Advances in the therapeutic study of oncolytic virus in colorectal cancer

Colorectal cancer(CRC)represents a considerable global health challenge,ranking third in incidence and second in mortality worldwide.However,existing therapies for diseases with advanced stages often fail,thereby necessitating the search for more comprehensive treatments.Oncolytic virus,a novel anticancer approach,exhibits promising capabilities in selectively targeting and destroying tumor cells while augmenting their efficacy through genetic engineering modifications.Anticipated as a new therapeutic paradigm for CRC,this study aimed to assess the performance of oncolytic virus in clinical trials and explore their potential synergies with other therapeutic modalities,offering insights into the future direction of CRC treatment.

Oncolytic virus-based hepatocellular carcinoma treatment:Current status,intravenous delivery strategies,and emerging combination therapeutic solutions

Current treatments for advanced hepatocellular carcinoma(HCC)have limited success in improving patients’quality of life and prolonging life expectancy.The clinical need for more efficient and safe therapies has contributed to the exploration of emerging strategies.Recently,there has been increased interest in oncolytic viruses(OVs)as a therapeutic modality for HCC.OVs undergo selective replication in cancerous tissues and kill tumor cells.Strikingly,pexastimogene devacirepvec(Pexa-Vec)was granted an orphan drug status in HCC by the U.S.Food and Drug Administration(FDA)in 2013.Meanwhile,dozens of OVs are being tested in HCC-directed clinical and preclinical trials.In this review,the pathogenesis and current therapies of HCC are outlined.Next,we summarize multiple OVs as single therapeutic agents for the treatment of HCC,which have demonstrated certain efficacy and lowtoxicity.Emerging carrier cell-,bioengineered cell mimetic-or nonbiological vehicle-mediated OV intravenous delivery systems in HCC therapy are described.In addition,we highlight the combination treatments between oncolytic virotherapy and other modalities.Finally,the clinical challenges and prospects of OV-based biotherapy are discussed,with the aim of continuing to develop a fascinating approach in HCC patients.

Progress in oncolytic viruses modified with nanomaterials for intravenous application

In oncolytic virus(OV)therapy,a critical component of tumor immunotherapy,viruses selectively infect,replicate within,and eventually destroy tumor cells.Simultaneously,this therapy activates immune responses and mobilizes immune cells,thereby eliminating residual or distant cancer cells.However,because of OVs’high immunogenicity and immune clearance during circulation,their clinical applications are currently limited to intratumoral injections,and their use is severely restricted.In recent years,numerous studies have used nanomaterials to modify OVs to decrease virulence and increase safety for intravenous injection.The most commonly used nanomaterials for modifying OVs are liposomes,polymers,and albumin,because of their biosafety,practicability,and effectiveness.The aim of this review is to summarize progress in the use of these nanomaterials in preclinical experiments to modify OVs and to discuss the challenges encountered from basic research to clinical application.

Oncolytic virus therapy in cancer: A current review

In view of the advancement in the understanding about the most diverse types of cancer and consequently a relentless search for a cure and increased survival rates of cancer patients,finding a therapy that is able to combat the mechanism of aggression of this disease is extremely important.Thus,oncolytic viruses(OVs)have demonstrated great benefits in the treatment of cancer because it mediates antitumor effects in several ways.Viruses can be used to infect cancer cells,especially over normal cells,to present tumor-associated antigens,to activate“danger signals”that generate a less immune-tolerant tumor microenvironment,and to serve transduction vehicles for expression of inflammatory and immunomodulatory cytokines.The success of therapies using OVs was initially demonstrated by the use of the genetically modified herpes virus,talimogene laherparepvec,for the treatment of melanoma.At this time,several OVs are being studied as a potential treatment for cancer in clinical trials.However,it is necessary to be aware of the safety and possible adverse effects of this therapy;after all,an effective treatment for cancer should promote regression,attack the tumor,and in the meantime induce minimal systemic repercussions.In this manuscript,we will present a current review of the mechanism of action of OVs,main clinical uses,updates,and future perspectives on this treatment.

Pharmacokinetic enhancement of oncolytic virus M1 by inhibiting JAK-STAT pathway

Oncolytic viruses(OVs),a group of replication-competent viruses that can selectively infect and kill cancer cells while leaving healthy cells intact,are emerging as promising living anticancer agents.Unlike traditional drugs composed of non-replicating compounds or biomolecules,the replicative nature of viruses confer unique pharmacokinetic properties that require further studies.Despite some pharmacokinetics studies of OVs,mechanistic insights into the connection between OV pharmacokinetics and antitumor efficacy remain vague.Here,we characterized the pharmacokinetic profile of oncolytic virus M1(OVM)in immunocompetent mouse tumor models and identified the JAK-STAT pathway as a key modulator of OVM pharmacokinetics.By suppressing the JAK-STAT pathway,early OVM pharmacokinetics are ameliorated,leading to enhanced tumor-specific viral accumulation,increased AUC and Cmax,and improved antitumor efficacy.Rather than compromising antitumor immunity after JAK-STAT inhibition,the improved pharmacokinetics of OVM promotes T cell recruitment and activation in the tumor microenvironment,providing an optimal opportunity for the therapeutic outcome of immune checkpoint blockade,such as anti-PD-L1.Taken together,this study advances our understanding of the pharmacokinetic-pharmacodynamic relationship in OV therapy.

Immune landscape and response to oncolytic virus-based immunotherapy

Oncolytic virus(OV)-based immunotherapy has emerged as a promising strategy for cancer treatment,offering a unique potential to selectively target malignant cells while sparing normal tissues.However,the immunosuppressive nature of tumor microenvironment(TME)poses a substantial hurdle to the development of OVs as effective immunotherapeutic agents,as it restricts the activation and recruitment of immune cells.This review elucidates the potential of OV-based immunotherapy in modulating the immune landscape within the TME to overcome immune resistance and enhance antitumor immune responses.We examine the role of OVs in targeting specific immune cell populations,including dendritic cells,T cells,natural killer cells,and macrophages,and their ability to alter the TME by inhibiting angiogenesis and reducing tumor fibrosis.Additionally,we explore strategies to optimize OV-based drug delivery and improve the efficiency of OV-mediated immunotherapy.In conclusion,this review offers a concise and comprehensive synopsis of the current status and future prospects of OV-based immunotherapy,underscoring its remarkable potential as an effective immunotherapeutic agent for cancer treatment.

Oncolytic Virus Senecavirus A Inhibits Hepatocellular Carcinoma Proliferation and Growth by Inducing Cell Cycle Arrest and Apoptosis

Background and Aims:Hepatocellular carcinoma(HCC)isa highly aggressive tumor with limited treatment options andhigh mortality.Senecavirus A(SVA)has shown potential inselectively targeting tumors while sparing healthy tissues.This study aimed to investigate the effects of SVA on HCCcells in vitro and in vivo and to elucidate its mechanisms ofaction.Methods:The cell counting kit-8 assay and colonyformation assay were conducted to examine cell proliferation.Flow cytometry and nuclear staining were employed toanalyze cell cycle distribution and apoptosis occurrence.Asubcutaneous tumor xenograft HCC mouse model was createdin vivo using HepG2 cells,and Ki67 expression in thetumor tissues was assessed.The terminal deoxynucleotidyltransferase dUTP nick end labeling assay and hematoxylinand eosin staining were employed to evaluate HCC apoptosisand the toxicity of SVA on mouse organs.Results:In vitro,SVA effectively suppressed the growth of tumor cells by inducingapoptosis and cell cycle arrest.However,it did nothave a notable effect on normal hepatocytes(MIHA cells).In an in vivo setting,SVA effectively suppressed the growthof HCC in a mouse model.SVA treatment resulted in a significantdecrease in Ki67 expression and an increase in apoptosisof tumor cells.No notable histopathological alterationswere observed in the organs of mice during SVA administration.Conclusions:SVA inhibits the growth of HCC cells byinducing cell cycle arrest and apoptosis.It does not causeany noticeable toxicity to vital organs.

Therapeutic potential of oncolytic viruses in the era of precision oncology

Oncolytic virus(OV)therapy has been shown to be an effective targeted cancer therapy treatment in recent years,providing an avenue of treatment that poses no damage to surrounding healthy tissues.Not only do OVs cause direct oncolysis,but they also amplify both innate and adaptive immune responses generating long-term anti-tumour immunity.Genetically engineered OVs have become the common promising strategy to enhance anti-tumour immunity,safety,and efficacy as well as targeted delivery.The studies of various OVs have been accomplished through phase I-III clinical trial studies.In addition,the uses of carrier platforms of organic materials such as polymer chains,liposomes,hydrogels,and cell carriers have played a vital role in the potentially targeted delivery of OVs.The mechanism,rational design,recent clinical trials,applications,and the development of targeted delivery platforms of OVs will be discussed in this review.

Polymer-based synthetic oncolytic virus-like nanoparticles for cancer immunotherapy

Oncolytic viruses have emerged as new powerful therapeutic agents for cancer therapy by specifically lysing cancer cells while activating innate immune responses at the same time.However,due to the thorny issues of safety concerns and host immune reaction,the clinical application of oncolytic viruses is still limited.Herein,we report a rationally designed oncolytic virus-like nanoparticles(OV-NPs)composed of stimulator of interferon genes(STING)-stimulating polymer loaded with therapeutic genes for cancer immunotherapy.After injection into tumor,the OV-NPs carrying OX40L plasmid could reprogram tumor cells to express OX40L immune checkpoint molecules and activate the STING pathway for cooperatively enhancing antitumor immunity,with a tumor suppression rate of 92.3%in B16F10 tumor model and 78.7%in MC38 tumor model without causing any toxicity.The OV-NPs could be further applied in carrying other plasmids(IL-12)and utilization in gene combination therapy.This study should inspire designing synthetic OV-NPs as alternative strategies for extending oncolytic virus application in cancer immunotherapy.

Preclinical and clinical trials of oncolytic vaccinia virus in cancer immunotherapy:a comprehensive review

Oncolytic virotherapy has emerged as a promising treatment for human cancers owing to an ability to elicit curative effects via systemic administration.Tumor cells often create an unfavorable immunosuppressive microenvironment that degrade viral structures and impede viral replication;however,recent studies have established that viruses altered via genetic modifications can serve as effective oncolytic agents to combat hostile tumor environments.Specifically,oncolytic vaccinia virus(OVV)has gained popularity owing to its safety,potential for systemic delivery,and large gene insertion capacity.This review highlights current research on the use of engineered mutated viruses and gene-armed OVVs to reverse the tumor microenvironment and enhance antitumor activity in vitro and in vivo,and provides an overview of ongoing clinical trials and combination therapies.In addition,we discuss the potential benefits and drawbacks of OVV as a cancer therapy,and explore different perspectives in this field.

Emerging systemic delivery strategies of oncolytic viruses:A key step toward cancer immunotherapy

Oncolytic virotherapy(OVT)is a novel type of immunotherapy that induces anti-tumor responses through selective self-replication within cancer cells and oncolytic virus(OV)-mediated immunostimulation.Notably,talimogene laherparepvec(T-Vec)developed by the Amgen company in 2015,is the first FDA-approved OV product to be administered via intratumoral injection and has been the most successful OVT treatment.However,the systemic administration of OVs still faces huge challenges,including in vivo pre-existing neutralizing antibodies and poor targeting delivery efficacy.Recently,state-of-the-art progress has been made in the development of systemic delivery of OVs,which demonstrates a promising step toward broadening the scope of cancer immunotherapy and improving the clinical efficacy of OV delivery.Herein,this review describes the general characteristics of OVs,focusing on the action mechanisms of OVs as well as the advantages and disadvantages of OVT.The emerging multiple systemic administration approaches of OVs are summarized in the past five years.In addition,the combination treatments between OVT and traditional therapies(chemotherapy,thermotherapy,immunotherapy,and radiotherapy,etc.)are highlighted.Last but not least,the future prospects and challenges of OVT are also discussed,with the aim of facilitating medical researchers to extensively apply the OVT in the cancer therapy.

Combining oncolytic virus and radiation therapy for cancer management

Cancer has caused a tremendous burden in developing countries.Oncolytic virus(OV)therapy is an emerging modality with the potential to be a single or combination agent with radiation therapy(RT).Following entry of OV to the cell,OV will replicate and assemble before exiting from tumor cells.Construction of OV can be done by modifying the capsid,genome,and chemical material of viruses.Irradiation will induce double-strand breaks,and further integration of OV with DNA damage response pathway will interact with the MRE11-Rad50-Nbs1 complex to regulate the mobilization of E4 open reading frame 6,protein phosphatase 2A,poly(ADP-ribose)polymerase,apoptosis-inducing factor,and topoisomerase-IIβ-binding protein 1.Degradation of DNA-dependent protein kinase catalytic subunits via human simplex virus-1-infected cell polypeptide 0 will inhibit DNA repair.OV and RT have a synergistic interaction to cause viral oncolysis and upregulation of immune response.In the clinical setting,most studies have demonstrated that OV is a safe treatment with less toxicity.Moreover,OV+RT resulted in longer median survival(62.4 vs.37.7 weeks)in malignant glioma.

Oncolytic Engineering of ICP34.5 and LAT of Herpes Simplex Virus Type 1

Oncolytic virus (OV) is a kind of virus that can preferentially infect and kill tumor cells. The second oncolytic virus drug was oncolytic herpes simplex virus (oHSV) Talimogene Laherparepvec (T-VEC). HSV-1 infectious cell culture protein 34.5 (ICP34.5) and latency-associated transcript (LAT) genes are closely related to virus selective infection and latent infection. Their engineering is essential for constructing efficient and safe oHSV. We summarized the mechanisms of ICP34.5 and LAT in the course of HSV-1 infection and reviewed the engineered oHSVs. We are aimed to provide an insight in developing oHSV in the future.

Novel Functional Motifs of the Cell Entry Glycoprotein D for Oncolytic Herpes Simplex Viruses

Background: Oncolytic herpes simplex virus (oHSV) have been proved effective and safe to treat tumors. Glycoprotein D (gD) has been engineered for targeting cancer cells and de-targeting normal cells successfully, however, the effectiveness and safety of oHSVs still need to be improved. Method: Here we sequenced the DNA encoding gD of our recently isolated new strain HSV-1-LXMW and compared the gD amino acid sequence with the gDs of other 7 HSV-1 and 3 HSV-2 strains. Results: Phylogenetic analysis revealed that HSV-1-LXMW is evolutionarily close to HSV-1-Patton and -KOS strains. The gD amino acid sequence alignment identified 19 conserved and 8 variable regions. We further predicted 10 new motifs in HSV gD for the first time and identified motif differences in HSV-1 and HSV-2. We summarized the gD-engineered oHSVs and found that some of the newly identified gD motifs are actually functional. Conclusion: Our results shed light on HSV gD biology and provided new directions for future gD functional studies and engineering in order to make better oHSVs.

Feasibility of herpes simplex virus type 1 mutants labeled with radionuclides for tumor treatment

For over one hundred years, viruses have been recognized as capable of killing tumor cells. At present, people are still researching and constructing more suitable oncolytic viruses for treating different malignant tumors. Although extensive studies have demonstrated that herpes simplex virus type 1 (HSV-1) is the most potential oncolytic virus, therapies based on herpes simplex virus type 1 vectors still arouse bio-safety and risk management issues. Researchers have therefore introduced the new idea of treating cancer with HSV-1 mutants labeled with radionuclides, combining radionuclide and oncolytic virus therapies. This overview briefly summarizes the status and mechanisms by which oncolytic viruses kill tumor cells, discusses the application of HSV-1 and HSV-1 derived vectors for tumor therapy, and demonstrates the feasibility and prospect of HSV-1 mutants labeled with radionuclides for treating tumors.

The antitumor effects of Newcastle disease virus on glioma

Glioma is the most common primary malignant brain tumor with a poor survival rate.In recent years,no significant progress has been made in the treatment of gliomas in contrast to the development of improved diagnosis via molecular typing.Newcastle disease virus(NDV),a negative-stranded RNA virus that exhibits oncolytic activity,has been investigated for its capacity to elicit antitumor activity in many types of cancers,including glioma.Therefore,application of oncolytic viruses,such as NDV,as a new treatment strategy to specifically target aberrant signaling in glioblastomas has brought new hope.For many years,NDV has been investigated for its in vivo and in vitro efficacy in the treatment of various tumor cells.Based on its safety in humans,specificity for tumor cells,and immunostimulatory properties,NDV represents a promising antitumor agent.In this review,we summarize the background of NDV and the antitumor mechanisms of NDV-mediated oncolysis,discuss the potential value and role of NDV in gliomas,and describe new advances and perspectives for future research.

Immunotherapy for advanced or recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is associated with high morbidity and mortality,and is prone to intra-and extrahepatic metastasis due to the anatomical and functional characteristics of the liver.Due to the complexity and high relapse rate associated with radical surgery or radiofrequency ablation,immune checkpoint inhibitors(ICIs)are increasingly being used to treat HCC.Several immunotherapeutic agents,along with their combinations,have been clinically approved to treat advanced or recurrent HCC.This review discusses the leading ICIs in practice and those currently undergoing randomized phase 1-3 trials as monotherapy or combination therapy.Furthermore,we summarize the rapidly developing alternative strategies such as chimeric antigen receptor-engineered T cell therapy and tumor vaccines.Combination therapy is a promising potential treatment option.These immunotherapies are also summarized in this review,which provides insights into the advantages,limitations,and novel angles for future research in establishing viable and alternative therapies against HCC.

Immunotherapy in glioblastoma treatment:Current state and future prospects

Glioblastoma remains as the most common and aggressive malignant brain tumor,standing with a poor prognosis and treatment prospective.Despite the aggressive standard care,such as surgical resection and chemoradiation,median survival rates are low.In this regard,immunotherapeutic strategies aim to become more attractive for glioblastoma,considering its recent advances and approaches.In this review,we provide an overview of the current status and progress in immunotherapy for glioblastoma,going through the fundamental knowledge on immune targeting to promising strategies,such as Chimeric antigen receptor T-Cell therapy,immune checkpoint inhibitors,cytokine-based treatment,oncolytic virus and vaccine-based techniques.At last,it is discussed innovative methods to overcome diverse challenges,and future perspectives in this area.

Role of homologous recombination/recombineering on human adenovirus genome engineering:Not the only but the most competent solution

Adenoviruses typically cause mild illnesses,but severe diseases may occur primarily in immunodeficient individuals,particularly children.Recently,adenoviruses have garnered significant interest as a versatile tool in gene therapy,tumor treatment,and vaccine vector development.Over the past two decades,the advent of recombineering,a method based on homologous recombination,has notably enhanced the utility of adenoviral vectors in therapeutic applications.This review summarizes recent advancements in the use of human adenoviral vectors in medicine and discusses the pivotal role of recombineering in the development of these vectors.Additionally,it highlights the current achievements and potential future impact of therapeutic adenoviral vectors.

Oncolytic herpes simplex virus vectors for the treatment of human breast cancer

Background Oncolytic herpes simplex virus (HSV) vectors can be used for cancer therapy as direct cytotoxic agents, inducers of anti-tumor immune responses, and as expressers of anti-cancer genes. In this study, the efficacy of HSV vectors, G47Delta and NV1023 were examined for the treatment of the human breast cancer. Methods Human breast cancer MDA-MB-435 cells were cultured or implanted subcutaneously in BALB/c nude mice. The cells or tumors were inoculated with G47Delta or NV1023, and cell killing or inhibition of tumor growth determined. Both viruses contained the LacZ gene and expression in infected cells was detected with X-gal histochemistry. Results G47Delta and NV1023 were highly cytotoxic to MDA-MB-435 cells in vitro at very low multiplicities of infection. X-gal staining of infected tumor cells in vitro and in vivo illustrated the replication and spread of both viruses. G47Delta and NV1023 inoculation inhibited tumor growth and prolonged mouse survival. Both vectors behaved similarly. Conclusions Oncolytic HSV vectors, G47Delta and NV1023, were extremely effective at killing human breast cancer cells in vitro and in tumor xenografts in vivo. This novel form of cancer therapy warrants further investigation and consideration of clinical application.