in normal cells and cause damage. For instance, T-VEC might remain a latent infection and cause long-term neurological AEs [153]. Using OVs with low pathogenicity in humans, such as parvovirus and reovirus, weakening OVs through repeated passages or deleting virulence genes, can increase the safety of OVT [241,242]. Thymidine kinase (TK) and infected cell protein (ICP)34.5 genes play a vital role in VACV and HSV-1 replication. The products of such genes are abundant in tumor cells, so the GMOVs lacking these genes can replicate in tumor cells, while the virus replication is impaired in healthy cells due to the low expression of such products [243,244]. The GL-ONC1 and Pexa-Vec (JX-594) are TK-free VACVs, and the T-VEC, HSV-1716, and G207 are ICP34.5-free HSVs showing acceptable safety in clinical trials [6,245,246,247]. Wild ZIKA virus has oncolytic potential in glioblastoma but also infects normal nerves with severe complications. Removal of 10 nucleotides from 3’ of its genome can increase safety without reducing oncolytic activity [248]. Mutation or deletion of the E1 gene in AdV, and deletion of TK, vaccinia growth factor (VGF), hemagglutinin, and B18R genes in poxvirus reduce the virulence of OVs in normal cells [153,249]. However, deleting virulence genes to increase safety sometimes reduces OVs’ antitumor activity [250].
Recombination of a safe OV such as NDV with an efficient OV like VSV is another way to increase the safety of OVs. Recombinant VSV-NDV (rVSV-NDV) comprises the envelope contents from NDV and the original backbone of VSV. Recombination of AdV with less harmful coxsackievirus or parvovirus constitutes OVs with high potency in tumor cell infection without damage to normal cells [250,251,252]. Using Ebolavirus (EBOV) glycoproteins also reduces the neurotoxicity of VSV in rVSV-EBOV [253]. Nevertheless, naturally occurring homologous recombination of GMOVs and wild-type OVs might result in a transgenic and pathogenic virus [153]. Transmission of OVs through body fluids to other people is rare but still a concern [254]. Also, the safety of OVT in immunocompromised individuals receiving radiotherapy and chemotherapy, as well as in pregnant women is still debated [153]. In general, due to the emergence of OVT with GMOVs, its long-term AEs are still unknown and require caution and further investigations.

3.5. Administration Routs

One of the factors influencing the response to OVT is the way of administration. Intratumoral injection results in precise control of the OV concentration in the TME, resulting in better therapeutic outcomes [255,256]. However, the complexity of intratumoral injection limits dosing repetition [257]. Besides, low perfusion of OVs into dense tumors requires ECM-degradation strategies [226]. Intravenous injection is popular due to its convenience, reproducibility, and possibility to target metastatic foci [258,259]. However, it requires tumor- specific delivery systems and is more likely to cause systemic toxicity [257]. Liver tropism, physical barriers such as BBB, complement activation, and the immune system response to OV before accessing the TME are the other disadvantages of intravenous injection [226,257]. Intraperitoneal, intrathecal/intracranial, and intrapleural injections are suitable for targeting intra-abdominal organs, central nervous system (CNS), and lung tumors, respectively, but are limited to use in laboratory animals [153]. The best route of administration is still a matter of debate with no specific guidelines. It seems that the less aggressive administration routs such as oral/mucosal and nasal administration, at least for gastrointestinal and cerebral malignancies, could increase the acceptability for patients and should be considered in future studies.

4. Combination Therapy

4.1. Immune-Checkpoint and Cell Therapy

Despite all the benefits, OVT as monotherapy cannot have a dramatic effect on tumor suppression and, like other immunotherapy methods, is used as combination therapy. A common complementary treatment strategy for OVT is ICI [260]. The overexpression of various immune checkpoints in the TME suppresses the response of immune cells. OVT and ICI seem to have synergistic effects [114,260]. OVT facilitates the infiltration of immune cells into the TME, and ICIs prevent the suppression of infiltrated immune cells activity. OVT also improves ICI access to the TME by destroying ECM and tumor vessels [6]. Recently, the use of OVs expressing mini-antibody (minibody) and single-chain variable fragment (scFv) against checkpoints has been able to block checkpoints locally in the TME, with fewer AEs [261,262]. Many clinical trials are currently examining the combination of ICI and OVT, the results of which primarily suggest that in order to achieve a better outcome, ICI should be prescribed after the onset of OV responses [6,263]. OVT increases the effectiveness of TIL and CAR-T cell therapy. OVT can increase the access of TILs and CAR-T cells to the tumor by altering the tumor matrix and increasing the chemokines such as CCL5 [264]. The secretion of IL-15, TNF-α and IL-2 from OVs in the TME increase the in situ proliferation and activation of TILs and enhances tumor response to CAR-T cell therapy [265,266]. Bispecific T-cell engagers (BiTEs) are fusion proteins containing two scAbs against tumor antigens and T cell surface CD3 [267]. The use of BiTE-expressing OVs can bridge T/CAR-T cells to TAA-expressing cells in the TME [267]. Furthermore, concomitant use of TAA-specific mAbs with OVT can enhance the antitumor response. However, the small size of OVs genome has made it difficult to encode whole antibodies [268] Combination of OVT with DC vaccines also improves the efficacy of DC vaccines by altering the TME immunosuppressive conditions [269]. OVs could be utilized as tumor vaccines in order to enhance the immune responses against established tumors or even prevent tumor recurrence. The main function of such OV-based tumor vaccines is the recruitment of APCs, facilitating the phagocytosis of tumor cells by APCs, and promoting the APC maturation to induce appropriate antitumor immune responses [270,271,272].

4.2. Metabolic Inhibitors as an Emerging Combination Therapy

Given the OV dependence on host cell metabolism for replication, the metabolic pathways can be considered effective modalities in OVT. For example, due to the role of glycolysis in the antiviral response, blocking this pathway increases the sensitivity of cells to OV infection [273,274]. On the other hand, increasing pyruvate flux into the tricarboxylic acid cycle, the increment of oxidative phosphorylation, and reactive oxygen species production lead to enhance OV replication and oncolytic activity [275,276,277]. However, there are contradictions in the enhancing or dampening roles of these metabolic pathways in the replication and function of OVs [278]. These discrepancies indicate that the metabolic pathway targeting should be based on the type of cancer and employed OV. Tumor cells deplete the glucose, tryptophan, and glutamine required by immune cells and produce lactate, kynurenine, and adenosine [279]. These changes cause induction of exhausted CTLs, M2-macrophages, and Tregs, creating an immunosuppressive TME [275,276,277,278]. The combination of metabolic inhibitors with OVT and the application of GMOVs to express metabolic inhibitors can alter the metabolism of cancer cells and immune cells to increase antitumor responses [278,280].

4.3. Other Combination Therapies

Along with the growing interest in OVT in the field of cancer treatment, many preclinical and clinical studies have suggested the use of OVs in combination with other common cancer therapies. OVT has been shown to potentiate the response to chemotherapy and radiotherapy, so that it could re-sensitize the chemo-/radio-resistant cells. Therefore, the combination of OVT with chemotherapy and radiotherapy is currently being evaluated in several clinical trials for chemo-resistant patients (Table 1). One of the shared mechanisms of OVT and chemo-/radiotherapy is ICD, in which a plethora of DAMPs is released, resulting in maximum induction of innate and adaptive immune responses. Hence, using OVT along with chemo-/radiotherapy could decrease the required doses of toxic agents and consequently lessen the adverse events of high dose treatments. Recombinant OVs can express enzymes such as cytosine deaminase, which converts the non-toxic prodrug 5-fuorocytosine (5-FC) into a toxic drug 5-fluorouracil (5-FU) in the tumor milieu [152]. Such local production of chemotherapeutic agents would decrease the systemic adverse events. GMOVs encoding the FCU1 gene can produce two enzymes, FCY1 and FUR1, that convert 5-FC to 5-FU and consequently 5-FU-monophosphate to target 5-FU-resistant tumors [152]. The tumor ECM prevents the access of therapeutic agents to the tumor cells, making the tumor resistant to chemotherapy [281]. Combination of ECM-degrading GMOVs with chemotherapy overrides the ECM-induced chemo-resistance observed in solid tumors [281]. Combination therapy of OVs and chemotherapy has been shown to exert synergistic antitumor activities via enhancing tumor cell killing capacity of chemotherapeutic agents, increasing virus proliferation in tumor cells, and invigorating oncolytic activities of OVs [282,283].
Besides conventional chemotherapy and radiotherapy, OVs could be administered in combination with targeted therapies [284]. Histone deacetylase inhibitors (HDIs) are recently entered the clinic as a promising treatment for cancers [285]. The companion of HDIs with OVT increases viral replication, upregulates the transgene expression (such as GM-CSF in T-VEC), enhances virus spread through the tumor cells, and augments oncolytic activities [286,287]. Moreover, HDIs induce antitumor immunity by inducing the expression of NK cell activating ligands and expression of TAAs, resulting NK cells and CTLs priming [286]. Co-administration of OVs with some protein kinase inhibitors such as MEK-1/2 and BRAF, and also inhibitors of some transcription factors like STAT-1 and NK-κB has been shown to enhance the oncolytic activities of OVs [288,289]. MEK/BRAF inhibitors do not affect viral replication. Instead, they enhance ER stress-induced apoptosis following OVT [288]. Interferon-stimulated genes (ISGs) are associated with resistance of tumors to chemotherapy, radiotherapy, and OVT. STAT-1 and NK-κB inhibitors diminish the expression of ISGs and thereby increase the cytotoxicity of OVs [289].

5. Conclusions

Although the OVT is not a new concept in cancer, the concerns of possible adverse events and unspecific infection hamper enough development in this era. The emerging genetic manipulations of OVs facilitate clinical studies with much lower concerns and reintroduce OVT as a promising immunotherapeutic approach. However, many questions should still be addressed. Finding the appropriate OV for each tumor, the best combination therapy, higher OVT efficacy and safety, and optimal delivery system require further knowledge about the cellular and molecular interaction between the OVs and the cells present in the TME. The results of current clinical trials could pave the way for OVT in the clinic.

Author Contributions

X.-Z.M. and J.-X.S.: Conception, design and inviting co-authors to participate. K.-T.J., W.-L.D., Y.-Y.L. and H.-R.L.: Writing original manuscript draft. X.-Z.M. and J.-X.S.: Review and editing of manuscript critically for important intellectual content and provided comments and feedback for the scientific contents of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

This work was supported by Zhejiang Provincial Science and Technology Projects (No. LGD19H160001 to K.-T.J.), Zhejiang Provincial Natural Science Foundation of China (No. LY21H160048 to J.-X.S.), National Natural Science Foundation of China (No. 81672430 to X.-Z.M.).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Dock, G. The influence of complicating diseases upon leukaemia. Am. J. Med. Sci. (1827–1924) 1904, 127, 563. [Google Scholar] [CrossRef]
  2. Kelly, E.; Russell, S.J. History of oncolytic viruses: Genesis to genetic engineering. Mol. Ther. 2007, 15, 651–659. [Google Scholar] [CrossRef] [PubMed]
  3. Russell, S.J.; Peng, K.-W.; Bell, J.C. Oncolytic virotherapy. Nat. Biotechnol. 2012, 30, 658. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Chiocca, E.A.; Rabkin, S.D. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol. Res. 2014, 2, 295–300. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Annels, N.E.; Mansfield, D.; Arif, M.; Ballesteros-Merino, C.; Simpson, G.R.; Denyer, M.; Sandhu, S.S.; Melcher, A.A.; Harrington, K.J.; Davies, B. Phase I trial of an ICAM-1-targeted immunotherapeutic-coxsackievirus A21 (CVA21) as an oncolytic agent against non muscle-invasive bladder cancer. Clin. Cancer Res. 2019, 25, 5818–5831. [Google Scholar] [CrossRef]
  6. Lan, Q.; Xia, S.; Wang, Q.; Xu, W.; Huang, H.; Jiang, S.; Lu, L. Development of oncolytic virotherapy: From genetic modification to combination therapy. Front. Med. 2020, 14, 1–25. [Google Scholar] [CrossRef] [Green Version]
  7. Kaufman, H.L.; Kohlhapp, F.J.; Zloza, A. Oncolytic viruses: A new class of immunotherapy drugs. Nat. Rev. Drug Discov. 2015, 14, 642–662. [Google Scholar] [CrossRef]
  8. Bommareddy, P.K.; Patel, A.; Hossain, S.; Kaufman, H.L. Talimogene laherparepvec (T-VEC) and other oncolytic viruses for the treatment of melanoma. Am. J. Clin. Dermatol. 2017, 18, 1–15. [Google Scholar] [CrossRef]
  9. Samson, A.; Scott, K.J.; Taggart, D.; West, E.J.; Wilson, E.; Nuovo, G.J.; Thomson, S.; Corns, R.; Mathew, R.K.; Fuller, M.J. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci. Transl. Med. 2018, 10, eaam7577. [Google Scholar] [CrossRef]
  10. Geletneky, K.; Hajda, J.; Angelova, A.L.; Leuchs, B.; Capper, D.; Bartsch, A.J.; Neumann, J.-O.; Schöning, T.; Hüsing, J.; Beelte, B. Oncolytic H-1 parvovirus shows safety and signs of immunogenic activity in a first phase I/IIa glioblastoma trial. Mol. Ther. 2017, 25, 2620–2634. [Google Scholar] [CrossRef] [Green Version]
  11. Yu, L.; Baxter, P.A.; Zhao, X.; Liu, Z.; Wadhwa, L.; Zhang, Y.; Su, J.M.; Tan, X.; Yang, J.; Adesina, A. A single intravenous injection of oncolytic picornavirus SVV-001 eliminates medulloblastomas in primary tumor-based orthotopic xenograft mouse models. Neuro Oncol. 2010, 13, 14–27. [Google Scholar] [CrossRef] [PubMed]
  12. Ohka, S.; Nihei, C.-I.; Yamazaki, M.; Nomoto, A. Poliovirus trafficking toward central nervous system via human poliovirus receptor-dependent and-independent pathway. Front. Microbiol. 2012, 3, 147. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Garcel, A.; Fauquette, W.; Dehouck, M.-P.; Crance, J.-M.; Favier, A.-L. Vaccinia virus-induced smallpox postvaccinal encephalitis in case of blood–brain barrier damage. Vaccine 2012, 30, 1397–1405. [Google Scholar] [CrossRef] [PubMed]
  14. Liu, H.; Qiu, K.; He, Q.; Lei, Q.; Lu, W. Mechanisms of blood-brain barrier disruption in herpes simplex encephalitis. J. Neuroimmune Pharmacol. 2019, 14, 157–172. [Google Scholar] [CrossRef] [PubMed]
  15. Yu, F.; Wang, X.; Guo, Z.S.; Bartlett, D.L.; Gottschalk, S.M.; Song, X.-T. T-cell engager-armed oncolytic vaccinia virus significantly enhances antitumor therapy. Mol. Ther. 2014, 22, 102–111. [Google Scholar] [CrossRef] [Green Version]
  16. Martuza, R.L.; Malick, A.; Markert, J.M.; Ruffner, K.L.; Coen, D.M. Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 1991, 252, 854–856. [Google Scholar] [CrossRef]
  17. Alberts, P.; Tilgase, A.; Rasa, A.; Bandere, K.; Venskus, D. The advent of oncolytic virotherapy in oncology: The Rigvir® story. Eur. J. Pharmacol. 2018, 837, 117–126. [Google Scholar] [CrossRef]
  18. Bommareddy, P.K.; Shettigar, M.; Kaufman, H.L. Integrating oncolytic viruses in combination cancer immunotherapy. Nat. Rev. Immunol. 2018, 18, 498. [Google Scholar] [CrossRef]
  19. Bourgeois-Daigneault, M.-C.; Roy, D.G.; Aitken, A.S.; El Sayes, N.; Martin, N.T.; Varette, O.; Falls, T.; St-Germain, L.E.; Pelin, A.; Lichty, B.D. Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy. Sci. Transl. Med. 2018, 10, 1641–1650. [Google Scholar] [CrossRef] [Green Version]
  20. Delwar, Z.M.; Kuo, Y.; Wen, Y.H.; Rennie, P.S.; Jia, W. Oncolytic virotherapy blockade by microglia and macrophages requires STAT1/3. Cancer Res. 2018, 78, 718–730. [Google Scholar] [CrossRef] [Green Version]
  21. Garcia-Carbonero, R.; Salazar, R.; Duran, I.; Osman-Garcia, I.; Paz-Ares, L.; Bozada, J.M.; Boni, V.; Blanc, C.; Seymour, L.; Beadle, J. Phase 1 study of intravenous administration of the chimeric adenovirus enadenotucirev in patients undergoing primary tumor resection. J. Immunother. Cancer 2017, 5, 1–13. [Google Scholar] [CrossRef] [PubMed]
  22. Lawler, S.E.; Speranza, M.-C.; Cho, C.-F.; Chiocca, E.A. Oncolytic viruses in cancer treatment: A review. JAMA Oncol. 2017, 3, 841–849. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Martikainen, M.; Essand, M. Virus-based immunotherapy of glioblastoma. Cancers 2019, 11, 186. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Haddad, D. Genetically engineered vaccinia viruses as agents for cancer treatment, imaging, and transgene delivery. Front. Oncol. 2017, 7, 96. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Bai, Y.; Hui, P.; Du, X.; Su, X. Updates to the antitumor mechanism of oncolytic virus. Thorac. Cancer 2019, 10, 1031–1035. [Google Scholar] [CrossRef] [PubMed]
  26. Ylösmäki, E.; Cerullo, V. Design and application of oncolytic viruses for cancer immunotherapy. Curr. Opin. Biotechnol. 2020, 65, 25–36. [Google Scholar] [CrossRef]
  27. De Graaf, J.F.; de Vor, L.; Fouchier, R.A.M.; Van Den Hoogen, B.G. Armed oncolytic viruses: A kick-start for anti-tumor immunity. Cytokine Growth Factor Rev. 2018, 41, 28–39. [Google Scholar] [CrossRef]
  28. Breitbach, C.J.; Arulanandam, R.; De Silva, N.; Thorne, S.H.; Patt, R.; Daneshmand, M.; Moon, A.; Ilkow, C.; Burke, J.; Hwang, T.-H. Oncolytic vaccinia virus disrupts tumor-associated vasculature in humans. Cancer Res. 2013, 73, 1265–1275. [Google Scholar] [CrossRef] [Green Version]
  29. Chesney, J.; Puzanov, I.; Collichio, F.; Singh, P.; Milhem, M.M.; Glaspy, J.; Hamid, O.; Ross, M.; Friedlander, P.; Garbe, C. Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. J. Clin. Oncol. 2018, 36, 1658. [Google Scholar] [CrossRef]
  30. Kelly, C.M.; Antonescu, C.R.; Bowler, T.; Munhoz, R.; Chi, P.; Dickson, M.A.; Gounder, M.M.; Keohan, M.L.; Movva, S.; Dholakia, R. Objective response rate among patients with locally advanced or metastatic sarcoma treated with talimogene laherparepvec in combination with pembrolizumab: A phase 2 clinical trial. JAMA Oncol. 2020, 6, 402–408. [Google Scholar] [CrossRef]
  31. Ribas, A.; Dummer, R.; Puzanov, I.; VanderWalde, A.; Andtbacka, R.H.; Michielin, O.; Olszanski, A.J.; Malvehy, J.; Cebon, J.; Fernandez, E. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 2017, 170, 1109–1119. e1110. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Chesney, J.; Awasthi, S.; Curti, B.; Hutchins, L.; Linette, G.; Triozzi, P.; Tan, M.C.; Brown, R.E.; Nemunaitis, J.; Whitman, E. Phase IIIb safety results from an expanded-access protocol of talimogene laherparepvec for patients with unresected, stage IIIB–IVM1c melanoma. Melanoma Res. 2018, 28, 44–51. [Google Scholar] [CrossRef] [PubMed]
  33. Andtbacka, R.; Kaufman, H.L.; Collichio, F.; Amatruda, T.; Senzer, N.; Chesney, J.; Delman, K.A.; Spitler, L.E.; Puzanov, I.; Agarwala, S.S. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 2015, 33, 2780–2788. [Google Scholar] [CrossRef] [PubMed]
  34. Harrington, K.J.; Hingorani, M.; Tanay, M.A.; Hickey, J.; Bhide, S.A.; Clarke, P.M.; Renouf, L.C.; Thway, K.; Sibtain, A.; McNeish, I.A. Phase I/II study of oncolytic HSVGM-CSF in combination with radiotherapy and cisplatin in untreated stage III/IV squamous cell cancer of the head and neck. Clin. Cancer Res. 2010, 16, 4005–4015. [Google Scholar] [CrossRef] [Green Version]
  35. Senzer, N.N.; Kaufman, H.L.; Amatruda, T.; Nemunaitis, M.; Reid, T.; Daniels, G.; Gonzalez, R.; Glaspy, J.; Whitman, E.; Harrington, K. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J. Clin. Oncol. 2009, 27, 5763. [Google Scholar] [CrossRef] [PubMed]
  36. Hu, J.C.; Coffin, R.S.; Davis, C.J.; Graham, N.J.; Groves, N.; Guest, P.J.; Harrington, K.J.; James, N.D.; Love, C.A.; McNeish, I. A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin. Cancer Res. 2006, 12, 6737–6747. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Streby, K.A.; Geller, J.I.; Currier, M.A.; Warren, P.S.; Racadio, J.M.; Towbin, A.J.; Vaughan, M.R.; Triplet, M.; Ott-Napier, K.; Dishman, D.J. Intratumoral injection of HSV1716, an oncolytic herpes virus, is safe and shows evidence of immune response and viral replication in young cancer patients. Clin. Cancer Res. 2017, 23, 3566–3574. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Mace, A.T.; Ganly, I.; Soutar, D.S.; Brown, S.M. Potential for efficacy of the oncolytic Herpes simplex virus 1716 in patients with oral squamous cell carcinoma. Head Neck J. Sci. Spec. Head Neck 2008, 30, 1045–1051. [Google Scholar] [CrossRef]
  39. Geevarghese, S.K.; Geller, D.A.; de Haan, H.A.; Hörer, M.; Knoll, A.E.; Mescheder, A.; Nemunaitis, J.; Reid, T.R.; Sze, D.Y.; Tanabe, K.K. Phase I/II study of oncolytic herpes simplex virus NV1020 in patients with extensively pretreated refractory colorectal cancer metastatic to the liver. Hum. Gene Ther. 2010, 21, 1119–1128. [Google Scholar] [CrossRef] [Green Version]
  40. Fong, Y.; Kim, T.; Bhargava, A.; Schwartz, L.; Brown, K.; Brody, L.; Covey, A.; Karrasch, M.; Getrajdman, G.; Mescheder, A. A herpes oncolytic virus can be delivered via the vasculature to produce biologic changes in human colorectal cancer. Mol. Ther. 2009, 17, 389–394. [Google Scholar] [CrossRef]
  41. Markert, J.M.; Razdan, S.N.; Kuo, H.-C.; Cantor, A.; Knoll, A.; Karrasch, M.; Nabors, L.B.; Markiewicz, M.; Agee, B.S.; Coleman, J.M. A phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses. Mol. Ther. 2014, 22, 1048–1055. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Hirooka, Y.; Kasuya, H.; Ishikawa, T.; Kawashima, H.; Ohno, E.; Villalobos, I.B.; Naoe, Y.; Ichinose, T.; Koyama, N.; Tanaka, M. A Phase I clinical trial of EUS-guided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer. BMC Cancer 2018, 18, 1–9. [Google Scholar] [CrossRef] [PubMed]
  43. Voit, C.; Kron, M.; Schwürzer-Voit, M.; Sterry, W. Intradermal injection of Newcastle disease virus-modified autologous melanoma cell lysate and interleukin-2 for adjuvant treatment of melanoma patients with resectable stage III disease: Adjuvante Therapie von Melanompatienten im Stadium III mit einer Kombination aus Newcastle-disease-Virus-modifiziertem Tumorzelllysat und Interleukin-2. JDDG J. Der Dtsch. Dermatol. Ges. 2003, 1, 120–125. [Google Scholar]
  44. Pecora, A.L.; Rizvi, N.; Cohen, G.I.; Meropol, N.J.; Sterman, D.; Marshall, J.L.; Goldberg, S.; Gross, P.; O’Neil, J.D.; Groene, W.S. Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J. Clin. Oncol. 2002, 20, 2251–2266. [Google Scholar] [CrossRef] [PubMed]
  45. Freeman, A.I.; Zakay-Rones, Z.; Gomori, J.M.; Linetsky, E.; Rasooly, L.; Greenbaum, E.; Rozenman-Yair, S.; Panet, A.; Libson, E.; Irving, C.S. Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme. Mol. Ther. 2006, 13, 221–228. [Google Scholar] [CrossRef]
  46. Rudin, C.; Pandha, H.; Gupta, S.; Zibelman, M.; Akerley, W.; Day, D.; Hill, A.; Sanborn, R.; O’Day, S.; Clay, T. Phase Ib KEYNOTE-200: A study of an intravenously delivered oncolytic virus, coxsackievirus A21 in combination with pembrolizumab in advanced NSCLC and bladder cancer patients. Ann. Oncol. 2018, 29, viii732. [Google Scholar] [CrossRef]
  47. Cook, M.; Chauhan, A. Clinical Application of Oncolytic Viruses: A Systematic Review. Int. J. Mol. Sci. 2020, 21, 7505. [Google Scholar] [CrossRef] [PubMed]
  48. A Study of Intratumoral CAVATAK in Patients with Stage IIIc and Stage IV Malignant Melanoma (VLA-007 CALM) (CALM). Available online: https://clinicaltrials.gov/ct2/show/results/NCT01227551 (accessed on 23 January 2021).
  49. Morris, D.G.; Feng, X.; DiFrancesco, L.M.; Fonseca, K.; Forsyth, P.A.; Paterson, A.H.; Coffey, M.C.; Thompson, B. REO-001: A phase I trial of percutaneous intralesional administration of reovirus type 3 dearing (Reolysin®) in patients with advanced solid tumors. Investig. New Drugs 2013, 31, 696–706. [Google Scholar] [CrossRef] [PubMed]
  50. Kicielinski, K.P.; Chiocca, E.A.; John, S.Y.; Gill, G.M.; Coffey, M.; Markert, J.M. Phase 1 clinical trial of intratumoral reovirus infusion for the treatment of recurrent malignant gliomas in adults. Mol. Ther. 2014, 22, 1056–1062. [Google Scholar] [CrossRef] [Green Version]
  51. Kolb, E.A.; Sampson, V.; Stabley, D.; Walter, A.; Sol-Church, K.; Cripe, T.; Hingorani, P.; Ahern, C.H.; Weigel, B.J.; Zwiebel, J. A phase I trial and viral clearance study of reovirus (Reolysin) in children with relapsed or refractory extra-cranial solid tumors: A Children’s Oncology Group Phase I Consortium report. Pediatr. Blood Cancer 2015, 62, 751–758. [Google Scholar] [CrossRef] [Green Version]
  52. Noonan, A.M.; Farren, M.R.; Geyer, S.M.; Huang, Y.; Tahiri, S.; Ahn, D.; Mikhail, S.; Ciombor, K.K.; Pant, S.; Aparo, S. Randomized phase 2 trial of the oncolytic virus pelareorep (Reolysin) in upfront treatment of metastatic pancreatic adenocarcinoma. Mol. Ther. 2016, 24, 1150–1158. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Galanis, E.; Markovic, S.N.; Suman, V.J.; Nuovo, G.J.; Vile, R.G.; Kottke, T.J.; Nevala, W.K.; Thompson, M.A.; Lewis, J.E.; Rumilla, K.M. Phase II trial of intravenous administration of Reolysin®(Reovirus Serotype-3-dearing Strain) in patients with metastatic melanoma. Mol. Ther. 2012, 20, 1998–2003. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Bernstein, V.; Ellard, S.; Dent, S.; Tu, D.; Mates, M.; Dhesy-Thind, S.; Panasci, L.; Gelmon, K.; Salim, M.; Song, X. A randomized phase II study of weekly paclitaxel with or without pelareorep in patients with metastatic breast cancer: Final analysis of Canadian Cancer Trials Group IND. 213. Breast Cancer Res. Treat. 2018, 167, 485–493. [Google Scholar] [CrossRef]
  55. Mahalingam, D.; Goel, S.; Aparo, S.; Patel Arora, S.; Noronha, N.; Tran, H.; Chakrabarty, R.; Selvaggi, G.; Gutierrez, A.; Coffey, M. A phase II study of pelareorep (REOLYSIN®) in combination with gemcitabine for patients with advanced pancreatic adenocarcinoma. Cancers 2018, 10, 160. [Google Scholar] [CrossRef] [Green Version]
  56. Mahalingam, D.; Fountzilas, C.; Moseley, J.; Noronha, N.; Tran, H.; Chakrabarty, R.; Selvaggi, G.; Coffey, M.; Thompson, B.; Sarantopoulos, J. A phase II study of REOLYSIN®(pelareorep) in combination with carboplatin and paclitaxel for patients with advanced malignant melanoma. Cancer Chemother. Pharmacol. 2017, 79, 697–703. [Google Scholar] [CrossRef]
  57. Cohn, D.E.; Sill, M.W.; Walker, J.L.; O’Malley, D.; Nagel, C.I.; Rutledge, T.L.; Bradley, W.; Richardson, D.L.; Moxley, K.M.; Aghajanian, C. Randomized phase IIB evaluation of weekly paclitaxel versus weekly paclitaxel with oncolytic reovirus (Reolysin®) in recurrent ovarian, tubal, or peritoneal cancer: An nrg oncology/gynecologic oncology group study. Gynecol. Oncol. 2017, 146, 477–483. [Google Scholar] [CrossRef]
  58. Roulstone, V.; Khan, K.; Pandha, H.S.; Rudman, S.; Coffey, M.; Gill, G.M.; Melcher, A.A.; Vile, R.; Harrington, K.J.; De Bono, J. Phase I trial of cyclophosphamide as an immune modulator for optimizing oncolytic reovirus delivery to solid tumors. Clin. Cancer Res. 2015, 21, 1305–1312. [Google Scholar] [CrossRef] [Green Version]
  59. Harrington, K.J.; Karapanagiotou, E.M.; Roulstone, V.; Twigger, K.R.; White, C.L.; Vidal, L.; Beirne, D.; Prestwich, R.; Newbold, K.; Ahmed, M. Two-stage phase I dose-escalation study of intratumoral reovirus type 3 dearing and palliative radiotherapy in patients with advanced cancers. Clin. Cancer Res. 2010, 16, 3067–3077. [Google Scholar] [CrossRef] [Green Version]
  60. Desjardins, A.; Gromeier, M.; Herndon, J.E.; Beaubier, N.; Bolognesi, D.P.; Friedman, A.H.; Friedman, H.S.; McSherry, F.; Muscat, A.M.; Nair, S. Recurrent glioblastoma treated with recombinant poliovirus. N. Engl. J. Med. 2018, 379, 150–161. [Google Scholar] [CrossRef] [PubMed]
  61. Nokisalmi, P.; Pesonen, S.; Escutenaire, S.; Särkioja, M.; Raki, M.; Cerullo, V.; Laasonen, L.; Alemany, R.; Rojas, J.; Cascallo, M. Oncolytic adenovirus ICOVIR-7 in patients with advanced and refractory solid tumors. Clin. Cancer Res. 2010, 16, 3035–3043. [Google Scholar] [CrossRef] [Green Version]
  62. Kimball, K.J.; Preuss, M.A.; Barnes, M.N.; Wang, M.; Siegal, G.P.; Wan, W.; Kuo, H.; Saddekni, S.; Stockard, C.R.; Grizzle, W.E. A phase I study of a tropism-modified conditionally replicative adenovirus for recurrent malignant gynecologic diseases. Clin. Cancer Res. 2010, 16, 5277–5287. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Kim, K.H.; Dmitriev, I.P.; Saddekni, S.; Kashentseva, E.A.; Harris, R.D.; Aurigemma, R.; Bae, S.; Singh, K.P.; Siegal, G.P.; Curiel, D.T. A phase I clinical trial of Ad5/3-Δ24, a novel serotype-chimeric, infectivity-enhanced, conditionally-replicative adenovirus (CRAd), in patients with recurrent ovarian cancer. Gynecol. Oncol. 2013, 130, 518–524. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Pesonen, S.; Diaconu, I.; Cerullo, V.; Escutenaire, S.; Raki, M.; Kangasniemi, L.; Nokisalmi, P.; Dotti, G.; Guse, K.; Laasonen, L. Integrin targeted oncolytic adenoviruses Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of patients with advanced chemotherapy refractory solid tumors. Int. J. Cancer 2012, 130, 1937–1947. [Google Scholar] [CrossRef] [PubMed]
  65. DeWeese, T.L.; van der Poel, H.; Li, S.; Mikhak, B.; Drew, R.; Goemann, M.; Hamper, U.; DeJong, R.; Detorie, N.; Rodriguez, R. A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy. Cancer Res. 2001, 61, 7464–7472. [Google Scholar] [PubMed]
  66. Chang, J.; Zhao, X.; Wu, X.; Guo, Y.; Guo, H.; Cao, J.; Guo, Y.; Lou, D.; Yu, D.; Li, J. A Phase I study of KH901, a conditionally replicating granulocyte-macrophage colony-stimulating factor: Armed oncolytic adenovirus for the treatment of head and neck cancers. Cancer Biol. Ther. 2009, 8, 676–682. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Packiam, V.T.; Lamm, D.L.; Barocas, D.A.; Trainer, A.; Fand, B.; Davis III, R.L.; Clark, W.; Kroeger, M.; Dumbadze, I.; Chamie, K. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non–muscle-invasive bladder cancer: Interim results. Urol. Oncol. Semin. Ori. 2018, 36, 440–447. [Google Scholar] [CrossRef] [PubMed]
  68. Nemunaitis, J.; Tong, A.W.; Nemunaitis, M.; Senzer, N.; Phadke, A.P.; Bedell, C.; Adams, N.; Zhang, Y.-A.; Maples, P.B.; Chen, S. A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors. Mol. Ther. 2010, 18, 429–434. [Google Scholar] [CrossRef]
  69. Nemunaitis, J.; Ganly, I.; Khuri, F.; Arseneau, J.; Kuhn, J.; McCarty, T.; Landers, S.; Maples, P.; Romel, L.; Randlev, B. Selective replication and oncolysis in p53 mutant tumors with ONYX-015, an E1B-55kD gene-deleted adenovirus, in patients with advanced head and neck cancer: A phase II trial. Cancer Res. 2000, 60, 6359–6366. [Google Scholar]
  70. Galanis, E.; Okuno, S.H.; Nascimento, A.; Lewis, B.; Lee, R.; Oliveira, A.; Sloan, J.A.; Atherton, P.; Edmonson, J.; Erlichman, C. Phase I–II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas. Gene Ther. 2005, 12, 437–445. [Google Scholar] [CrossRef] [Green Version]
  71. Reid, T.R.; Freeman, S.; Post, L.; McCormick, F.; Sze, D.Y. Effects of Onyx-015 among metastatic colorectal cancer patients that have failed prior treatment with 5-FU/leucovorin. Cancer Gene Ther. 2005, 12, 673–681. [Google Scholar] [CrossRef]
  72. Nemunaitis, J.; Senzer, N.; Sarmiento, S.; Zhang, Y.; Arzaga, R.; Sands, B.; Maples, P.; Tong, A. A phase I trial of intravenous infusion of ONYX-015 and enbrel in solid tumor patients. Cancer Gene Ther. 2007, 14, 885–893. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Wheeler, L.A.; Manzanera, A.G.; Bell, S.D.; Cavaliere, R.; McGregor, J.M.; Grecula, J.C.; Newton, H.B.; Lo, S.S.; Badie, B.; Portnow, J. Phase II multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma. Neuro Oncol. 2016, 18, 1137–1145. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Freytag, S.O.; Stricker, H.; Lu, M.; Elshaikh, M.; Aref, I.; Pradhan, D.; Levin, K.; Kim, J.H.; Peabody, J.; Siddiqui, F. Prospective randomized phase 2 trial of intensity modulated radiation therapy with or without oncolytic adenovirus-mediated cytotoxic gene therapy in intermediate-risk prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 2014, 89, 268–276. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Freytag, S.O.; Movsas, B.; Aref, I.; Stricker, H.; Peabody, J.; Pegg, J.; Zhang, Y.; Barton, K.N.; Brown, S.L.; Lu, M. Phase I trial of replication-competent adenovirus-mediated suicide gene therapy combined with IMRT for prostate cancer. Mol. Ther. 2007, 15, 1016–1023. [Google Scholar] [CrossRef]
  76. Machiels, J.-P.; Salazar, R.; Rottey, S.; Duran, I.; Dirix, L.; Geboes, K.; Wilkinson-Blanc, C.; Pover, G.; Alvis, S.; Champion, B. A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE). J. Immunother. Cancer 2019, 7, 1–15. [Google Scholar] [CrossRef]
  77. Cripe, T.P.; Ngo, M.C.; Geller, J.I.; Louis, C.U.; Currier, M.A.; Racadio, J.M.; Towbin, A.J.; Rooney, C.M.; Pelusio, A.; Moon, A. Phase 1 study of intratumoral Pexa-Vec (JX-594), an oncolytic and immunotherapeutic vaccinia virus, in pediatric cancer patients. Mol. Ther. 2015, 23, 602–608. [Google Scholar] [CrossRef] [Green Version]
  78. Heo, J.; Breitbach, C.; Cho, M.; Hwang, T.-H.; Kim, C.W.; Jeon, U.B.; Woo, H.Y.; Yoon, K.T.; Lee, J.W.; Burke, J. Phase II Trial of Pexa-Vec (Pexastimogene Devacirepvec; JX-594), an Oncolytic and Immunotherapeutic Vaccinia Virus, Followed by Sorafenib in Patients with Advanced Hepatocellular Carcinoma (HCC); American Society of Clinical Oncology: Alexandria, VA, USA, 2013. [Google Scholar]
  79. Park, S.H.; Breitbach, C.J.; Lee, J.; Park, J.O.; Lim, H.Y.; Kang, W.K.; Moon, A.; Mun, J.-H.; Sommermann, E.M.; Avidal, L.M. Phase 1b trial of biweekly intravenous Pexa-Vec (JX-594), an oncolytic and immunotherapeutic vaccinia virus in colorectal cancer. Mol. Ther. 2015, 23, 1532–1540. [Google Scholar] [CrossRef]
  80. Hwang, T.-H.; Moon, A.; Burke, J.; Ribas, A.; Stephenson, J.; Breitbach, C.J.; Daneshmand, M.; De Silva, N.; Parato, K.; Diallo, J.-S. A mechanistic proof-of-concept clinical trial with JX-594, a targeted multi-mechanistic oncolytic poxvirus, in patients with metastatic melanoma. Mol. Ther. 2011, 19, 1913–1922. [Google Scholar] [CrossRef] [Green Version]
  81. Husseini, F.; Delord, J.-P.; Fournel-Federico, C.; Guitton, J.; Erbs, P.; Homerin, M.; Halluard, C.; Jemming, C.; Orange, C.; Limacher, J.-M. Vectorized gene therapy of liver tumors: Proof-of-concept of TG4023 (MVA-FCU1) in combination with flucytosine. Ann. Oncol. 2017, 28, 169–174. [Google Scholar] [CrossRef]
  82. Downs-Canner, S.; Guo, Z.S.; Ravindranathan, R.; Breitbach, C.J.; O’malley, M.E.; Jones, H.L.; Moon, A.; McCart, J.A.; Shuai, Y.; Zeh, H.J. Phase 1 study of intravenous oncolytic poxvirus (vvDD) in patients with advanced solid cancers. Mol. Ther. 2016, 24, 1492–1501. [Google Scholar] [CrossRef] [Green Version]
  83. Zeh, H.J.; Downs-Canner, S.; McCart, J.A.; Guo, Z.S.; Rao, U.N.; Ramalingam, L.; Thorne, S.H.; Jones, H.L.; Kalinski, P.; Wieckowski, E. First-in-man study of western reserve strain oncolytic vaccinia virus: Safety, systemic spread, and antitumor activity. Mol. Ther. 2015, 23, 202–214. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Mell, L.K.; Brumund, K.T.; Daniels, G.A.; Advani, S.J.; Zakeri, K.; Wright, M.E.; Onyeama, S.-J.; Weisman, R.A.; Sanghvi, P.R.; Martin, P.J. Phase I trial of intravenous oncolytic vaccinia virus (GL-ONC1) with cisplatin and radiotherapy in patients with locoregionally advanced head and neck carcinoma. Clin. Cancer Res. 2017, 23, 5696–5702. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Galanis, E.; Hartmann, L.C.; Cliby, W.A.; Long, H.J.; Peethambaram, P.P.; Barrette, B.A.; Kaur, J.S.; Haluska, P.J.; Aderca, I.; Zollman, P.J. Phase I trial of intraperitoneal administration of an oncolytic measles virus strain engineered to express carcinoembryonic antigen for recurrent ovarian cancer. Cancer Res. 2010, 70, 875–882. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Rudin, C.M.; Poirier, J.T.; Senzer, N.N.; Stephenson, J.; Loesch, D.; Burroughs, K.D.; Reddy, P.S.; Hann, C.L.; Hallenbeck, P.L. Phase I clinical study of Seneca Valley Virus (SVV-001), a replication-competent picornavirus, in advanced solid tumors with neuroendocrine features. Clin. Cancer Res. 2011, 17, 888–895. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Burke, M.J.; Ahern, C.; Weigel, B.J.; Poirier, J.T.; Rudin, C.M.; Chen, Y.; Cripe, T.P.; Bernhardt, M.B.; Blaney, S.M. Phase I trial of Seneca Valley Virus (NTX-010) in children with relapsed/refractory solid tumors: A report of the Children’s Oncology Group. Pediatr. Blood Cancer 2015, 62, 743–750. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Kaufman, H.L.; Kim, D.W.; Kim-Schulze, S.; DeRaffele, G.; Jagoda, M.C.; Broucek, J.R.; Zloza, A. Results of a randomized phase I gene therapy clinical trial of nononcolytic fowlpox viruses encoding T cell costimulatory molecules. Hum. Gene Ther. 2014, 25, 452–460. [Google Scholar] [CrossRef] [Green Version]
  89. Angelova, A.L.; Barf, M.; Geletneky, K.; Unterberg, A.; Rommelaere, J. Immunotherapeutic potential of oncolytic H-1 parvovirus: Hints of glioblastoma microenvironment conversion towards immunogenicity. Viruses 2017, 9, 382. [Google Scholar] [CrossRef] [Green Version]
  90. Achard, C.; Surendran, A.; Wedge, M.-E.; Ungerechts, G.; Bell, J.; Ilkow, C.S. Lighting a fire in the tumor microenvironment using oncolytic immunotherapy. EBioMedicine 2018, 31, 17–24. [Google Scholar] [CrossRef] [Green Version]
  91. Allegrezza, M.J.; Conejo-Garcia, J.R. Targeted therapy and immunosuppression in the tumor microenvironment. Trends Cancer 2017, 3, 19–27. [Google Scholar] [CrossRef]
  92. Pol, J.G.; Bridle, B.W.; Lichty, B.D. Detection of Tumor Antigen-Specific T-Cell Responses after Oncolytic Vaccination. In Oncolytic Viruses; Springer: Humana, NY, USA, 2020; pp. 191–211. [Google Scholar] [CrossRef]
  93. Bakhshaei, P.; Kazemi, M.H.; Golara, M.; Abdolmaleki, S.; Khosravi-Eghbal, R.; Khoshnoodi, J.; Judaki, M.A.; Salimi, V.; Douraghi, M.; Jeddi-Tehrani, M.; et al. Investigation of the Cellular Immune Response to Recombinant Fragments of Filamentous Hemagglutinin and Pertactin of Bordetella pertussis in BALB/c Mice. J. Interferon Cytokine Res. 2018, 38. [Google Scholar] [CrossRef]
  94. Kuryk, L.; Møller, A.S.W. Chimeric oncolytic Ad5/3 virus replicates and lyses ovarian cancer cells through desmoglein-2 cell entry receptor. J. Med. Virol. 2020, 92, 1309–1315. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Wang, M.; Liu, W.; Zhang, Y.; Dang, M.; Zhang, Y.; Tao, J.; Chen, K.; Peng, X.; Teng, Z. Intercellular adhesion molecule 1 antibody-mediated mesoporous drug delivery system for targeted treatment of triple-negative breast cancer. J. Colloid Interface Sci. 2019, 538, 630–637. [Google Scholar] [CrossRef] [PubMed]
  96. Wenthe, J.; Naseri, S.; Hellström, A.-C.; Wiklund, H.J.; Eriksson, E.; Loskog, A. Immunostimulatory oncolytic virotherapy for multiple myeloma targeting 4-1BB and/or CD40. Cancer Gene Ther. 2020, 27, 948–959. [Google Scholar] [CrossRef] [PubMed]
  97. Zhang, Y.; Ye, M.; Huang, F.; Wang, S.; Wang, H.; Mou, X.; Wang, Y. Oncolytic Adenovirus Expressing ST13 Increases Antitumor Effect of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Against Pancreatic Ductal Adenocarcinoma. Hum. Gene Ther. 2020, 31, 15–16. [Google Scholar] [CrossRef] [PubMed]
  98. Heiniö, C.; Havunen, R.; Santos, J.; Lint, K.D.; Cervera-Carrascon, V.; Kanerva, A.; Hemminki, A. TNFa and IL2 encoding oncolytic adenovirus activates pathogen and danger-associated immunological signaling. Cells 2020, 9, 798. [Google Scholar] [CrossRef] [Green Version]
  99. Delaunay, T.; Achard, C.; Boisgerault, N.; Grard, M.; Petithomme, T.; Chatelain, C.; Dutoit, S.; Blanquart, C.; Royer, P.-J.; Minvielle, S. Frequent homozygous deletions of type I interferon genes in pleural mesothelioma confer sensitivity to oncolytic measles virus. J. Thorac. Oncol. 2020, 15, 827–842. [Google Scholar] [CrossRef]
  100. Hindupur, S.V.; Schmid, S.C.; Koch, J.A.; Youssef, A.; Baur, E.-M.; Wang, D.; Horn, T.; Slotta-Huspenina, J.; Gschwend, J.E.; Holm, P.S. STAT3/5 inhibitors suppress proliferation in bladder cancer and enhance oncolytic adenovirus therapy. Int. J. Mol. Sci. 2020, 21, 1106. [Google Scholar] [CrossRef] [Green Version]
  101. McLaughlin, M.; Pedersen, M.; Roulstone, V.; Bergerhoff, K.F.; Smith, H.G.; Whittock, H.; Kyula, J.N.; Dillon, M.T.; Pandha, H.S.; Vile, R. The PERK Inhibitor GSK2606414 Enhances Reovirus Infection in Head and Neck Squamous Cell Carcinoma via an ATF4-Dependent Mechanism. Mol. Ther. Oncolytics 2020, 16, 238–249. [Google Scholar] [CrossRef] [Green Version]
  102. Kaufman, H.L.; Kim, D.W.; DeRaffele, G.; Mitcham, J.; Coffin, R.S.; Kim-Schulze, S. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann. Surg. Oncol. 2010, 17, 718–730. [Google Scholar] [CrossRef]
  103. Moesta, A.K.; Cooke, K.; Piasecki, J.; Mitchell, P.; Rottman, J.B.; Fitzgerald, K.; Zhan, J.; Yang, B.; Le, T.; Belmontes, B. Local Delivery of OncoVEXmGM-CSF Generates Systemic Antitumor Immune Responses Enhanced by Cytotoxic T-Lymphocyte–Associated Protein Blockade. Clin. Cancer Res. 2017, 23, 6190–6202. [Google Scholar] [CrossRef] [Green Version]
  104. Galanis, E.; Atherton, P.J.; Maurer, M.J.; Knutson, K.L.; Dowdy, S.C.; Cliby, W.A.; Haluska, P.; Long, H.J.; Oberg, A.; Aderca, I. Oncolytic measles virus expressing the sodium iodide symporter to treat drug-resistant ovarian cancer. Cancer Res. 2015, 75, 22–30. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. DuPage, M.; Mazumdar, C.; Schmidt, L.M.; Cheung, A.F.; Jacks, T. Expression of tumour-specific antigens underlies cancer immunoediting. Nature 2012, 482, 405–409. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Segal, N.H.; Parsons, D.W.; Peggs, K.S.; Velculescu, V.; Kinzler, K.W.; Vogelstein, B.; Allison, J.P. Epitope landscape in breast and colorectal cancer. Cancer Res. 2008, 68, 889–892. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Wang, G.; Kang, X.; Chen, K.S.; Jehng, T.; Jones, L.; Chen, J.; Huang, X.F.; Chen, S.-Y. An engineered oncolytic virus expressing PD-L1 inhibitors activates tumor neoantigen-specific T cell responses. Nat. Commun. 2020, 11, 1–14. [Google Scholar] [CrossRef]
  108. Kanerva, A.; Nokisalmi, P.; Diaconu, I.; Koski, A.; Cerullo, V.; Liikanen, I.; Tähtinen, S.; Oksanen, M.; Heiskanen, R.; Pesonen, S. Antiviral and antitumor T-cell immunity in patients treated with GM-CSF–coding oncolytic adenovirus. Clin. Cancer Res. 2013, 19, 2734–2744. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  109. Woller, N.; Gürlevik, E.; Fleischmann-Mundt, B.; Schumacher, A.; Knocke, S.; Kloos, A.M.; Saborowski, M.; Geffers, R.; Manns, M.P.; Wirth, T.C. Viral infection of tumors overcomes resistance to PD-1-immunotherapy by broadening neoantigenome-directed T-cell responses. Mol. Ther. 2015, 23, 1630–1640. [Google Scholar] [CrossRef] [Green Version]
  110. Wang, X.; Shao, X.; Gu, L.; Jiang, K.; Wang, S.; Chen, J.; Fang, J.; Guo, X.; Yuan, M.; Shi, J. Targeting STAT3 enhances NDV-induced immunogenic cell death in prostate cancer cells. J. Cell. Mol. Med. 2020, 24, 4286–4297. [Google Scholar] [CrossRef] [Green Version]
  111. Ma, J.; Ramachandran, M.; Jin, C.; Quijano-Rubio, C.; Martikainen, M.; Yu, D.; Essand, M. Characterization of virus-mediated immunogenic cancer cell death and the consequences for oncolytic virus-based immunotherapy of cancer. Cell Death Dis. 2020, 11, 1–15. [Google Scholar] [CrossRef] [Green Version]
  112. van Vloten, J.P.; Workenhe, S.T.; Wootton, S.K.; Mossman, K.L.; Bridle, B.W. Critical interactions between immunogenic cancer cell death, oncolytic viruses, and the immune system define the rational design of combination immunotherapies. J. Immunol. 2018, 200, 450–458. [Google Scholar] [CrossRef]
  113. Guo, Z.S.; Liu, Z.; Bartlett, D.L. Oncolytic immunotherapy: Dying the right way is a key to eliciting potent antitumor immunity. Front. Oncol. 2014, 4, 74. [Google Scholar] [CrossRef] [Green Version]
  114. Hajifathali, A.; Parkhideh, S.; Kazemi, M.H.; Chegeni, R.; Roshandel, E.; Gholizadeh, M. Immune checkpoints in hematologic malignancies: What made the immune cells and clinicians exhausted! J. Cell. Physiol. 2020, 235, 9080–9097. [Google Scholar] [CrossRef]
  115. Kepp, O.; Senovilla, L.; Vitale, I.; Vacchelli, E.; Adjemian, S.; Agostinis, P.; Apetoh, L.; Aranda, F.; Barnaba, V.; Bloy, N. Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology 2014, 3, e955691. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Lin, H.D.; Fong, C.-Y.; Biswas, A.; Bongso, A. Hypoxic Wharton’s Jelly Stem Cell Conditioned Medium Induces Immunogenic Cell Death in Lymphoma Cells. Stem Cells Int. 2020, 20, 1–14. [Google Scholar] [CrossRef] [PubMed]
  117. Burke, S.; Shergold, A.; Elder, M.J.; Whitworth, J.; Cheng, X.; Jin, H.; Wilkinson, R.W.; Harper, J.; Carroll, D.K. Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro. Cancer Immunol. Immunother. 2020, 69, 1015–1027. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Ghasemi, K.; Parkhideh, S.; Kazemi, M.H.; Salimi, M.; Salari, S.; Nalini, R.; Hajifathali, A. The role of serum uric acid in the prediction of graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. J. Clin. Lab. Anal. 2020, 34, e23271. [Google Scholar] [CrossRef] [PubMed]
  119. Schuster, P.; Lindner, G.; Thomann, S.; Haferkamp, S.; Schmidt, B. Prospect of plasmacytoid dendritic cells in enhancing anti-tumor immunity of oncolytic herpes viruses. Cancers 2019, 11, 651. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  120. Dai, P.; Wang, W.; Yang, N.; Serna-Tamayo, C.; Ricca, J.M.; Zamarin, D.; Shuman, S.; Merghoub, T.; Wolchok, J.D.; Deng, L. Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells. Sci. Immunol. 2017, 2, 1713–1725. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  121. Woo, S.-R.; Fuertes, M.B.; Corrales, L.; Spranger, S.; Furdyna, M.J.; Leung, M.Y.K.; Duggan, R.; Wang, Y.; Barber, G.N.; Fitzgerald, K.A. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 2014, 41, 830–842. [Google Scholar] [CrossRef] [Green Version]
  122. Bhat, H.; Zaun, G.; Hamdan, T.A.; Lang, J.; Adomati, T.; Schmitz, R.; Friedrich, S.-K.; Bergerhausen, M.; Cham, L.B.; Li, F. Arenavirus Induced CCL5 Expression Causes NK Cell-Mediated Melanoma Regression. Front. Immunol. 2020, 11, 1849. [Google Scholar] [CrossRef]
  123. Zamarin, D.; Ricca, J.M.; Sadekova, S.; Oseledchyk, A.; Yu, Y.; Blumenschein, W.M.; Wong, J.; Gigoux, M.; Merghoub, T.; Wolchok, J.D. PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy. J. Clin. Investig. 2018, 128, 1413–1428. [Google Scholar] [CrossRef] [Green Version]
  124. Gujar, S.A.; Lee, P.W.K. Oncolytic virus-mediated reversal of impaired tumor antigen presentation. Front. Oncol. 2014, 4, 77. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Ilkow, C.S.; Marguerie, M.; Batenchuk, C.; Mayer, J.; Neriah, D.B.; Cousineau, S.; Falls, T.; Jennings, V.A.; Boileau, M.; Bellamy, D. Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity. Nat. Med. 2015, 21, 530. [Google Scholar] [CrossRef] [PubMed]
  126. Altomonte, J.; Marozin, S.; De Toni, E.N.; Rizzani, A.; Esposito, I.; Steiger, K.; Feuchtinger, A.; Hellerbrand, C.; Schmid, R.M.; Ebert, O. Antifibrotic properties of transarterial oncolytic VSV therapy for hepatocellular carcinoma in rats with thioacetamide-induced liver fibrosis. Mol. Ther. 2013, 21, 2032–2042. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Arulanandam, R.; Batenchuk, C.; Angarita, F.A.; Ottolino-Perry, K.; Cousineau, S.; Mottashed, A.; Burgess, E.; Falls, T.J.; De Silva, N.; Tsang, J. VEGF-mediated induction of PRD1-BF1/Blimp1 expression sensitizes tumor vasculature to oncolytic virus infection. Cancer Cell 2015, 28, 210–224. [Google Scholar] [CrossRef] [Green Version]
  128. Alessandrini, F.; Menotti, L.; Avitabile, E.; Appolloni, I.; Ceresa, D.; Marubbi, D.; Campadelli-Fiume, G.; Malatesta, P. Eradication of glioblastoma by immuno-virotherapy with a retargeted oncolytic HSV in a preclinical model. Oncogene 2019, 38, 4467–4479. [Google Scholar] [CrossRef]
  129. Shibata, T.; Uchida, H.; Shiroyama, T.; Okubo, Y.; Suzuki, T.; Ikeda, H.; Yamaguchi, M.; Miyagawa, Y.; Fukuhara, T.; Cohen, J.B. Development of an oncolytic HSV vector fully retargeted specifically to cellular EpCAM for virus entry and cell-to-cell spread. Gene Ther. 2016, 23, 479–488. [Google Scholar] [CrossRef]
  130. Uchida, H.; Marzulli, M.; Nakano, K.; Goins, W.F.; Chan, J.; Hong, C.-S.; Mazzacurati, L.; Yoo, J.Y.; Haseley, A.; Nakashima, H. Effective treatment of an orthotopic xenograft model of human glioblastoma using an EGFR-retargeted oncolytic herpes simplex virus. Mol. Ther. 2013, 21, 561–569. [Google Scholar] [CrossRef] [Green Version]
  131. Foreman, P.M.; Friedman, G.K.; Cassady, K.A.; Markert, J.M. Oncolytic virotherapy for the treatment of malignant glioma. Neurotherapeutics 2017, 14, 333–344. [Google Scholar] [CrossRef] [Green Version]
  132. Stepanenko, A.A.; Chekhonin, V.P. Tropism and transduction of oncolytic adenovirus 5 vectors in cancer therapy: Focus on fiber chimerism and mosaicism, hexon and pIX. Virus Res. 2018, 257, 40–51. [Google Scholar] [CrossRef]
  133. Betancourt, D.; Ramos, J.C.; Barber, G.N. Retargeting oncolytic vesicular stomatitis virus to human T-cell lymphotropic virus type 1-associated adult T-cell leukemia. J. Virol. 2015, 89, 11786–11800. [Google Scholar] [CrossRef] [Green Version]
  134. Garant, K.A.; Shmulevitz, M.; Pan, L.; Daigle, R.M.; Ahn, D.G.; Gujar, S.A.; Lee, P.W.K. Oncolytic reovirus induces intracellular redistribution of Ras to promote apoptosis and progeny virus release. Oncogene 2016, 35, 771–782. [Google Scholar] [CrossRef] [PubMed]
  135. Lu, Y.; Zhang, Y.; Chang, G.; Zhang, J. Comparison of prostate-specific promoters and the use of PSP-driven virotherapy for prostate cancer. BioMed Res. Int. 2013, 13, 1–15. [Google Scholar] [CrossRef]
  136. Zhang, W.; Ge, K.; Zhao, Q.; Zhuang, X.; Deng, Z.; Liu, L.; Li, J.; Zhang, Y.; Dong, Y.; Zhang, Y. A novel oHSV-1 targeting telomerase reverse transcriptase-positive cancer cells via tumor-specific promoters regulating the expression of ICP4. Oncotarget 2015, 6, 20345. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Leber, M.F.; Baertsch, M.-A.; Anker, S.C.; Henkel, L.; Singh, H.M.; Bossow, S.; Engeland, C.E.; Barkley, R.; Hoyler, B.; Albert, J. Enhanced control of oncolytic measles virus using microrna target sites. Mol. Ther. Oncolytics 2018, 9, 30–40. [Google Scholar] [CrossRef] [Green Version]
  138. Liu, W.; Dai, E.; Liu, Z.; Ma, C.; Guo, Z.S.; Bartlett, D.L. In Situ Therapeutic Cancer Vaccination with an Oncolytic Virus Expressing Membrane-Tethered IL-2. Mol. Ther. Oncolytics 2020, 17, 350–360. [Google Scholar] [CrossRef] [PubMed]
  139. Ardakani, M.T.; Mehrpooya, M.; Mehdizadeh, M.; Beiraghi, N.; Hajifathali, A.; Kazemi, M.H. Sertraline treatment decreased the serum levels of interleukin-6 and high-sensitivity C-reactive protein in hematopoietic stem cell transplantation patients with depression; a randomized double-blind, placebo-controlled clinical trial. Bone Marrow Transpl. 2020, 55, 830–832. [Google Scholar] [CrossRef]
  140. Hock, K.; Laengle, J.; Kuznetsova, I.; Egorov, A.; Hegedus, B.; Dome, B.; Wekerle, T.; Sachet, M.; Bergmann, M. Oncolytic influenza A virus expressing interleukin-15 decreases tumor growth in vivo. Surgery 2017, 161, 735–746. [Google Scholar] [CrossRef]
  141. Patel, D.M.; Foreman, P.M.; Nabors, L.B.; Riley, K.O.; Gillespie, G.Y.; Markert, J.M. Design of a phase I clinical trial to evaluate M032, a genetically engineered HSV-1 expressing IL-12, in patients with recurrent/progressive glioblastoma multiforme, anaplastic astrocytoma, or gliosarcoma. Hum. Gene Ther. Clin. Dev. 2016, 27, 69–78. [Google Scholar] [CrossRef]
  142. Pearl, T.M.; Markert, J.M.; Cassady, K.A.; Ghonime, M.G. Oncolytic virus-based cytokine expression to improve immune activity in brain and solid tumors. Mol. Ther. Oncolytics 2019, 13, 14–21. [Google Scholar] [CrossRef] [Green Version]
  143. Li, J.; O’Malley, M.; Sampath, P.; Kalinski, P.; Bartlett, D.L.; Thorne, S.H. Expression of CCL19 from oncolytic vaccinia enhances immunotherapeutic potential while maintaining oncolytic activity. Neoplasia 2012, 14, 1115–1121. [Google Scholar] [CrossRef] [Green Version]
  144. Li, Y.; Li, Y.-F.; Si, C.-Z.; Zhu, Y.-H.; Jin, Y.; Zhu, T.-T.; Liu, M.-Y.; Liu, G.-Y. CCL21/IL21-armed oncolytic adenovirus enhances antitumor activity against TERT-positive tumor cells. Virus Res. 2016, 220, 172–178. [Google Scholar] [CrossRef] [PubMed]
  145. Ye, J.-F.; Qi, W.-X.; Liu, M.-Y.; Li, Y. The combination of NK and CD8+ T cells with CCL20/IL15-armed oncolytic adenoviruses enhances the growth suppression of TERT-positive tumor cells. Cell. Immunol. 2017, 318, 35–41. [Google Scholar] [CrossRef] [PubMed]
  146. Kazemi, M.H.; Malakootikhah, F.; Momeni-Varposhti, Z.; Falak, R.; Delbandi, A.-A.; Tajik, N. Human platelet antigen 1-6, 9 and 15 in the Iranian population: An anthropological genetic analysis. Sci. Rep. 2020, 10, 1–10. [Google Scholar] [CrossRef]
  147. Hou, W.; Sampath, P.; Rojas, J.J.; Thorne, S.H. Oncolytic virus-mediated targeting of PGE2 in the tumor alters the immune status and sensitizes established and resistant tumors to immunotherapy. Cancer Cell 2016, 30, 108–119. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  148. Gil, M.; Komorowski, M.P.; Seshadri, M.; Rokita, H.; McGray, A.J.R.; Opyrchal, M.; Odunsi, K.O.; Kozbor, D. CXCL12/CXCR4 blockade by oncolytic virotherapy inhibits ovarian cancer growth by decreasing immunosuppression and targeting cancer-initiating cells. J. Immunol. 2014, 193, 5327–5337. [Google Scholar] [CrossRef] [Green Version]
  149. Cui, C.-X.; Li, Y.-Q.; Sun, Y.-J.; Zhu, Y.-L.; Fang, J.-B.; Bai, B.; Li, W.-J.; Li, S.-Z.; Ma, Y.-Z.; Li, X. Antitumor effect of a dual cancer-specific oncolytic adenovirus on prostate cancer PC-3 cells. Urol. Oncol. Semin. Orig. 2019, 37, 351–352. [Google Scholar] [CrossRef]
  150. Jeong, S.-N.; Yoo, S.Y. Novel Oncolytic Virus Armed with Cancer Suicide Gene and Normal Vasculogenic Gene for Improved Anti-Tumor Activity. Cancers 2020, 12, 1070. [Google Scholar] [CrossRef]
  151. Hajeri, P.B.; Sharma, N.S.; Yamamoto, M. Oncolytic Adenoviruses: Strategies for Improved Targeting and Specificity. Cancers 2020, 12, 1504. [Google Scholar] [CrossRef]
  152. Ricordel, M.; Foloppe, J.; Antoine, D.; Findeli, A.; Kempf, J.; Cordier, P.; Gerbaud, A.; Grellier, B.; Lusky, M.; Quemeneur, E. Vaccinia virus shuffling: deVV5, a novel chimeric poxvirus with improved oncolytic potency. Cancers 2018, 10, 231. [Google Scholar] [CrossRef] [Green Version]
  153. Li, L.; Liu, S.; Han, D.; Tang, B.; Ma, J. Delivery and Biosafety of Oncolytic Virotherapy. Front. Oncol. 2020, 10, 475. [Google Scholar] [CrossRef] [Green Version]
  154. Cronin, M.; Le Boeuf, F.; Murphy, C.; Roy, D.G.; Falls, T.; Bell, J.C.; Tangney, M. Bacterial-mediated knockdown of tumor resistance to an oncolytic virus enhances therapy. Mol. Ther. 2014, 22, 1188–1197. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Chen, H.; Sampath, P.; Hou, W.; Thorne, S.H. Regulating cytokine function enhances safety and activity of genetic cancer therapies. Mol. Ther. 2013, 21, 167–174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  156. Draganov, D.D.; Santidrian, A.F.; Minev, I.; Nguyen, D.; Kilinc, M.O.; Petrov, I.; Vyalkova, A.; Lander, E.; Berman, M.; Minev, B. Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers. J. Transl. Med. 2019, 17, 1–22. [Google Scholar] [CrossRef] [PubMed]
  157. Hadryś, A.; Sochanik, A.; McFadden, G.; Jazowiecka-Rakus, J. Mesenchymal stem cells as carriers for systemic delivery of oncolytic viruses. Eur. J. Pharmacol. 2020, 874, 172991. [Google Scholar] [CrossRef]
  158. Josiah, D.T.; Zhu, D.; Dreher, F.; Olson, J.; McFadden, G.; Caldas, H. Adipose-derived stem cells as therapeutic delivery vehicles of an oncolytic virus for glioblastoma. Mol. Ther. 2010, 18, 377–385. [Google Scholar] [CrossRef]
  159. Hammad, M.; Cornejo, Y.R.; Batalla-Covello, J.; Majid, A.A.; Burke, C.; Liu, Z.; Yuan, Y.-C.; Li, M.; Dellinger, T.H.; Lu, J. Neural Stem Cells Improve the Delivery of Oncolytic Chimeric Orthopoxvirus in a Metastatic Ovarian Cancer Model. Mol. Ther. Oncolytics 2020, 18, 326–334. [Google Scholar] [CrossRef]
  160. Adair, R.A.; Roulstone, V.; Scott, K.J.; Morgan, R.; Nuovo, G.J.; Fuller, M.; Beirne, D.; West, E.J.; Jennings, V.A.; Rose, A. Cell carriage, delivery, and selective replication of an oncolytic virus in tumor in patients. Sci. Transl. Med. 2012, 4, 138ra77. [Google Scholar] [CrossRef] [Green Version]
  161. Lilly, C.L.; Villa, N.Y.; de Matos, A.L.; Ali, H.M.; Dhillon, J.-K.S.; Hofland, T.; Rahman, M.M.; Chan, W.; Bogen, B.; Cogle, C. Ex vivo oncolytic virotherapy with myxoma virus arms multiple allogeneic bone marrow transplant leukocytes to enhance graft versus tumor. Mol. Ther. Oncolytics 2017, 4, 31–40. [Google Scholar] [CrossRef] [Green Version]
  162. Iankov, I.D.; Msaouel, P.; Allen, C.; Federspiel, M.J.; Bulur, P.A.; Dietz, A.B.; Gastineau, D.; Ikeda, Y.; Ingle, J.N.; Russell, S.J. Demonstration of anti-tumor activity of oncolytic measles virus strains in a malignant pleural effusion breast cancer model. Breast Cancer Res. Treat. 2010, 122, 745–754. [Google Scholar] [CrossRef]
  163. Ilett, E.J.; Prestwich, R.J.; Kottke, T.; Errington, F.; Thompson, J.M.; Harrington, K.J.; Pandha, H.S.; Coffey, M.; Selby, P.J.; Vile, R.G. Dendritic cells and T cells deliver oncolytic reovirus for tumour killing despite pre-existing anti-viral immunity. Gene Ther. 2009, 16, 689–699. [Google Scholar] [CrossRef] [Green Version]
  164. Balvers, R.K.; Belcaid, Z.; Van den Hengel, S.K.; Kloezeman, J.; De Vrij, J.; Wakimoto, H.; Hoeben, R.C.; Debets, R.; Leenstra, S.; Dirven, C. Locally-delivered T-cell-derived cellular vehicles efficiently track and deliver adenovirus delta24-RGD to infiltrating glioma. Viruses 2014, 6, 3080–3096. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  165. Kanzaki, A.; Kasuya, H.; Yamamura, K.; Sahin, T.T.; Nomura, N.; Shikano, T.; Shirota, T.; Tan, G.; Fukuda, S.; Misawa, M. Antitumor efficacy of oncolytic herpes simplex virus adsorbed onto antigen-specific lymphocytes. Cancer Gene Ther. 2012, 19, 292–298. [Google Scholar] [CrossRef] [Green Version]
  166. Muthana, M.; Giannoudis, A.; Scott, S.D.; Fang, H.-Y.; Coffelt, S.B.; Morrow, F.J.; Murdoch, C.; Burton, J.; Cross, N.; Burke, B. Use of macrophages to target therapeutic adenovirus to human prostate tumors. Cancer Res. 2011, 71, 1805–1815. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  167. Muthana, M.; Rodrigues, S.; Chen, Y.-Y.; Welford, A.; Hughes, R.; Tazzyman, S.; Essand, M.; Morrow, F.; Lewis, C.E. Macrophage delivery of an oncolytic virus abolishes tumor regrowth and metastasis after chemotherapy or irradiation. Cancer Res. 2013, 73, 490–495. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  168. Gao, J.; Zhang, W.; Mese, K.; Bunz, O.; Lu, F.; Ehrhardt, A. Transient chimeric Ad5/37 fiber enhances NK-92 carrier cell mediated delivery of oncolytic adenovirus type 5 to tumor cells. Mol. Ther. Methods Clin. Dev. 2020, 18, 376–389. [Google Scholar] [CrossRef] [PubMed]
  169. Liu, C.; Suksanpaisan, L.; Chen, Y.-W.; Russell, S.J.; Peng, K.-W. Enhancing cytokine-induced killer cell therapy of multiple myeloma. Exp. Hematol. 2013, 41, 508–517. [Google Scholar] [CrossRef] [Green Version]
  170. Adair, R.A.; Scott, K.J.; Fraser, S.; Errington-Mais, F.; Pandha, H.; Coffey, M.; Selby, P.; Cook, G.P.; Vile, R.; Harrington, K.J. Cytotoxic and immune-mediated killing of human colorectal cancer by reovirus-loaded blood and liver mononuclear cells. Int. J. Cancer 2013, 132, 2327–2338. [Google Scholar] [CrossRef] [PubMed]
  171. Villa, N.Y.; Rahman, M.M.; Mamola, J.; D’Isabella, J.; Goras, E.; Kilbourne, J.; Lowe, K.; Daggett-Vondras, J.; Torres, L.; Christie, J. Autologous Transplantation Using Donor Leukocytes Loaded Ex Vivo with Oncolytic Myxoma Virus Can Eliminate Residual Multiple Myeloma. Mol. Ther. Oncolytics 2020, 18, 171–188. [Google Scholar] [CrossRef]
  172. Eisenstein, S.; Coakley, B.A.; Briley-Saebo, K.; Ma, G.; Chen, H.-M.; Meseck, M.; Ward, S.; Divino, C.; Woo, S.; Chen, S.-H. Myeloid-derived suppressor cells as a vehicle for tumor-specific oncolytic viral therapy. Cancer Res. 2013, 73, 5003–5015. [Google Scholar] [CrossRef] [Green Version]
  173. Marelli, G.; Howells, A.; Lemoine, N.R.; Wang, Y. Oncolytic viral therapy and the immune system: A double-edged sword against cancer. Front. Immunol. 2018, 9, 866. [Google Scholar] [CrossRef] [Green Version]
  174. Liu, X.; Li, Y.-P.; Zhong, Z.-M.; Tan, H.-Q.; Lin, H.-P.; Chen, S.-J.; Fu, Y.-C.; Xu, W.-C.; Wei, C.-J. Incorporation of viral glycoprotein VSV-G improves the delivery of DNA by erythrocyte ghost into cells refractory to conventional transfection. Appl. Biochem. Biotechnol. 2017, 181, 748–761. [Google Scholar] [CrossRef] [PubMed]
  175. Sun, C.W.; Willmon, C.; Wu, L.-C.; Knopick, P.; Thoerner, J.; Vile, R.; Townes, T.M.; Terman, D.S. sickle cells abolish Melanoma Tumorigenesis in hemoglobin ss Knockin Mice and augment the Tumoricidal effect of Oncolytic Virus In Vivo. Front. Oncol. 2016, 6, 166. [Google Scholar] [CrossRef] [PubMed]
  176. Guo, Z.S.; Parimi, V.; O’Malley, M.E.; Thirunavukarasu, P.; Sathaiah, M.; Austin, F.; Bartlett, D.L. The combination of immunosuppression and carrier cells significantly enhances the efficacy of oncolytic poxvirus in the pre-immunized host. Gene Ther. 2010, 17, 1465–1475. [Google Scholar] [CrossRef] [Green Version]
  177. Iankov, I.D.; Blechacz, B.; Liu, C.; Schmeckpeper, J.D.; Tarara, J.E.; Federspiel, M.J.; Caplice, N.; Russell, S.J. Infected cell carriers: A new strategy for systemic delivery of oncolytic measles viruses in cancer virotherapy. Mol. Ther. 2007, 15, 114–122. [Google Scholar] [CrossRef] [PubMed]
  178. Yokoda, R.; Nagalo, B.M.; Vernon, B.; Oklu, R.; Albadawi, H.; DeLeon, T.T.; Zhou, Y.; Egan, J.B.; Duda, D.G.; Borad, M.J. Oncolytic virus delivery: From nano-pharmacodynamics to enhanced oncolytic effect. Oncolytic Virother. 2017, 6, 39. [Google Scholar] [CrossRef] [Green Version]
  179. Patel, M.R.; Jacobson, B.A.; Ji, Y.; Hebbel, R.P.; Kratzke, R.A. Blood Outgrowth Endothelial Cells as a Cellular Carrier for Oncolytic Vesicular Stomatitis Virus Expressing Interferon-β in Preclinical Models of Non-Small Cell Lung Cancer. Transl. Oncol. 2020, 13, 100782. [Google Scholar] [CrossRef]
  180. Garofalo, M.; Villa, A.; Rizzi, N.; Kuryk, L.; Rinner, B.; Cerullo, V.; Yliperttula, M.; Mazzaferro, V.; Ciana, P. Extracellular vesicles enhance the targeted delivery of immunogenic oncolytic adenovirus and paclitaxel in immunocompetent mice. J. Control. Release 2019, 294, 165–175. [Google Scholar] [CrossRef]
  181. Saari, H.; Turunen, T.; Lõhmus, A.; Turunen, M.; Jalasvuori, M.; Butcher, S.J.; Ylä-Herttuala, S.; Viitala, T.; Cerullo, V.; Siljander, P.R.M. Extracellular vesicles provide a capsid-free vector for oncolytic adenoviral DNA delivery. J. Extracell. Vesicles 2020, 9, 1747206. [Google Scholar] [CrossRef]
  182. Fusciello, M.; Fontana, F.; Tähtinen, S.; Capasso, C.; Feola, S.; Martins, B.; Chiaro, J.; Peltonen, K.; Ylösmäki, L.; Ylösmäki, E. Artificially cloaked viral nanovaccine for cancer immunotherapy. Nat. Commun. 2019, 10, 1–13. [Google Scholar] [CrossRef] [Green Version]
  183. Yang, Y.; Du, T.; Zhang, J.; Kang, T.; Luo, L.; Tao, J.; Gou, Z.; Chen, S.; Du, Y.; He, J. A 3D-Engineered Conformal Implant Releases DNA Nanocomplexs for Eradicating the Postsurgery Residual Glioblastoma. Adv. Sci. 2017, 4, 1600491. [Google Scholar] [CrossRef]
  184. Kong, H.; Zhao, R.; Zhang, Q.; Iqbal, M.Z.; Lu, J.; Zhao, Q.; Luo, D.; Feng, C.; Zhang, K.; Liu, X. Biosilicified Oncolytic Adenovirus for Cancer Viral Gene Therapy. Biomater. Sci. 2020, 8, 5317–5328. [Google Scholar] [CrossRef] [PubMed]
  185. Kiyokawa, J.; Wakimoto, H. Preclinical and clinical development of oncolytic adenovirus for the treatment of malignant glioma. Oncolytic Virother. 2019, 8, 27. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  186. Park, J.W.; Mok, H.; Park, T.G. Physical adsorption of PEG grafted and blocked poly-L-lysine copolymers on adenovirus surface for enhanced gene transduction. J. Control. Release 2010, 142, 238–244. [Google Scholar] [CrossRef] [PubMed]
  187. Badrinath, N.; Jeong, Y.I.; Woo, H.Y.; Bang, S.Y.; Kim, C.; Heo, J.; Kang, D.H.; Yoo, S.Y. Local delivery of a cancer-favoring oncolytic vaccinia virus via poly (lactic-co-glycolic acid) nanofiber for theranostic purposes. Int. J. Pharm. 2018, 552, 437–442. [Google Scholar] [CrossRef]
  188. Nosaki, K.; Hamada, K.; Takashima, Y.; Sagara, M.; Matsumura, Y.; Miyamoto, S.; Hijikata, Y.; Okazaki, T.; Nakanishi, Y.; Tani, K. A novel, polymer-coated oncolytic measles virus overcomes immune suppression and induces robust antitumor activity. Mol. Ther. Oncolytics 2016, 3, 16022. [Google Scholar] [CrossRef]
  189. Mok, H.; Park, J.W.; Park, T.G. Microencapsulation of PEGylated adenovirus within PLGA microspheres for enhanced stability and gene transfection efficiency. Pharm. Res. 2007, 24, 2263–2269. [Google Scholar] [CrossRef]
  190. Choi, J.-W.; Kim, J.; Bui, Q.N.; Li, Y.; Yun, C.-O.; Lee, D.S.; Kim, S.W. Tuning surface charge and PEGylation of biocompatible polymers for efficient delivery of nucleic acid or adenoviral vector. Bioconjug. Chem. 2015, 26, 1818–1829. [Google Scholar] [CrossRef]
  191. Kim, J.; Kim, P.-H.; Kim, S.W.; Yun, C.-O. Enhancing the therapeutic efficacy of adenovirus in combination with biomaterials. Biomaterials 2012, 33, 1838–1850. [Google Scholar] [CrossRef] [Green Version]
  192. Choi, J.-W.; Nam, J.-P.; Nam, K.; Lee, Y.S.; Yun, C.-O.; Kim, S.W. Oncolytic adenovirus coated with multidegradable bioreducible core-cross-linked polyethylenimine for cancer gene therapy. Biomacromolecules 2015, 16, 2132–2143. [Google Scholar] [CrossRef]
  193. Oh, I.K.; Mok, H.; Park, T.G. Folate immobilized and PEGylated adenovirus for retargeting to tumor cells. Bioconjugate Chem. 2006, 17, 721–727. [Google Scholar] [CrossRef]
  194. Green, N.K.; Herbert, C.W.; Hale, S.J.; Hale, A.B.; Mautner, V.; Harkins, R.; Hermiston, T.; Ulbrich, K.; Fisher, K.D.; Seymour, L.W. Extended plasma circulation time and decreased toxicity of polymer-coated adenovirus. Gene Ther. 2004, 11, 1256–1263. [Google Scholar] [CrossRef] [PubMed]
  195. Espenlaub, S.; Wortmann, A.; Engler, T.; Corjon, S.; Kochanek, S.; Kreppel, F. Reductive amination as a strategy to reduce adenovirus vector promiscuity by chemical capsid modification with large polysaccharides. J. Gene Med. Cross Discip. J. Res. Sci. Gene Transf. Clin. Appl. 2008, 10, 1303–1314. [Google Scholar] [CrossRef] [PubMed]
  196. Price, D.L.; Li, P.; Chen, C.H.; Wong, D.; Yu, Z.; Chen, N.G.; Yu, Y.A.; Szalay, A.A.; Cappello, J.; Fong, Y. Silk-elastin-like protein polymer matrix for intraoperative delivery of an oncolytic vaccinia virus. Head Neck 2016, 38, 237–246. [Google Scholar] [CrossRef] [PubMed]
  197. Robles-Planells, C.; Sánchez-Guerrero, G.; Barrera-Avalos, C.; Matiacevich, S.; Rojo, L.E.; Pavez, J.; Salas-Huenuleo, E.; Kogan, M.J.; Escobar, A.; Milla, L.A. Chitosan-based nanoparticles for intracellular delivery of ISAV fusion protein cDNA into melanoma cells: A path to develop oncolytic anticancer therapies. Mediat. Inflamm. 2020, 20, 1–13. [Google Scholar] [CrossRef] [PubMed]
  198. Breen, A.; Strappe, P.; Kumar, A.; O’Brien, T.; Pandit, A. Optimization of a fibrin scaffold for sustained release of an adenoviral gene vector. J. Biomed. Mater. Res. Part A Off. J. Soc. Biomater. Jpn. Soc. Biomater. Aust. Soc. Biomater. Korean Soc. Biomater. 2006, 78, 702–708. [Google Scholar] [CrossRef]
  199. Yoon, A.-R.; Kasala, D.; Li, Y.; Hong, J.; Lee, W.; Jung, S.-J.; Yun, C.-O. Antitumor effect and safety profile of systemically delivered oncolytic adenovirus complexed with EGFR-targeted PAMAM-based dendrimer in orthotopic lung tumor model. J. Control. Release 2016, 231, 2–16. [Google Scholar] [CrossRef]
  200. Oh, E.; Oh, J.-E.; Hong, J.; Chung, Y.; Lee, Y.; Park, K.D.; Kim, S.; Yun, C.-O. Optimized biodegradable polymeric reservoir-mediated local and sustained co-delivery of dendritic cells and oncolytic adenovirus co-expressing IL-12 and GM-CSF for cancer immunotherapy. J. Control. Release 2017, 259, 115–127. [Google Scholar] [CrossRef]
  201. Liao, I.-C.; Chen, S.; Liu, J.B.; Leong, K.W. Sustained viral gene delivery through core-shell fibers. J. Control. Release 2009, 139, 48–55. [Google Scholar] [CrossRef] [Green Version]
  202. Denton, N.L.; Chen, C.-Y.; Hutzen, B.; Currier, M.A.; Scott, T.; Nartker, B.; Leddon, J.L.; Wang, P.-Y.; Srinivas, R.; Cassady, K.A. Myelolytic treatments enhance oncolytic herpes virotherapy in models of Ewing sarcoma by modulating the immune microenvironment. Mol. Ther. Oncolytics 2018, 11, 62–74. [Google Scholar] [CrossRef] [Green Version]
  203. Sakurai, F.; Inoue, S.; Kaminade, T.; Hotani, T.; Katayama, Y.; Hosoyamada, E.; Terasawa, Y.; Tachibana, M.; Mizuguchi, H. Cationic liposome-mediated delivery of reovirus enhances the tumor cell-killing efficiencies of reovirus in reovirus-resistant tumor cells. Int. J. Pharm. 2017, 524, 238–247. [Google Scholar] [CrossRef]
  204. Zhong, Z.; Shi, S.; Han, J.; Zhang, Z.; Sun, X. Anionic liposomes increase the efficiency of adenovirus-mediated gene transfer to coxsackie-adenovirus receptor deficient cells. Mol. Pharm. 2010, 7, 105–115. [Google Scholar] [CrossRef] [PubMed]
  205. Kasala, D.; Lee, S.-H.; Hong, J.W.; Choi, J.-W.; Nam, K.; Chung, Y.H.; Kim, S.W.; Yun, C.-O. Synergistic antitumor effect mediated by a paclitaxel-conjugated polymeric micelle-coated oncolytic adenovirus. Biomaterials 2017, 145, 207–222. [Google Scholar] [CrossRef] [PubMed]
  206. Almstätter, I.; Mykhaylyk, O.; Settles, M.; Altomonte, J.; Aichler, M.; Walch, A.; Rummeny, E.J.; Ebert, O.; Plank, C.; Braren, R. Characterization of magnetic viral complexes for targeted delivery in oncology. Theranostics 2015, 5, 667. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  207. Muthana, M.; Kennerley, A.J.; Hughes, R.; Fagnano, E.; Richardson, J.; Paul, M.; Murdoch, C.; Wright, F.; Payne, C.; Lythgoe, M.F. Directing cell therapy to anatomic target sites in vivo with magnetic resonance targeting. Nat. Commun. 2015, 6, 1–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  208. Roy, D.G.; Bell, J.C.; Bourgeois-Daigneault, M.-C. Magnetic targeting of oncolytic VSV-based therapies improves infection of tumor cells in the presence of virus-specific neutralizing antibodies in vitro. Biochem. Biophys. Res. Commun. 2020, 526, 641–646. [Google Scholar] [CrossRef] [PubMed]
  209. Sendra, L.; Miguel, A.; Navarro-Plaza, M.C.; Herrero, M.J.; de la Higuera, J.; Cháfer-Pericás, C.; Aznar, E.; Marcos, M.D.; Martínez-Máñez, R.; Rojas, L.A. Gold Nanoparticle-Assisted Virus Formation by Means of the Delivery of an Oncolytic Adenovirus Genome. Nanomaterials 2020, 10, 1183. [Google Scholar] [CrossRef]
  210. Bazan-Peregrino, M.; Arvanitis, C.D.; Rifai, B.; Seymour, L.W.; Coussios, C.-C. Ultrasound-induced cavitation enhances the delivery and therapeutic efficacy of an oncolytic virus in an in vitro model. J. Control. Release 2012, 157, 235–242. [Google Scholar] [CrossRef]
  211. He, X.; Yang, Y.; Li, L.; Zhang, P.; Guo, H.; Liu, N.; Yang, X.; Xu, F. Engineering extracellular matrix to improve drug delivery for cancer therapy. Drug Discov. Today 2020, 25, 1727–1734. [Google Scholar] [CrossRef]
  212. Nande, R.; Howard, C.M.; Claudio, P.P. Ultrasound-mediated oncolytic virus delivery and uptake for increased therapeutic efficacy: State of art. Oncolytic Virother. 2015, 4, 193. [Google Scholar]
  213. Raeesi, V.; Chan, W.C.W. Improving nanoparticle diffusion through tumor collagen matrix by photo-thermal gold nanorods. Nanoscale 2016, 8, 12524–12530. [Google Scholar] [CrossRef]
  214. Hagihara, Y.; Sakamoto, A.; Tokuda, T.; Yamashita, T.; Ikemoto, S.; Kimura, A.; Haruta, M.; Sasagawa, K.; Ohta, J.; Takayama, K. Photoactivatable oncolytic adenovirus for optogenetic cancer therapy. Cell Death Dis. 2020, 11, 1–9. [Google Scholar] [CrossRef] [PubMed]
  215. Ilett, E.; Kottke, T.; Donnelly, O.; Thompson, J.; Willmon, C.; Diaz, R.; Zaidi, S.; Coffey, M.; Selby, P.; Harrington, K. Cytokine conditioning enhances systemic delivery and therapy of an oncolytic virus. Mol. Ther. 2014, 22, 1851–1863. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  216. Howard, F.; Muthana, M. Designer nanocarriers for navigating the systemic delivery of oncolytic viruses. Nanomedicine 2020, 15, 93–110. [Google Scholar] [CrossRef] [PubMed]
  217. Na, Y.; Choi, J.-W.; Kasala, D.; Hong, J.; Oh, E.; Li, Y.; Jung, S.-J.; Kim, S.W.; Yun, C.-O. Potent antitumor effect of neurotensin receptor-targeted oncolytic adenovirus co-expressing decorin and Wnt antagonist in an orthotopic pancreatic tumor model. J. Control. Release 2015, 220, 766–782. [Google Scholar] [CrossRef]
  218. Choi, J.-W.; Kim, H.A.; Nam, K.; Na, Y.; Yun, C.-O.; Kim, S. Hepatoma targeting peptide conjugated bio-reducible polymer complexed with oncolytic adenovirus for cancer gene therapy. J. Control. Release 2015, 220, 691–703. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  219. Kirn, D.H.; Wang, Y.; Liang, W.; Contag, C.H.; Thorne, S.H. Enhancing poxvirus oncolytic effects through increased spread and immune evasion. Cancer Res. 2008, 68, 2071–2075. [Google Scholar] [CrossRef] [Green Version]
  220. Baran, N.; Konopleva, M. Molecular pathways: Hypoxia-activated prodrugs in cancer therapy. Clin. Cancer Res. 2017, 23, 2382–2390. [Google Scholar] [CrossRef] [Green Version]
  221. Ferguson, M.; Dunmall, L.S.C.; Gangeswaran, R.; Marelli, G.; Tysome, J.R.; Burns, E.; Whitehead, M.A.; Aksoy, E.; Alusi, G.; Hiley, C. Transient inhibition of phosphoinositide 3-kinase δ enhances the therapeutic effect of intravenous delivery of oncolytic Vaccinia virus. Mol. Ther. 2020, 28, 1263–1275. [Google Scholar] [CrossRef] [Green Version]
  222. Evgin, L.; Acuna, S.A.; De Souza, C.T.; Marguerie, M.; Lemay, C.G.; Ilkow, C.S.; Findlay, C.S.; Falls, T.; Parato, K.A.; Hanwell, D. Complement inhibition prevents oncolytic vaccinia virus neutralization in immune humans and cynomolgus macaques. Mol. Ther. 2015, 23, 1066–1076. [Google Scholar] [CrossRef] [Green Version]
  223. Lun, X.Q.; Jang, J.-H.; Tang, N.; Deng, H.; Head, R.; Bell, J.C.; Stojdl, D.F.; Nutt, C.L.; Senger, D.L.; Forsyth, P.A. Efficacy of systemically administered oncolytic vaccinia virotherapy for malignant gliomas is enhanced by combination therapy with rapamycin or cyclophosphamide. Clin. Cancer Res. 2009, 15, 2777–2788. [Google Scholar] [CrossRef] [Green Version]
  224. Liu, Y.-P.; Tong, C.; Dispenzieri, A.; Federspiel, M.J.; Russell, S.J.; Peng, K.-W. Polyinosinic acid decreases sequestration and improves systemic therapy of measles virus. Cancer Gene Ther. 2012, 19, 202–211. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  225. Berkey, S.E.; Thorne, S.H.; Bartlett, D.L. Oncolytic virotherapy and the tumor microenvironment. In Tumor Immune Microenvironment in Cancer Progression and Cancer Therapy; Springer: Berlin, Germany, 2017; pp. 157–172. [Google Scholar]
  226. Goradel, N.H.; Negahdari, B.; Ghorghanlu, S.; Jahangiri, S.; Arashkia, A. Strategies for enhancing intratumoral spread of oncolytic adenoviruses. Pharmacol. Ther. 2020, 213, 75–86. [Google Scholar] [CrossRef]
  227. Ravindra, P.; Tiwari, A.K.; Ratta, B.; Chaturvedi, U.; Palia, S.K.; Chauhan, R. Newcastle disease virus-induced cytopathic effect in infected cells is caused by apoptosis. Virus Res. 2009, 141, 13–20. [Google Scholar] [CrossRef] [PubMed]
  228. Duncan, R. Fusogenic reoviruses and their fusion-associated small transmembrane (FAST) proteins. Annu. Rev. Virol. 2019, 6, 341–363. [Google Scholar] [CrossRef] [PubMed]
  229. Moss, B. Membrane fusion during poxvirus entry. Semin. Cell Dev. Biol. 2016, 60, 89–96. [Google Scholar]
  230. Nakatake, M.; Kuwano, N.; Kaitsurumaru, E.; Kurosaki, H.; Nakamura, T. Fusogenic oncolytic vaccinia virus enhances systemic antitumor immune response by modulating the tumor microenvironment. Mol. Ther. 2020, 12, 24–38. [Google Scholar]
  231. Burton, C.; Bartee, E. Syncytia formation in oncolytic virotherapy. Mol. Ther. Oncolytics 2019, 15, 131–139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  232. Krabbe, T.; Altomonte, J. Fusogenic viruses in oncolytic immunotherapy. Cancers 2018, 10, 216. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  233. Matuszewska, K.; Santry, L.A.; Van Vloten, J.P.; AuYeung, A.W.K.; Major, P.P.; Lawler, J.; Wootton, S.K.; Bridle, B.W.; Petrik, J. Combining vascular normalization with an oncolytic virus enhances immunotherapy in a preclinical model of advanced-stage ovarian cancer. Clin. Cancer Res. 2019, 25, 1624–1638. [Google Scholar] [CrossRef] [Green Version]
  234. Na, Y.; Nam, J.-P.; Hong, J.; Oh, E.; Shin, H.C.; Kim, H.S.; Kim, S.W.; Yun, C.-O. Systemic administration of human mesenchymal stromal cells infected with polymer-coated oncolytic adenovirus induces efficient pancreatic tumor homing and infiltration. J. Control. Release 2019, 305, 75–88. [Google Scholar] [CrossRef]
  235. Jaime-Ramirez, A.C.; Dmitrieva, N.; Yoo, J.Y.; Banasavadi-Siddegowda, Y.; Zhang, J.; Relation, T.; Bolyard, C.; Wojton, J.; Kaur, B. Humanized chondroitinase ABC sensitizes glioblastoma cells to temozolomide. J. Gene Med. 2017, 19, e2942. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  236. Pascual-Pasto, G.; Bazan-Peregrino, M.; Olaciregui, N.G.; Restrepo-Perdomo, C.A.; Mato-Berciano, A.; Ottaviani, D.; Weber, K.; Correa, G.; Paco, S.; Vila-Ubach, M. Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN-01. Sci. Transl. Med. 2019, 11, 1–11. [Google Scholar] [CrossRef] [PubMed]
  237. Schäfer, S.; Weibel, S.; Donat, U.; Zhang, Q.; Aguilar, R.J.; Chen, N.G.; Szalay, A.A. Vaccinia virus-mediated intra-tumoral expression of matrix metalloproteinase 9 enhances oncolysis of PC-3 xenograft tumors. BMC Cancer 2012, 12, 366. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  238. Goodwin, J.M.; Schmitt, A.D.; McGinn, C.M.; Fuchs, B.C.; Kuruppu, D.; Tanabe, K.K.; Lanuti, M. Angiogenesis inhibition using an oncolytic herpes simplex virus expressing endostatin in a murine lung cancer model. Cancer Investig. 2012, 30, 243–250. [Google Scholar] [CrossRef]
  239. Tsuji, T.; Nakamori, M.; Iwahashi, M.; Nakamura, M.; Ojima, T.; Iida, T.; Katsuda, M.; Hayata, K.; Ino, Y.; Todo, T. An armed oncolytic herpes simplex virus expressing thrombospondin-1 has an enhanced in vivo antitumor effect against human gastric cancer. Int. J. Cancer 2013, 132, 485–494. [Google Scholar] [CrossRef]
  240. Adelfinger, M.; Bessler, S.; Frentzen, A.; Cecil, A.; Langbein-Laugwitz, J.; Gentschev, I.; Szalay, A.A. Preclinical testing oncolytic vaccinia virus strain GLV-5b451 expressing an anti-VEGF single-chain antibody for canine cancer therapy. Viruses 2015, 7, 4075–4092. [Google Scholar] [CrossRef] [Green Version]
  241. Angelova, A.L.; Geletneky, K.; Nüesch, J.P.F.; Rommelaere, J. Tumor selectivity of oncolytic parvoviruses: From in vitro and animal models to cancer patients. Front. Bioeng. Biotechnol. 2015, 3, 55. [Google Scholar] [CrossRef] [Green Version]
  242. Yamaguchi, T.; Uchida, E. Oncolytic virus: Regulatory aspects from quality control to clinical studies. Curr. Cancer Drug Targets 2018, 18, 202–208. [Google Scholar] [CrossRef]
  243. Chiocca, E.A.; Nakashima, H.; Kasai, K.; Fernandez, S.A.; Oglesbee, M. Preclinical toxicology of rQNestin34. 5v. 2, an oncolytic herpes virus with transcriptional regulation of the ICP34. 5 neurovirulence gene. Mol. Ther. Methods Clin. Dev. 2020, 17, 871–893. [Google Scholar] [CrossRef]
  244. Islam, S.M.; Lee, B.; Jiang, F.; Kim, E.-K.; Ahn, S.C.; Hwang, T.-H. Engineering and Characterization of Oncolytic Vaccinia Virus Expressing Truncated Herpes Simplex Virus Thymidine Kinase. Cancers 2020, 12, 228. [Google Scholar] [CrossRef] [Green Version]
  245. Bernstock, J.D.; Bag, A.; Fiveash, J.; Kachurak, K.; Elsayed, G.; Chagoya, G.; Gessler, F.; Valdes, P.A.; Madan-Swain, A.; Whitley, R. Design and Rationale for First-In-Human Phase 1 Immunovirotherapy Clinical Trial of Oncolytic HSV G207 to Treat Malignant Pediatric Cerebellar Brain Tumors. Hum. Gene Ther. 2020, 31, 19–20. [Google Scholar] [CrossRef] [PubMed]
  246. Mori, K.M.; Giuliano, P.D.; Lopez, K.L.; King, M.M.; Bohart, R.; Goldstein, B.H. Pronounced clinical response following the oncolytic vaccinia virus GL-ONC1 and chemotherapy in a heavily pretreated ovarian cancer patient. Anti Cancer Drugs 2019, 30, 1064–1066. [Google Scholar] [CrossRef] [PubMed]
  247. Tenneti, P.; Borad, M.J.; Babiker, H.M. Exploring the role of oncolytic viruses in hepatobiliary cancers. Immunotherapy 2018, 10, 971–986. [Google Scholar] [CrossRef]
  248. Chen, Q.; Wu, J.; Ye, Q.; Ma, F.; Zhu, Q.; Wu, Y.; Shan, C.; Xie, X.; Li, D.; Zhan, X. Treatment of human glioblastoma with a live attenuated Zika virus vaccine candidate. MBio 2018, 9, e01683-18. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  249. Gao, J.; Zhang, W.; Ehrhardt, A. Expanding the Spectrum of Adenoviral Vectors for Cancer Therapy. Cancers 2020, 12, 1139. [Google Scholar] [CrossRef]
  250. Abdullahi, S.; Jäkel, M.; Behrend, S.J.; Steiger, K.; Topping, G.; Krabbe, T.; Colombo, A.; Sandig, V.; Schiergens, T.S.; Thasler, W.E. A novel chimeric oncolytic virus vector for improved safety and efficacy as a platform for the treatment of hepatocellular carcinoma. J. Virol. 2018, 92, 1386–1398. [Google Scholar] [CrossRef] [Green Version]
  251. Coughlan, L.; Vallath, S.; Gros, A.; Giménez-Alejandre, M.; Van Rooijen, N.; Thomas, G.J.; Baker, A.H.; Cascalló, M.; Alemany, R.; Hart, I.R. Combined fiber modifications both to target αvβ6 and detarget the coxsackievirus–adenovirus receptor improve virus toxicity profiles in vivo but fail to improve antitumoral efficacy relative to adenovirus serotype 5. Hum. Gene Ther. 2012, 23, 960–979. [Google Scholar] [CrossRef] [Green Version]
  252. Marchini, A.; Bonifati, S.; Scott, E.M.; Angelova, A.L.; Rommelaere, J. Oncolytic parvoviruses: From basic virology to clinical applications. Virol. J. 2015, 12, 1–16. [Google Scholar] [CrossRef] [Green Version]
  253. Zhang, X.; Zhang, T.; Davis, J.N.; Marzi, A.; Marchese, A.M.; Robek, M.D.; van den Pol, A.N. Mucin-like domain of Ebola virus glycoprotein enhances selective oncolytic actions against brain tumors. J. Virol. 2020, 94, 967–979. [Google Scholar] [CrossRef]
  254. Harrington, K.J.; Michielin, O.; Malvehy, J.; Grüter, I.P.; Grove, L.; Frauchiger, A.L.; Dummer, R. A practical guide to the handling and administration of talimogene laherparepvec in Europe. Oncotargets Ther. 2017, 10, 3867. [Google Scholar] [CrossRef] [Green Version]
  255. Selman, M.; Ou, P.; Rousso, C.; Bergeron, A.; Krishnan, R.; Pikor, L.; Chen, A.; Keller, B.A.; Ilkow, C.; Bell, J.C. Dimethyl fumarate potentiates oncolytic virotherapy through NF-κB inhibition. Sci. Transl. Med. 2018, 10, eaao1613. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  256. Xiao, X.; Liang, J.; Huang, C.; Li, K.; Xing, F.; Zhu, W.; Lin, Z.; Xu, W.; Wu, G.; Zhang, J. DNA-PK inhibition synergizes with oncolytic virus M1 by inhibiting antiviral response and potentiating DNA damage. Nat. Commun. 2018, 9, 1–15. [Google Scholar] [CrossRef] [PubMed]
  257. Tang, B.; Guo, Z.S.; Bartlett, D.L.; Liu, J.; McFadden, G.; Shisler, J.L.; Roy, E.J. A cautionary note on the selectivity of oncolytic poxviruses. Oncolytic Virother. 2019, 8, 3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  258. Liu, Y.; Cai, J.; Liu, W.; Lin, Y.; Guo, L.; Liu, X.; Qin, Z.; Xu, C.; Zhang, Y.; Su, X. Intravenous injection of the oncolytic virus M1 awakens antitumor T cells and overcomes resistance to checkpoint blockade. Cell Death Dis. 2020, 11, 1–13. [Google Scholar] [CrossRef] [PubMed]
  259. Puzanov, I.; Milhem, M.M.; Minor, D.; Hamid, O.; Li, A.; Chen, L.; Chastain, M.; Gorski, K.S.; Anderson, A.; Chou, J. Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma. J. Clin. Oncol. 2016, 34, 2619. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  260. Sivanandam, V.; LaRocca, C.J.; Chen, N.G.; Fong, Y.; Warner, S.G. Oncolytic viruses and immune checkpoint inhibition: The best of both worlds. Mol. Ther. Oncolytics 2019, 13, 93–106. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  261. Lin, C.; Ren, W.; Luo, Y.; Li, S.; Chang, Y.; Li, L.; Xiong, D.; Huang, X.; Xu, Z.; Yu, Z. Intratumoral Delivery of a PD-1–Blocking scFv Encoded in Oncolytic HSV-1 Promotes Antitumor Immunity and Synergizes with TIGIT Blockade. Cancer Immunol. Res. 2020, 8, 632–647. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  262. Postow, M.A.; Sidlow, R.; Hellmann, M.D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 2018, 378, 158–168. [Google Scholar] [CrossRef] [PubMed]
  263. Rojas, J.J.; Sampath, P.; Hou, W.; Thorne, S.H. Defining effective combinations of immune checkpoint blockade and oncolytic virotherapy. Clin. Cancer Res. 2015, 21, 5543–5551. [Google Scholar] [CrossRef] [Green Version]
  264. Santos, J.M.; Havunen, R.; Hemminki, A. Modulation of the tumor microenvironment with an oncolytic adenovirus for effective T-cell therapy and checkpoint inhibition. Meth. Enzymol. 2020, 635, 205–230. [Google Scholar]
  265. Nishio, N.; Diaconu, I.; Liu, H.; Cerullo, V.; Caruana, I.; Hoyos, V.; Bouchier-Hayes, L.; Savoldo, B.; Dotti, G. Armed oncolytic virus enhances immune functions of chimeric antigen receptor–modified T cells in solid tumors. Cancer Res. 2014, 74, 5195–5205. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  266. Watanabe, K.; Luo, Y.; Da, T.; Guedan, S.; Ruella, M.; Scholler, J.; Keith, B.; Young, R.M.; Engels, B.; Sorsa, S. Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses. JCI Insight 2018, 3, 1–17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  267. Scott, E.M.; Duffy, M.R.; Freedman, J.D.; Fisher, K.D.; Seymour, L.W. Solid Tumor Immunotherapy with T Cell Engager-Armed Oncolytic Viruses. Macromol. Biosci. 2018, 18, 1700187. [Google Scholar] [CrossRef] [PubMed]
  268. Hamano, S.; Mori, Y.; Aoyama, M.; Kataoka, H.; Tanaka, M.; Ebi, M.; Kubota, E.; Mizoshita, T.; Tanida, S.; Johnston, R.N. Oncolytic reovirus combined with trastuzumab enhances antitumor efficacy through TRAIL signaling in human HER2-positive gastric cancer cells. Cancer Lett. 2015, 356, 846–854. [Google Scholar] [CrossRef] [PubMed]
  269. Koske, I.; Rössler, A.; Pipperger, L.; Petersson, M.; Barnstorf, I.; Kimpel, J.; Tripp, C.H.; Stoitzner, P.; Bánki, Z.; von Laer, D. Oncolytic virotherapy enhances the efficacy of a cancer vaccine by modulating the tumor microenvironment. Int. J. Cancer 2019, 145, 1958–1969. [Google Scholar] [CrossRef] [Green Version]
  270. Schirrmacher, V. Cancer vaccines and oncolytic viruses exert profoundly lower side effects in cancer patients than other systemic therapies: A comparative analysis. Biomedicines 2020, 8, 61. [Google Scholar] [CrossRef] [Green Version]
  271. Lemay, C.G.; Rintoul, J.L.; Kus, A.; Paterson, J.M.; Garcia, V.; Falls, T.J.; Ferreira, L.; Bridle, B.W.; Conrad, D.P.; Tang, V.A. Harnessing oncolytic virus-mediated antitumor immunity in an infected cell vaccine. Mol. Ther. 2012, 20, 1791–1799. [Google Scholar] [CrossRef] [Green Version]
  272. Xu, X.; Sun, Q.; Mei, Y.; Liu, Y.; Zhao, L. Newcastle disease virus co-expressing interleukin 7 and interleukin 15 modified tumor cells as a vaccine for cancer immunotherapy. Cancer Sci. 2018, 109, 279–288. [Google Scholar] [CrossRef] [Green Version]
  273. Burke, J.D.; Platanias, L.C.; Fish, E.N. Beta interferon regulation of glucose metabolism is PI3K/Akt dependent and important for antiviral activity against coxsackievirus B3. J. Virol. 2014, 88, 3485–3495. [Google Scholar] [CrossRef] [Green Version]
  274. Jiang, H.; Shi, H.; Sun, M.; Wang, Y.; Meng, Q.; Guo, P.; Cao, Y.; Chen, J.; Gao, X.; Li, E. PFKFB3-driven macrophage glycolytic metabolism is a crucial component of innate antiviral defense. J. Immunol. 2016, 197, 2880–2890. [Google Scholar] [CrossRef]
  275. da Costa, L.S.; da Silva, A.P.P.; Da Poian, A.T.; El-Bacha, T. Mitochondrial bioenergetic alterations in mouse neuroblastoma cells infected with Sindbis virus: Implications to viral replication and neuronal death. PloS ONE 2012, 7, e33871. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  276. Kennedy, B.E.; Murphy, J.P.; Clements, D.R.; Konda, P.; Holay, N.; Kim, Y.; Pathak, G.P.; Giacomantonio, M.A.; El Hiani, Y.; Gujar, S. Inhibition of pyruvate dehydrogenase kinase enhances the antitumor efficacy of oncolytic reovirus. Cancer Res. 2019, 79, 3824–3836. [Google Scholar] [CrossRef] [PubMed]
  277. Li, C.; Meng, G.; Su, L.; Chen, A.; Xia, M.; Xu, C.; Yu, D.; Jiang, A.; Wei, J. Dichloroacetate blocks aerobic glycolytic adaptation to attenuated measles virus and promotes viral replication leading to enhanced oncolysis in glioblastoma. Oncotarget 2015, 6, 1544. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  278. Kennedy, B.E.; Sadek, M.; Gujar, S.A. Targeted metabolic reprogramming to improve the efficacy of oncolytic virus therapy. Mol. Ther. 2020, 28, 1417–1421. [Google Scholar] [CrossRef] [PubMed]
  279. Roy, D.G.; Kaymak, I.; Williams, K.S.; Ma, E.H.; Jones, R.G. Immunometabolism in the Tumor Microenvironment. Annu. Rev. Cancer Biol. 2020, 4, 17–40. [Google Scholar]
  280. Chang, C.-H.; Qiu, J.; O’Sullivan, D.; Buck, M.D.; Noguchi, T.; Curtis, J.D.; Chen, Q.; Gindin, M.; Gubin, M.M.; Van Der Windt, G.J.W. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 2015, 162, 1229–1241. [Google Scholar] [CrossRef] [Green Version]
  281. Jung, K.H.; Choi, I.-K.; Lee, H.-S.; Yan, H.H.; Son, M.K.; Ahn, H.M.; Hong, J.; Yun, C.-O.; Hong, S.-S. Oncolytic adenovirus expressing relaxin (YDC002) enhances therapeutic efficacy of gemcitabine against pancreatic cancer. Cancer Lett. 2017, 396, 155–166. [Google Scholar] [CrossRef]
  282. Habiba, U.; Hossain, E.; Yanagawa-Matsuda, A.; Chowdhury, A.F.M.A.; Tsuda, M.; Zaman, A.-U.; Tanaka, S.; Higashino, F. Cisplatin relocalizes RNA binding protein HuR and enhances the oncolytic activity of E4orf6 deleted adenovirus. Cancers 2020, 12, 809. [Google Scholar] [CrossRef] [Green Version]
  283. Gomez-Gutierrez, J.G.; Nitz, J.; Sharma, R.; Wechman, S.L.; Riedinger, E.; Martinez-Jaramillo, E.; Zhou, H.S.; McMasters, K.M. Combined therapy of oncolytic adenovirus and temozolomide enhances lung cancer virotherapy in vitro and in vivo. Virology 2016, 487, 249–259. [Google Scholar] [CrossRef] [Green Version]
  284. Malfitano, A.M.; Di Somma, S.; Iannuzzi, C.A.; Pentimalli, F.; Portella, G. Virotherapy: From single agents to combinatorial treatments. Biochem. Pharmacol. 2020, 113986. [Google Scholar] [CrossRef]
  285. Ganesan, A. HDAC inhibitors in cancer therapy. Histone Modif. Ther. 2020, 2, 19–49. [Google Scholar]
  286. Jennings, V.A.; Scott, G.B.; Rose, A.M.; Scott, K.J.; Migneco, G.; Keller, B.; Reilly, K.; Donnelly, O.; Peach, H.; Dewar, D. Potentiating oncolytic virus-induced immune-mediated tumor cell killing using histone deacetylase inhibition. Mol. Ther. 2019, 27, 1139–1152. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  287. Fox, C.R.; Parks, G.D. Histone Deacetylase Inhibitors Enhance Cell Killing and Block Interferon-Beta Synthesis Elicited by Infection with an Oncolytic Parainfluenza Virus. Viruses 2019, 11, 431. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  288. Roulstone, V.; Pedersen, M.; Kyula, J.; Mansfield, D.; Khan, A.A.; McEntee, G.; Wilkinson, M.; Karapanagiotou, E.; Coffey, M.; Marais, R. BRAF-and MEK-targeted small molecule inhibitors exert enhanced antimelanoma effects in combination with oncolytic reovirus through ER stress. Mol. Ther. 2015, 23, 931–942. [Google Scholar] [CrossRef] [Green Version]
  289. Jackson, J.D.; Markert, J.M.; Li, L.; Carroll, S.L.; Cassady, K.A. STAT1 and NF-κB inhibitors diminish basal interferon-stimulated gene expression and improve the productive infection of oncolytic HSV in MPNST cells. Mol. Cancer Res. 2016, 14, 482–492. [Google Scholar] [CrossRef] [Green Version]
Cancers 13 00588 g001 550
Figure 1. Recent approaches in oncolytic virotherapy. Expression of TAA-receptors and scFvs, recombination of specific domains and motifs, using tumor-specific promoters, and application of miRNA-TS could enhance the tumor targeting. GMOVs expressed inflammatory cytokines, enzymes, chemokine receptors, costimulatory molecules, and proapoptotic proteins achieve high antitumor potency. ECM and vasculature degradation by enzymes and molecules result in a higher spread of OVs. Administration routs are a critical factor in achieving better results with lower adverse effects. Besides, deleting virulence genes and recombination of OVs together could diminish the concerns of adverse events. However, several biosafety concerns still remained unmet. The combination of OVT with other immunotherapy, such as ICIs, TIL therapy, CART cell therapy, DC vaccines, mAbs, BiTEs, and metabolic inhibitors could potentiate the immunotherapy against tumors. OV. Oncolytic virus; OVT. OV therapy; TAA. Tumor-associated antigen; scFv. Single-chain variable fragment; Her-2. Human epidermal growth factor receptor 2; EpCAM. Epithelial cell adhesion molecule; CEA. Carcinoembryonic antigen; AdV. Adenovirus; RGD. Arginine-glycine-aspartate; GP-160. Glycoprotein-160; miRNA-TS. microRNA targeting sequence; PSA. Prostate-specific antigen; hTERT. Human telomerase reverse transcriptase; DC. Dendritic cell; CD. Cytosine deaminase; 5-FC. 5-fuorocytosine; 5-FU. 5-fluorouracil; HPGD. Hydroxyprostaglandin dehydrogenase; PGE2. Prostagalndin-E2; MDSC. Myeloid-derived suppressor cell; IFN. Interferon; TRAIL. TNF-related apoptosis-inducing ligand; siRNA. Small interfering RNA; TLR-9. Toll-like receptor-9; ICI. Immune checkpoint inhibitor; BiTE. Bispecific T cell engager; mAb. Monoclonal antibody; TIL. Tumor0infiltraring lymphocyte; CART cell. Chimeric-antigen receptor T cell; TME. Tumor microenvironment; ECM. Extracellular matrix; VEGF. Vascular-endothelial growth factor.
Figure 1. Recent approaches in oncolytic virotherapy. Expression of TAA-receptors and scFvs, recombination of specific domains and motifs, using tumor-specific promoters, and application of miRNA-TS could enhance the tumor targeting. GMOVs expressed inflammatory cytokines, enzymes, chemokine receptors, costimulatory molecules, and proapoptotic proteins achieve high antitumor potency. ECM and vasculature degradation by enzymes and molecules result in a higher spread of OVs. Administration routs are a critical factor in achieving better results with lower adverse effects. Besides, deleting virulence genes and recombination of OVs together could diminish the concerns of adverse events. However, several biosafety concerns still remained unmet. The combination of OVT with other immunotherapy, such as ICIs, TIL therapy, CART cell therapy, DC vaccines, mAbs, BiTEs, and metabolic inhibitors could potentiate the immunotherapy against tumors. OV. Oncolytic virus; OVT. OV therapy; TAA. Tumor-associated antigen; scFv. Single-chain variable fragment; Her-2. Human epidermal growth factor receptor 2; EpCAM. Epithelial cell adhesion molecule; CEA. Carcinoembryonic antigen; AdV. Adenovirus; RGD. Arginine-glycine-aspartate; GP-160. Glycoprotein-160; miRNA-TS. microRNA targeting sequence; PSA. Prostate-specific antigen; hTERT. Human telomerase reverse transcriptase; DC. Dendritic cell; CD. Cytosine deaminase; 5-FC. 5-fuorocytosine; 5-FU. 5-fluorouracil; HPGD. Hydroxyprostaglandin dehydrogenase; PGE2. Prostagalndin-E2; MDSC. Myeloid-derived suppressor cell; IFN. Interferon; TRAIL. TNF-related apoptosis-inducing ligand; siRNA. Small interfering RNA; TLR-9. Toll-like receptor-9; ICI. Immune checkpoint inhibitor; BiTE. Bispecific T cell engager; mAb. Monoclonal antibody; TIL. Tumor0infiltraring lymphocyte; CART cell. Chimeric-antigen receptor T cell; TME. Tumor microenvironment; ECM. Extracellular matrix; VEGF. Vascular-endothelial growth factor.
Cancers 13 00588 g001
Table
Table 1. Oncolytic viruses that reached the clinical phase.
Table 1. Oncolytic viruses that reached the clinical phase.
Oncolytic VirusModificationCombination TherapyCancer Type (Clinical Trial Phase)Ref.
HSV-1Virulence gene ICP34.5 and ICP47 are deleted and human GM-CSF gene is insertedICIs (anti-PD1, anti-CTLA4Melanoma (I, II), Sarcoma (I, II)[29,30,31]
-Breast cancer (I), Head and neck cancer (I, I/II), Gastrointestinal cancers (I), Melanoma (I, II, III)[32,33,34,35,36]
Virulence gene ICP34.5 is deleted-Oral SCC (I), Pediatric extracranial cancers (I)[37,38]
ChemotherapyChemo-resistant metastatic colon cancer (I, I/II)[39,40]
Virulence gene ICP34.5 is deleted and ICP6 gene is inactivatedRadiotherapyGlioblastoma (I)[41]
Naturally mutated-Pancreatic cancer (I)[42]
NDVAutologous tumor lysate and IL-2 is added-Stage III of Melanoma (I)[43]
Naturally attenuated-Advanced solid tumors (I)[44]
One-cycle replicating cytopathogenic NDV-Glioblastoma (I/II)[45]
CVA21-ICIs (anti-PD1)NSCLC (Ib), Bladder cancer (Ib)[46]
-Bladder cancer (II), Advanced melanoma (II)[47,48]
RV--Advanced solid tumors (I), Recurrent glioma (I), Extracranial solid tumors (I), Melanoma (II), Pancreatic adenocarcinoma (II)[49,50,51,52,53]
ChemotherapyAdvanced solid tumors (I), Ovarian cancer (IIb), Peritoneal cancer (IIb), Melanoma (II), Metastatic breast cancer (II), Advanced head and neck cancer (I/II) Pancreatic adenocarcinoma (II)[54,55,56,57,58]
RadiotherapyAdvanced solid tumors (I)[59]
PoVRecombinant oral PoV Sabin-1:
the internal ribosome entry site (IRES) is replaced with the IRES from human rhinovirus-2: nonpathogenic		-Recurrent glioblastoma (I)[60]
AdVAdV3 fiber knob is inserted into the backbone of AdV5,
A 24-base pair in the E1 gene is deleted: CRAd
GM-CSF gene is inserted		-Ovarian Cancer (I), Gynecologic malignancies (I), Advanced solid tumors (I)[61,62,63]
ChemotherapyChemo-resistant advanced solid tumors (I)[61]
RGD motif is inserted into the AdV5 fiber knob: Integrin targeted instead of CAR dependence
GM-CSF gene is inserted		-Chemo-resistant advanced solid tumors (I)[64]
Prostate-specific antigen (PSA)-selectiveRadiotherapyMetastatic prostate cancer (I)[65]
Conditionally replicating GM-CSF expressing AdV-Bladder Cancer (I, II), Head and neck cancers (I)[66,67]
Human telomerase reverse transcriptase (hTERT) is inserted: tumor selective replication-Advanced solid tumors (I)[68]
E1B-deleted AdV: selective replication in P53-deficient cellsChemotherapyAdvanced solid tumors (I), Malignant glioma (I), Recurrent head and neck cancer (I, II), Gastrointestinal cancers (II), Colorectal cancer (II), Advanced sarcoma (I/II),[69,70,71,72]
Chimeric AdV:
Ad11p/Ad3,
AdV5- cytosine deaminase/HSV-1 thymidine kinase: suicide gene for safety		-RCC (I), NSCLC (I), Colorectal cancer (I), Urothelial cancer (I),Prostate cancer (I, II), Glioma (II)[73,74,75,76]
VACVGM-CSF gene is inserted
Thymidine kinase gene is deleted		ChemotherapyMetastatic melanoma (I), HCC (I, II), Colorectal cancer (I), Ewing sarcoma (I), neuroblastoma (I),[77,78,79,80]
FCU1 transgene is inserted: metabolize 5-FC to 5-FU-monophosphateChemotherapyChemo-resistant liver tumors (I)[81]
Thymidine kinase gene and hemagglutinin gene and F14.5 gene are deleted
Luciferase gene, beta-galactosidase, and beta-glucuronidase are inserted		Chemotherapy and radiotherapyHead and neck cancer (I), Colorectal cancer (I)
Advanced solid tumors (I)		[82,83,84]
MeVGenetically modified to
express carcinoembryonic antigen		-Ovarian cancer (I)[85]
SVV--Neuroblstoma (I), rhabdomyosarcoma (I), Neuroendocrine malignancies (I)[86,87]
PoxvirusGenetically modified expressing costimulatory and adhesion molecules such as B7-1, LFA-3, ICAM-1-Colorectal cancer (I), Melanoma (I)[88]
PV--Glioblastoma (I/II)[89]
HSV-1. Herpes simplex virus-1; ICP. Infected cell protein; GM-CSF. Granulocyte-macrophage colony-stimulating factor; ICI. Immune-checkpoint inhibitor; PD1. Programmed cell death protein 1; CTLA4. cytotoxic T-lymphocyte-associated protein 4; SCC. Squamous cell carcinoma; NDV. Newcastle disease virus; CVA21. Coxsackievirus A21; NSCLC. Nonsmall-cell lung carcinoma; RV. Reovirus; PoV. Poliovirus; AdV. Adenovirus; CRAd. Conditionally replicative adenoviruses; RGD. Arginine-Glycine-Aspartate; CAR. Coxsackievirus and adenovirus receptor; RCC. Renal cell carcinoma; VACV. Vaccinia virus; HCC. Hepatocellular carcinoma; FCU1. Fusion suicide gene; 5-FC. 5-fluorocytosine; 5-FU.5-Fluorouracil; MeV. Measles virus; SVV. Seneca Valley virus; LFA-3. Lymphocyte function-associated antigen-3; ICAM-1. Intercellular adhesion molecule-1; PV. Parvovirus.
Table
Table 2. Delivery approaches to enhance tumor access by oncolytic viruses.
Table 2. Delivery approaches to enhance tumor access by oncolytic viruses.
StrategyApproachMethodOutcomeReferences
Organic carriersStem cell carrierMesenchymal Stem cells (Bone marrow, adipose, umbilical cord- menstrual blood)Off-the-shelf;
both systemic and local application; OV shielding;
better replication; deliver more viral copies; enhanced tumor tropism; delivery of Ovs to hard-to-access
metastatic foci; antiviral immune response evasion; increased persistence of OVs; enhance tumor cell apoptosis;
probable toxicity due to trapping mesenchymal stem cells in the lung		[156,157,158]
Neural Stem cellsOff-the-shelf; improved OV delivery to brain tumors;
better response in chemo-resistant ovarian cancer		[159]
Immune and blood cell carrierGranulocytes,
neutrophils		Delivery to cancer cells located in the bone marrow or spleen;
circumvent the problems of systemic delivery;
OV shielding		[160,161]
Dendritic cellsProtect OVs from systemic neutralization, long-term tumor regression;
decrease pleural exudation in breast cancer		[162,163]
T cellsFacilitate systemic OVT in the presence of antiviral nAbs;
delivery to cancer cells located in the bone marrow or spleen; Increased efficacy in intratumoral injection; prolonged survival; enhance the efficacy of adoptive cell therapy and OVT; increase selectivity for metastatic tumors; viral concentration in tumor;		[163,164,165]
MacrophageMigration to hypoxic tumors; enhanced OV proliferation and antitumor effect in hypoxia; inhibited tumor growth and metastasis; more resistant to antibody neutralization[166,167]
Natural killer cell (NK-92 cells transduced with Ad5/37 chimeric fiber)Strong antitumor effects[168]
Cytokine-induced killer cellsImproved tumor trafficking;
enhanced antitumor effects		[169]
Peripheral-blood mononuclear cellsOV shielding from nAb;
retained proliferation and selective cytotoxicity for tumor cells, enhanced OV delivery to treat minimal residual disease		[160,170,171]
Myeloid-derived suppressor cells
(MDSC)		Avoid of antiviral responses; preferential migration into tumors; less toxicity following multiple administration;
induction of MDSC differentiation towards the M1-like macrophage		[172]
PlateletsOV shielding from nAb,
retained proliferation and cytotoxicity		[160]
MonocytesOVs shielding; possibility of multiple administration;
more resistant to antibody neutralization		[160,173]
Erythrocyte,
Sickle cell		Improved transfection,
high absorption and infection despite nAbs presence		[174,175]
Carrier Cell linesHS 578T
HeLa
A549
MCF-7
CT26
SF268
U937
UR-D7
MC38
MH3924A		Better in vitro manipulation,
Trapped in small vessels and decrease circulation,
more resistant to antibody neutralization, Iproved viral delivery, replication and intratumoral spread,
reduce OV spreading to peripheral organs 		[168,176,177,178]
Other CellsBlood outgrowth endothelial
cells		Shield OVs from nAbs;
reduced tumor burden;
superior antitumor activity;		[179]
Extracellular vesicles (EVs)infected cell-derived EVs,
A549-derived EVs,
LL/2-derived EVs		increased the transduction and infectious titer;
reduced tumor growth;
specifically target the tumor;
immunological cell death;
immune cell infiltration;
localized inflammatory effect;
provide
alternative entry pathways into tumor cells		[180,181]
Tumor cell membraneExtraCRAd (Extra conditionallyreplicating adenoviruses): Membrane of B16.OVA, B16.F10, LL/2, CMT64.OVA, MB49, A549, and SKOV-3 cell linesOVs wrapped with cancer cell membranes carrying TAA,
increased in vitro and in vivo infectivity;
control tumor growth with preventive and therapeutic applications;
high specific antitumor immune response		[182]
Biomaterials
Polymeric carriers		Implant3D-engineered conformal implantConstant release of OVs;
apoptosis induction;
delays tumor recurrence; eradicating post-surgery residual tumors		[183]
PolymersSilica, Biosilicificationreduced viral clearance in the liver; evaded nAbs; efficacious anticancer effect; biocompatibility[184]
Polylysine-encoded fiber,
poly-L-lysine polymer		Better infection capacity[185,186]
Lactic-co-glycolic acid nanofiberEnhanced delivery and therapeutic efficacy; reduced antiviral response[187]
multilayer ionic polymerenhanced oncolytic activity;
complement-dependent cytotoxicity; prolonged antitumor activities		[188]
AlginateReduced antiviral response[189]
Poly-2-dibutylamino-ethylamine-L-glutamateHigh safety and efficacy[190]
PolycationsPolybreneShielding OVs; bridge virion and cell surface;
efficient gene transduction and viral progeny		[191]
core-cross-linked polyethyleneiminelow immunogenicity and toxicity;
higher transduction; stability;
improved anticancer cytotoxicity		[192]
Polyethylene glycol (PEG)ylation,
PH-sensitive pegylation		shield virions from nAbs;
possibility of dose reduction; increased half-life in circulation		[178,193]
Poly hydroxypropyl methacrylamideOVs shielding, increased half-life[194]
PolysaccharideFailed to evade nAbs[195]
Silk-elastin-like polymerOV shielding; better delivery and transduction;
higher expression of viral genes; cause acute toxicity		[196]
ChitosanOV shielding;
enhanced infectivity;
induce cell fusion;
delay in tumor growth		[197]
Fibrin and collagenSustained release of viral particles[198]
DendrimersEGFR-targeted dendrimer,
Poly-amidoamine dendrimers		selective internalization into EGFR-positive cells; low immunogenicity, toxicity and liver sequestration;
Better transduction;
OV shielding from nAbs		[199]
Hydrogelgelatin-based hydrogelDecrease antiviral phagocyte response;
better DC migration and activation;
induction of tumor-specific IFN-γ+ immune cells		[200]
ScaffoldsMicroporous scaffoldsPrevent phagocytosis[201]
Lipid-based carriersLiposomesAnionic liposome,
Cationic liposome,
Clondrosome (clodronate-loaded liposomes)		Shielding OVs;
promoted OV delivery to the cytosol;
enhance the tumor cell killing;
macrophage depletion and better OV replication; induced expression of antitumorigenic genes		[202,203,204]
MicellesMicelleshigher transduction;
efficient cellular internalization; improved cancer cell killing;
attenuated the host antiviral response;
minimal hepatotoxicity; good safety		[205]
Metal-based carriersMagnetosomealternating magnetic field (iron oxide)
Magnetic nanoparticles
magnetically label OV-loaded macrophages and cells
OVs labeled with magnetic particle		ECM degradation;
enhanced OV uptake;
prevention of tumor growth and metastasis; improved targeted therapy;
increased tumor macrophage infiltrations; Protection against nAbs,		[206,207,208]
Metal nanoparticlesGold nanoparticlesProtected OVs;
efficient transduction; enhanced viral cytopathic effect;
safe vector for OVs		[209]
Ultrasound Ultrasound-induced cavitation,
Ultrasound + polymers,
Ultrasound mediated microbubbles,
Ultrasound contrast agents		improve OV extravasation and distribution;
kill tumor cells within the
ultrasound focal area;
retardation of tumor growth;
enhanced cell-based OVT		[210,211,212]
PhotodynamicsInfraredNear infrared light (plus gold nanoparticle)ECM degradation[213]
Blue lightPhotoactivatable OVs + blue light irradiationinduced replication; no off-tumor toxicity; inhibition subcutaneous tumor growth; therapeutic effect on cancer stem cells[214]
Pre-treatmentPreconditioningGranulocyte-macrophage colony-stimulating factor (GM-CSF)Provide a pool of
Potential OV carriers in the circulation: monocyte, macrophage, granulocytes, MDSCs, and CD11b+ cells;
enhanced viral delivery;
protected OVs from nAb		[215]
Targeting ligandsNanoparticle natural and engineered ligandsBiTEs,
Trispecific Abs,
Arginine-glycine-aspartic acid motif (RGD),
Glycoprotein B/C,
Neurotensin,
Folic acid,
Trastuzumab,
Cetuximab,
VEGF/bFGF,
Biotin-EGF,
CD71 and CD62E/P- immunovirosomes		Bridge tumor cells and OVs/immune cells;
OV release in hypoxic/acidic TME; better cell entry; enhanced tumor tropism, nAb evasion; prolonged blood retention time; improved transduction;		[15,157,178,216,217,218]
Viral particlesextracellular
enveloped viral particle		Rapid OV spread within the TME; prevent removal by immune response;
well adapted for systemic infusion;		[219]
Pharmacologic manipulationSystemic and local pharmacotherapyAngiotensin receptor blocker, paclitaxel, nitric oxide, nitroglycerin, bradykinin, Histamine
TH-302 and PR-104
IC87114 or idelalisib (PI3Kδ-inhibitor)		activated local matrix metalloproteinases to disrupt the ECM; temporal vasodilation and better perfusion;
OV activation in hypoxia;
potentiateintravenous delivery of OV		[178,211,220,221]
Cobra venom factor (CP40)Complement inhibition; increase in OV titer in the blood;
Prolonged OV existence		[222]
Cyclophosphamide,
Rapamycin		enhanced OV replication and activity; Avoid antiviral immune response[223]
Polyinosinic acideSaturate scavenger receptors;
prevent OV sequestration by Kupffer cells (liver macrophages);
requirement of low dose OVs; lower toxicity; improve transduction		[224]
Intratumoral spread of OVsECM-degradationHyaloronidase,
Decorin,
Relaxin,
Chondroitinase,
Matrix metalloproteinases,
Collagenase,
Bromelain,
TAF depletion,
LOX inhibition antibodies		Enhanced intratumoral spread of OVs;
decrease matrix crosslinking and deposition		[6,211,225,226]
Cellular junction openerpenton-dodecahedra, Junction Opener-1Enhanced intratumoral spread of OVs[226]
Fusogenic proteinsNatural or engineered fusogenic OVs: MeV, NDV, RV, SeV, MuV, RSV, GALV, PoxV, VACV, VSV, HSV, and AdV Improved infection; Enhanced tumor killing capability[226,227,228,229,230,231,232]
Vasculature degradation agentsTrombospondin-1 (TSP-1)
TSP-1 peptide 3TSR
Endostatin
Anti-VEGF scAb		Better perfusion and delivery; enhanced intratumoral spread of OVs;
Tumor necrosis;
reduced hypoxia		[6,233]
OV. Oncolytic virus; OVT. OV therapy; ECM. Extracellular matrix; BiTE. Bispecific T cell engager; VEGF. Vascular-endothelial growth factor; bFGF. basic fibroblast GF; PI3K. Phosphoinositide 3-kinase; TAF. Tumor-associated fibroblast; Lox. Lipoxygenase.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Jin, K.-T.; Du, W.-L.; Liu, Y.-Y.; Lan, H.-R.; Si, J.-X.; Mou, X.-Z. Oncolytic Virotherapy in Solid Tumors: The Challenges and Achievements. Cancers 2021, 13, 588. https://doi.org/10.3390/cancers13040588

AMA Style

Jin K-T, Du W-L, Liu Y-Y, Lan H-R, Si J-X, Mou X-Z. Oncolytic Virotherapy in Solid Tumors: The Challenges and Achievements. Cancers. 2021; 13(4):588. https://doi.org/10.3390/cancers13040588

Chicago/Turabian Style

Jin, Ke-Tao, Wen-Lin Du, Yu-Yao Liu, Huan-Rong Lan, Jing-Xing Si, and Xiao-Zhou Mou. 2021. "Oncolytic Virotherapy in Solid Tumors: The Challenges and Achievements" Cancers 13, no. 4: 588. https://doi.org/10.3390/cancers13040588

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop