Onyx virus cancer

Theranostic potential of oncolytic vaccinia virus. Oncolytic measles virus expressing the sodium iodide symporter to treat drug-resistant ovarian cancer. Cancer Res. Phase I study of noninvasive imaging of adenovirus-mediated gene expression in the human prostate. Oncolytic vaccinia virus expressing the human somatostatin receptor SSTR2: molecular imaging after systemic delivery using In-pentetreotide. Oncolytic adenoviruses armed with thymidine kinase can be traced by PET imaging and show potent antitumoural effects by ganciclovir dosing.

PLoS One. Positron emission tomography-based imaging of transgene expression mediated by replication-conditional, oncolytic herpes simplex virus type 1 mutant vectors in vivo. Radiovirotherapy: principles and prospects in oncology. Curr Pharm Des. Molecular imaging with bioluminescence and PET reveals viral oncolysis kinetics and tumor viability. Vaccinia virus GLV-1h is a novel agent for detection and effective local control of positive surgical margins for breast cancer.

Breast Cancer Res. Feasibility of adenovirus-mediated hNIS gene transfer and I radioiodine therapy as a definitive treatment for localized prostate cancer. A novel oncolytic viral therapy and imaging technique for gastric cancer using a genetically engineered vaccinia virus carrying the human sodium iodide symporter.

J Exp Clin Cancer Res. Doxycycline inducible melanogenic vaccinia virus as theranostic anti-cancer agent. Adapted ECHO-7 virus Rigvir immunotherapy oncolytic virotherapy prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study. Melanoma Res. Oncolytic virotherapy including Rigvir and standard therapies in malignant melanoma. Oncolytic Virother. Liang M. Oncorine, the world first oncolytic virus medicine and its update in China.

Curr Cancer Drug Targets. Ries S, Korn WM. ONYX mechanisms of action and clinical potential of a replication-selective adenovirus. J Virol. The early region 1B kilodalton oncoprotein of adenovirus relieves growth restrictions imposed on viral replication by the cell cycle.

Going viral: a review of replication-selective oncolytic adenoviruses. Seroprevalence of neutralizing antibodies to human adenoviruses type-5 and type and chimpanzee adenovirus type in healthy Chinese adults. J Med Virol. Prevalence of neutralizing antibodies to adenoviral serotypes 5 and 35 in the adult populations of The Gambia, South Africa, and the United States.

Clin Diagn Lab Immunol. Genome sequence of herpes simplex virus 1 strain KOS. Experimental therapy of human glioma by means of a genetically engineered virus mutant. Mohr I, Gluzman Y. A herpesvirus genetic element which affects translation in the absence of the viral GADD34 function. EMBO J. Into the clinic: talimogene laherparepvec T-VEC , a first-in-class intratumoral oncolytic viral therapy. J Immunother Cancer.

Intratumoral injection of HSV, an oncolytic herpes virus, is safe and shows evidence of immune response and viral replication in young cancer patients. Clin Cancer Res. A phase 1 trial of oncolytic HSV-1, G, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses.

Hum Gene Ther. Genomic signature of the natural oncolytic herpes simplex virus HF10 and its therapeutic role in preclinical and clinical trials. Ann Surg Oncol. Gene Ther. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves Anti-PD-1 immunotherapy.

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. The adenovirus capsid: major progress in minor proteins. J Gen Virol. Components of adenovirus genome packaging. Front Microbiol. Vesicular stomatitis virus: re-inventing the bullet. Trends Mol Med. A phase I study of telomerase-specific replication competent oncolytic adenovirus telomelysin for various solid tumors.

An open label, single-arm, phase II multicenter study of the safety and efficacy of CG oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: interim results. Urol Oncol. Conserved fiber-penton base interaction revealed by nearly atomic resolution cryo-electron microscopy of the structure of adenovirus provides insight into receptor interaction.

Zhang Y, Bergelson JM. Adenovirus receptors. Multiple adenovirus serotypes use alpha v integrins for infection. Arnberg N. Adenovirus receptors: implications for targeting of viral vectors.

Trends Pharmacol Sci. Preclinical characterization of the antiglioma activity of a tropism-enhanced adenovirus targeted to the retinoblastoma pathway. Int J Cancer. The oncolytic adenovirus VCN as therapeutic approach against pediatric osteosarcoma. Replacement of adenovirus type 5 fiber shaft heparan sulfate proteoglycan-binding domain with RGD for improved tumor infectivity and targeting.

Oncolytic adenovirus research evolution: from cell-cycle checkpoints to immune checkpoints. Phase 1b trial of biweekly intravenous Pexa-Vec JX , an oncolytic and immunotherapeutic vaccinia virus in colorectal cancer.

Seroprevalence of herpes simplex virus types 1 and 2—United States, J Infect Dis. Systemic therapy of malignant human melanoma tumors by a common cold-producing enterovirus, coxsackievirus a Type B coxsackieviruses and their interactions with the innate and adaptive immune systems. Future Microbiol. A retroviral replicating vector encoding cytosine deaminase and 5-FC induces immune memory in metastatic colorectal cancer models.

Mol Ther Oncolytics. Design and selection of Toca for clinical use: modified retroviral replicating vector with improved stability and gene expression. Toca plus 5-fluorocytosine in combination with lomustine shows chemotoxic and immunotherapeutic activity with no additive toxicity in rodent glioblastoma models.

Neuro Oncol. Going viral with cancer immunotherapy. Nat Rev Cancer. Viruses as anticancer drugs. The case of oncolytic viruses versus the immune system: waiting on the judgment of Solomon. Oncolytic viruses. Adv Virol. J Exp Med. Oncolytic vaccinia virus disrupts tumor-associated vasculature in humans. Targeted inflammation during oncolytic virus therapy severely compromises tumor blood flow.

Jiang H, Fueyo J. Healing after death: antitumor immunity induced by oncolytic adenoviral therapy. Antitumor benefits of antiviral immunity: an underappreciated aspect of oncolytic virotherapies. Trends Immunol. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. Pure E, Lo A. Can targeting stroma pave the way to enhanced antitumor immunity and immunotherapy of solid tumors? Cancer Immunol Res. Lighting a fire in the tumor microenvironment using oncolytic immunotherapy.

Dolgin E. Oncolytic viruses get a boost with first FDA-approval recommendation. Complement inhibition prevents oncolytic vaccinia virus neutralization in immune humans and cynomolgus macaques.

Patient-derived mesenchymal stem cells as delivery vehicles for oncolytic virotherapy: novel state-of-the-art technology. Carrier cell-based delivery of an oncolytic virus circumvents antiviral immunity. Systemic administration of human mesenchymal stromal cells infected with polymer-coated oncolytic adenovirus induces efficient pancreatic tumor homing and infiltration.

J Control Release. Targeted release of oncolytic measles virus by blood outgrowth endothelial cells in situ inhibits orthotopic gliomas. Can the viruses kill tumors faster than the body's immune system kills the viruses?

If the viruses fall short, giving drugs to suppress B cells, or using multiple different oncolytic viruses in succession, are possible solutions. Safety concerns about virulent strains arising during viral replication in tumors have not entirely disappeared. Nor has the memory of the massive immune and inflammatory reaction that killed Pennsylvania teenager Jesse Gelsinger in a gene therapy trial using an adenoviral vector.

But recent human oncolytic virus trials have shown consistent safety, with most unable to even reach the maximum tolerated dose. Immune and inflammatory responses, Bell pointed out, are monitored especially closely, with at least one company using small doses of virus to desensitize patients to side effects before administering the therapeutic dose. With the success in China, the newer viruses will have more chances to prove their worth in the clinic. Oxford University Press is a department of the University of Oxford.

It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In.

Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Virus Interruptus. Final Judgment. A Rebounding Field. Overcoming Obstacles. Ken Garber Ken Garber. Oxford Academic. In situ hybridization experiments demonstrated spread of virus replication throughout the tumour, beginning in focal areas near blood vessels Heise et al, b.

However, complete remissions occurred in only a small number of tumours. The reduced efficacy of ONYX given systemically could be the result of a number factors including deficient adenovirus receptor expression, extensive removal of virus by hepatic up-take, and effects of the immune system despite the impaired immunity.

These issues will be discussed in the context of clinical studies below. Nevertheless, the anti-tumour efficacy of systemically administered ONYX was dramatically improved when the virus was combined with the chemotherapeutic agent 5-FU. Based on the encouraging preclinical experience with ONYX, clinical trials have been initiated in patients with squamous carcinomas of the head and neck HNSCC , and pancreatic cancer. Additional studies were performed in patients with premalignant oral dysplasia, ovarian cancer, and liver metastases from colorectal cancer Figure 2.

As these studies have not been published in peer-reviewed journals yet, they will not be discussed in this review. Abdominal CT-scans from a patient with liver metastases from colorectal cancer who received infusions of ONYX into the hepatic artery in combination with 5-FU and Leucovorin i. In all cases, escalation of the virus dose was possible without that a dose-limiting toxicity was observed and the maximum virus dose that could be administered was based on manufacturing capabilities Ganly et al, ; Mulvihill et al, The spectrum of side effects was similar: Most frequently observed were fever, nausea, chills, and a flu-like syndrome Table 1.

No significant liver toxicity occurred and there were no signs of disseminated intravascular coagulation. Based on these results, intratumoural injection of ONYX appears to be safe.

While detection of viral DNA using in situ hybridization technology revealed evidence of intratumoural virus replication in four tumour biopsies that all harboured mutant p53, no statistically significant correlation between pstatus and tumour response could be established.

It should be noted, however, that these biopsies were obtained on day eight following injection of the virus, demonstrating prolonged intratumoural replication of ONYX In the same study, the humoural immune response to virus injection was assessed. However, the presence of pre-existing antibodies did not correlate with tumour response. This finding agrees with the experience using non-replicating adenoviruses for the delivery of p53 into tumour cells, where a correlation between neutralizing antibodies and transgene delivery could not be established Clayman et al, As a consequence of the animal studies described above, which had shown that sequential doses of virus are superior to single applications, two dosing regimens were examined.

The therapy consisted either of intratumoural injection for five days standard regimen or twice daily for two consecutive weeks hyperfractionated regimen. Main side effects were mild to moderate fever and pain at the site of injection; the latter was particularly frequent in patients receiving hyper fractionated therapy.

There were no significant differences in therapeutic activity between the treatment schedules. The number of patients with detectable virus declined significantly in subsequent cycles. In parallel, serum levels of neutralizing antibodies increased dramatically mean titer at baseline, ; titer after cycle 1, It is most likely that such high titers of neutralizing antibodies will contribute to a rapid clearance of virus particles shed from the tumours into the peripheral blood.

To what extent antibodies interfere with intratumoural virus spread is unclear at this time. Nevertheless, this study demonstrated again the favourable toxicity profile of ONYX and showed unambiguously the anti-tumour activity of the virus in a subset of patients, in particular those with a mutated p53 gene. As discussed above, preclinical studies suggested a potential synergistic effect of chemotherapy and ONYX The results mirrored the preclinical data, including the frequent occurrence of complete remissions.

Most interestingly, none of the 19 tumours that had shown objective responses progressed during the observation time of this study. In patients with multiple lesions, only the largest and clinically most relevant tumour had been injected, so that the other tumours served as intra-patient controls.

Despite the fact that the injected tumours were generally larger, nine of 11 responded, in contrast to three of 11 non-injected tumours. This statistically significant difference represents one of most convincing pieces of evidence for a specific anti-tumour effect of ONYX Encouraged by these results, a clinical phase-III study has been initiated and is ongoing; patients with first relapse of HNSCC are receiving either combined cisplatin-based chemotherapy and intratumourally injected ONYX or standard chemotherapy.

Intravenous administration of ONYX has been explored in a pilot study of advanced lung tumours Nemunaitis et al, The main side effects included, again, fever and rigours. In contrast to the previous study, however, a transient, dose-dependent increase of serum aminotransferase was also observed.

In the context of recent concerns regarding the safety of adenovirus vectors, it is important to note that these changes were mild maximal four-fold increase of serum ALT In one patient, intratumoural virus replication was documented although no objective tumour responses were observed.

The reasons for a potential lower efficacy of systemic administration of ONYX, relative to tumour injection, will be discussed below. It is well documented in animal models that hepatic uptake of systemically injected adenovirus is efficient, reducing the number of infectious virus particles significantly that may reach the target tumour Fechner et al, Another factor is the frequent presence of pre-existing neutralizing antibodies against adenovirus. In the clinical studies with ONYX, the majority of patients presented with neutralizing antibodies and almost all showed a dramatic increase in antibody following the first virus injection.

It has been demonstrated that anti-adenovirus antibodies are important inhibitors of antitumour activity of systemically administered adenoviruses and it has been proposed to use methods such as immunoapheresis to remove these antibodies from the circulation before initiation of treatment Chen et al, Our knowledge about possible mechanisms that are contributing to resistance of target cells against virus infection is still limited. Nevertheless, it is evident that adenovirus-based therapies depend critically on the ability of the virus to enter target cells, a process for which the recently identified Coxsackie- and Adenovirus Receptor CAR is most important as it mediates the attachment of the adenovirus fiber protein to the cell surface Bergelson et al, Recent reports as well as our own experience indicate that CAR expression is frequently lost or reduced in highly malignant tumours Li et al, Taken together, these mechanisms potentially diminish the amount of virus available to target cells, notably in the context of systemically administered virus.

In addition, intercellular barriers, including tissue stroma containing collagen fibers and CAR-negative fibroblasts and necrotic areas within the tumour, could limit the spread of ONYX within a tumour. At this point it is unclear, whether pro-inflammatory cytokines, including IL-2 and TNF are inhibiting or promoting viral spread. Equally uncertain is the contribution of T cells. It is therefore conceivable that the recognition of adenovirus antigens leads to elimination of infected cells before production of ONYX is sufficient for successfully infecting neighboring cells.

However, it is also possible that the co-presentation of tumour- and viral antigens triggers an immune response against tumour cells, in which case ONYX would promote vaccination against tumour antigens. These questions are a subject of current studies.

Nevertheless, mathematical models of virus replication in an immune-competent host suggest that the immune-response to ONYX could play a decisive role for the success of this treatment Wodarz, This is supported by recent studies illustrating a balance between growth of xenograft tumours in mice and replication of wild-type adenovirus, resulting in detection of replicating virus days following infection without reduction of the tumour mass Harrison et al, The results from the clinical phase-III study in HNSCC will be available in the first half of the year and will have a crucial impact on the further development of this therapeutic approach.

In addition, future studies of ONYX might include new strategies to overcome the limitations described above. These include the design of replication-restricted viruses with altered receptor specificity, capable of circumventing the problem of loss of expression of adenovirus receptors on target cells, in particular CAR, by utilizing other, cancer specific proteins as alternate receptors.

We are currently investigating the possibility of pharmacological restoration of CAR expression at the surface of cancer cells Anders et al , manuscript in preparation. To overcome the need to infect all tumour cells to achieve complete remission, new versions of ONYX have been created that deliver pro-drug converting enzymes to tumour cells, which create high local concentrations of cytotoxic compounds following systemic administration of non-toxic substrates. For example, an E1B55K-deleted adenovirus has been devised, expressing herpes simplex virus-thymidine kinase HCV-TK , which catalyzes phosphorylation of gancyclovir resulting in highly cytotoxic metabolites Wildner and Morris, ONYX is an interesting new agent for the treatment of solid tumours that shows unambiguous evidence of antitumour activity in a broader range of tumours than initially anticipated.

However, the biological mechanisms defining the interaction of this virus with its human host need further exploration. Arulanandam et al. In their study, activated vascular endothelial growth factor receptor 2 VEGFR2 signaling within tumor endothelial cells upregulated the transcriptional repressor, positive regulatory domain I—binding factor 1 PRD-BF1 , which suppresses genes involved in type I interferon-mediated anti-viral activity, thereby making tumor vessels sensitive to OV infection [ 30 ].

In turn, CAFs dampen the anti-viral response within tumor cells by secreting high levels of fibroblast growth factor 2 FGF2. Therefore, cellular crosstalk between CAFs and tumor cells promotes OV growth and killing in both cell types [ 31 ]. Over the past two decades, OV therapeutics have grown very rapidly with the advancement of molecular biology, virology, immunology, and genetic engineering [ 32 ].

Table 1 summarizes the OVs currently in development and their associated genetic modifications [ 33 ]. Oncolytic viruses OVs under development modified from Eissa et al. Melanoma is one of the most sensitive types of malignancy for cancer immunotherapy. T-VEC demonstrated its clinical efficacy in patients with melanoma and has inaugurated the era of oncolytic virotherapy.

T-VEC is the first FDA-approved oncolytic herpesvirus, genetically modified to selectively replicate within tumor cells and to increase tumor antigen presentation by dendritic cells through granulocyte-macrophage colony-stimulating factor GM-CSF transgene expression [ 16 ].

HSV-1 is a double-stranded DNA virus, inherently highly lytic, which can infect skin and peripheral nerves, thereby causing recurrent fever blisters such as skin vesicles or mucosal ulcers under high-stress conditions [ 52 ].

T-VEC has been engineered to avoid the development of fever blisters by deleting the neurovirulence gene, infected cell protein Moreover, it uses surface nectins to selectively penetrate tumor cells and proliferate within by using disrupted oncogenic and anti-viral pathways such as protein kinase R PKR and type I interferon IFN pathways [ 53 ].

The medial overall survival OS was The anti-tumor effects of OVs have been investigated in other malignancies as well. Malignant gliomas are highly aggressive primary brain tumors. Because statistical significance was higher than the criteria of early termination, the study was terminated early, and a further pivotal trial is now under development [ 55 ].

Pancreatic cancer remains one of those with the poorest prognosis and major causes of cancer-related deaths worldwide [ 56 ]. Its poor prognosis is related to its unique TME, which is poorly immunogenic with very low expression of tumor neoantigens, thus limiting anti-cancer immune responses.

Even worse, the TME of pancreatic cancer is enriched with immunosuppressive stromal cells and has a very dense fibrotic extracellular matrix ECM , which acts as a biophysical barrier disturbing intratumoral delivery of anti-cancer drugs and immune cells.

These factors suppress the anti-tumor effects of both chemotherapy and immunotherapy in patients with pancreatic cancer [ 57 , 58 , 59 ]. To overcome these unfavorable TMEs in pancreatic cancer, several OVs have been investigated in preclinical in vivo models, and some OVs are already under development in phase I and II clinical trials.

An oncolytic adenovirus, OBP, expressing tumor suppressor p53, significantly suppressed tumor growth in an orthotropic xenograft model of pancreatic cancer by disruption of extracellular signal regulated kinase ERK signaling [ 60 ].

Breast cancer is the most commonly diagnosed cancer among women. Despite recent advances in molecularly targeted therapies, there are still treatment-resistant cases; thus, OVs have become new therapeutic options against these intractable breast cancers. Various types of OVs have been investigated in patients with breast cancer. Because OVs as single agents showed limited efficacy in clinical trials [ 33 ], a combination of OVs with other anti-cancer agents is being tested to overcome this limitation.

Among various agents, the combination of OV with immunotherapeutic agents, especially ICI, has been extensively studied because OV is a natural activator of both innate and adaptive immunity. Immune checkpoint blockade has revolutionized the therapeutic landscape of advanced cancer over the last decade.

ICIs are monoclonal antibodies that block immune checkpoint proteins, such as PD-1, PD-L1, or CTLA-4, which are natural brakes of the immune system, from interacting with their binding partners [ 19 , 62 ].

This interrupts the immunologic shutdown signal being sent to T cells so that they can recognize and attack tumor cells [ 8 , 15 ]. OV can increase tumor immunogenicity by acting as an in situ cancer vaccine and promote intratumoral T cell infiltration, serving as an ideal immunologic platform to potentiate and expand the anti-tumor efficacy of ICIs [ 5 , 24 ].

Combinations of ICIs with either unmodified or modified OVs armed with cytokines and chemokines have demonstrated promising therapeutic efficacies for metastatic or unresectable tumors [ 6 , 64 , 65 ]. T-VEC is leading this promising combination immunotherapy. The combo arm showed a significantly higher objective response rate compared to ipi monotherapy The median progression-free survival was Therefore, the T-VEC plus ipi combo showed remarkable tumor burden reduction and durable activity in patients with melanoma [ 66 ].

Current clinical trials of combination therapy with OVs and immune checkpoint inhibitors modified from Tao et al. In a phase Ib trial for patients with advanced melanoma, 21 patients were treated with T-VEC followed by combination therapy with pembrolizumab.

This combination therapy was well tolerated and showed no dose-limiting toxicities. On the basis of tolerable safety for intrahepatic injection of T-VEC [ 67 ], a phase Ib trial of intrahepatic T-VEC injection in combination with intravenous pembrolizumab assessed the maximum tolerated concentration MTC in patients with progressive hepatocellular carcinoma HCC , breast cancer, colorectal cancer, gastroesophageal cancer, melanoma, non-small cell lung cancer, or renal cell cancer with liver metastasis and reported MTC and tolerability in an American Society of Clinical Oncology ASCO meeting [ 68 ].

There were no fatal adverse events. Thus, intrahepatic injection of T-VEC in combination with intravenous anti-PD-1 therapy has demonstrated feasibility and tolerability.

Thus, ONCOS, in combination with ICIs, are being tested for advanced solid malignancies such as prostate cancer, melanoma, and peritoneal cancers in clinical trials Table 1 and Table 2.

The overall response and disease control rates in 16 evaluable patients were Overall, 12 out of adverse events 5. Thus, IV Pexa-Vec and cemiplimab combination therapy showed an acceptable safety profile in patients with renal cell carcinoma.

Further investigation is ongoing with an expansion cohort and another cohort with intratumoral Pexa-Vec and cemiplimab combination therapy. After amplification in the laboratory, these CAR-T cells are administered intravenously to the patient with cancer. Moreover, Park et al.

These preclinical studies suggest the promising potential of this combination therapeutic strategy for cancer treatment. Bispecific antibodies are a novel class of anti-tumor agents that simultaneously target two different types of antigens or epitopes by combining two antibodies [ 73 ]. Bispecific T cell engagers BiTEs are a subclass of bispecific antibodies that have specific antibodies for CD3 on one arm and another specific antibody for a tumor antigen on the second arm [ 74 ].

BiTE applications in solid tumors have shown some limitations, such as low tumor penetration and off-target effects [ 8 ]. To overcome these limitations, the combination of BiTEs and OVs has been evaluated and displayed promising results [ 76 , 77 ]. Fajardo et al. This new cBiTE-expressing adenovirus increased the accumulation and persistence of tumor-infiltrating T cells in human lung and colon cancer xenograft mouse models [ 76 ]. Wing et al. Recently, tri-specific killer cell engagers TriKEs have also been developed.

Eric Vivier et al. They demonstrated that this trifunctional antibody significantly decreased tumor size and improved survival in a Raji B lymphoma xenograft mouse model [ 79 ].

Although OVs can induce anti-tumor immunity through multiple mechanisms and serve as an ideal platform for combination immunotherapy, there are still many issues to be solved to optimize OV-based immunotherapy. These include viral species, delivery platforms, intratumoral viral spread, and dosing strategies [ 5 , 8 , 27 ]. In addition, anti-viral immunity in the host immune system is continuously trying to clear OVs within the TME [ 80 ]. Here, we summarize the barriers of oncolytic virotherapy and discuss how to overcome these hurdles to translate OV more feasibly into clinical practice.

A variety of viral species have been developed as OVs. Because different kinds of viruses have diverse sizes, shapes, genetic materials, and pathogenicity, understanding the unique biological characteristics of OVs is an essential step for developing the most effective anti-tumor oncolytic virotherapy [ 3 , 27 ].

For example, the size of the virus within the TME matters; smaller viruses infiltrate and spread more easily within tumors, while larger viruses have larger genomes allowing a greater number of therapeutic genes to be inserted [ 27 ]. Moreover, RNA viruses can replicate within the cytoplasm, but DNA viruses must enter the nuclei of the target cells to replicate. These differences indicate that RNA viruses exert anti-tumor effects faster and are less selective with regards to tumors compared to DNA viruses.

The presence of a viral capsid is also an important factor in OV development because enveloped viruses are less oncolytic and can be more easily cleared by the host immune system [ 27 ].

OVs can be delivered locally mainly intratumorally or systemically mainly intravenously. Local intratumoral injection is the most common route of administration; intratumoral delivery maximizes the concentration of OVs at target tumor lesions while minimizing systemic toxicity [ 27 , 82 , 83 ]. However, this method cannot be applied to inaccessible or multifocal tumors. Furthermore, viable tumor cells at the OV injection site are essential for viral transfection and immune cell recruitment.

In addition, treatment efficacy can vary depending on the skill level of the operator [ 83 ]. On the other hand, theoretically, systemic administration is an ideal delivery route because it is minimally invasive and highly repeatable, covering both primary and metastatic tumors. However, viral particles can be cleared rapidly by the host immune system, including neutralizing antibodies. To avoid this issue, envelope modification and the development of novel delivery systems using MDSCs as viral carriers have been explored as a means to deliver OVs to tumor sites [ 82 ].

New delivery platforms have also improved the therapeutic effects of OVs. Usually, viral particles are rapidly degraded by the host immune system. Various agents such as nanoparticles, liposomes, polyethylene glycol, and polymeric particles have been used to deliver OVs from the systemic circulation to the local TME [ 84 , 85 ]. Magnetic drug targeted systems have also become a promising carrier system to effectively deliver viruses to tumor cells [ 86 ].

Therefore, finding the optimal route of administration and enhancing the homing of OVs to tumor sites is pivotal for improving anti-tumor efficacy. The intratumoral distribution of OV within the TME is also a critical factor that determines its anti-tumor efficacy. Besides the aforementioned virus size and envelope type, a dense ECM within tumors serves as a physical barrier to intratumoral OV infiltration and diffusion [ 27 , 28 , 83 ].

To overcome this barrier, new OVs with specific enzymes capable of ECM degradation have been generated and have shown significant anti-tumor effects in preclinical studies [ 87 , 88 ].

For example, relaxin is a peptide hormone that can inhibit interstitial collagen synthesis and upregulate collagenase expression. Oncolytic adenoviruses expressing relaxin YDC show potent anti-tumor effects in pancreatic tumor xenograft mice [ 87 ].

Moreover, Guedan et al. Thus, ICOVIR17 showed enhanced intratumoral spread, better viral distribution, and more potent anti-tumor effect compared to the parental virus [ 89 ]. OV clearance through anti-viral immunity can also limit OV-induced anti-tumor efficacy [ 25 , 82 ]. There are many cases where anti-viral immunity already exists because most OVs used in anti-cancer therapy are human pathogens that are abundant in the environment.

Moreover, repeated OV administration not only induces anti-tumor immunity but also triggers anti-viral immunity [ 82 , 90 ]. Anti-viral immunity can suppress viral replication, facilitate viral clearance, and attenuate anti-tumor activity in immunocompetent patients [ 25 , 82 ]. For example, neutralizing antibodies against Vaccinia virus target H3L envelope protein and interrupt viral-host fusion [ 91 ].

In the case of adenovirus, pre-existing neutralizing antibodies reduced the anti-tumor efficacy of oncolytic adenovirus [ 90 ]. Furthermore, T-VEC administration is limited to intratumoral injection because of high anti-HSV-1 antibody prevalence in humans [ 90 , 92 ]. In addition to pre-existing neutralizing antibodies, anti-viral immunity can also be mediated by the complement system, anti-viral cytokines, and non-specific uptake by off-target organs [ 82 ].

Therefore, to tackle anti-viral immunity, multiple strategies, including genetic manipulation of OV, cytokines, immunomodulators, nanoparticles, and the depletion of neutralizing antibodies, have been explored [ 82 , 83 , 90 ].

On the other hand, there are several conflicting reports suggesting anti-viral immunity could sometimes be beneficial for anti-tumor immunity because anti-viral immunity can recruit anti-tumor immune cells into the TME and reverse the immunosuppressive TME [ 5 , 27 ].