Interstitial hypertension and extracellular matrix(ECM)barriers imposed by cancer-associated fibroblasts(CAFs)at the tumor site significantly impede the retention of intratumorally administered oncolytic viruses(OVs)a...Interstitial hypertension and extracellular matrix(ECM)barriers imposed by cancer-associated fibroblasts(CAFs)at the tumor site significantly impede the retention of intratumorally administered oncolytic viruses(OVs)as well as their efficacy in infecting and eradicating tumor cells.Herein,a stable,controllable,and easily prepared hydrogel was developed for employing a differential release strategy to deliver OVs.The oncolytic herpes simplex virus-2(oH2)particles were loaded within sodium alginate(ALG),together with the small molecule drug PT-100 targeting CAFs.The rapid release of PT-100 functions as an anti-CAFs agent,reducing ECM,and alleviating interstitial pressure at the tumor site.Consequently,the delayed release of oH2 could more effectively invade and eradicate tumor cells while also facilitating enhanced infiltration of immune cells into the tumor microenvironment,thereby establishing an immunologically favorable milieu against tumors.This approach holds significant potential for achieving highly efficient oncolytic virus therapy with minimal toxicity,particularly in tumors rich in stromal components.展开更多
Though oncolytic viruses(OVs)hold significant potential for comprehensive treatment of malignant tumors,their systemic administration faces substantial challenges such as insufficient circulation time,inadequate tumor...Though oncolytic viruses(OVs)hold significant potential for comprehensive treatment of malignant tumors,their systemic administration faces substantial challenges such as insufficient circulation time,inadequate tumor targeting,and spontaneous antiviral immune response of the body,which seriously limits the clinical application of OVs.Herein,we proposed a tumor targeting strategy of tumor cell membrane biomimetic liposomes to encapsulate OVs for intravenous delivery,which enables OVs to target the homotypic tumor lesions and exert their oncolytic effect.On the one hand,this cell membrane biomimetic carrier enhanced the encapsulation of OVs by the hybrid lipid membranes,concealed the viral capsid proteins,and diminished the neutralization and clearance of the virions from the bloodstream.On the other hand,enhanced tumor targeted delivery can be achieved through the utilization of homologous adhesion molecules on the surface of tumor cell membrane.In addition,this strategy also promoted the tumor infiltration of CD4^(+),CD8^(+)T cells mediated by the oncolytic effect of OVs and increased the levels of inflammatory factors such as tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6)in the tumor,thereby effectively enhancing the anti-tumor effect of intravenous administration of OVs.The findings of our study demonstrate that T-L@Ad11 offers a handy and efficient approach for targeting tumors,thereby enhancing the antitumor efficacy of intravenous administration of OVs.展开更多
Liver cancer is the fifth most common cancer in the world,with China bearing a disproportionate burden of cases.Typically diagnosed at advanced stages,liver cancer often utilizes surgical treatments such as resection,...Liver cancer is the fifth most common cancer in the world,with China bearing a disproportionate burden of cases.Typically diagnosed at advanced stages,liver cancer often utilizes surgical treatments such as resection,transcatheter hepatic artery chemoembolization(TACE),and radiofrequency ablation.However,advancements in genetic engineering and tumor immunology have unveiled the distinct potential of targeted oncolytic virus therapy.Oncolytic virus,in particular,can selectively destroy tumor cells without harming normal cells,offering a promising avenue for liver cancer treatment through immune system activation,tumor microenvironment modulation,and other mechanisms.This review describes the mechanism of action of oncolytic viruses,the new development of several common oncolytic viruses,and the combination with traditional therapies,aiming to provide directions for the subsequent therapeutic research on hepatocellular carcinoma(HCC).展开更多
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 contr...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.展开更多
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 mobil...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.展开更多
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 ...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.展开更多
Oncolytic virotherapy(OVT)is a promising option for cancer treatment.OVT involves selective oncolytic virus(OV)replication within cancer cells,which triggers anti-tumor responses and immunostimulation.Despite promisin...Oncolytic virotherapy(OVT)is a promising option for cancer treatment.OVT involves selective oncolytic virus(OV)replication within cancer cells,which triggers anti-tumor responses and immunostimulation.Despite promising potential,OVT faces critical challenges,including insufficient tumor-specific targeting,which results in limited tumor penetration and variability in therapeutic efficacy.These challenges are particularly pronounced in solid tumors with complex microenvironments and heterogeneous vascularization.A comprehensive research program is currently underway to develop and refine innovative delivery methods to address these issues to enhance OVT precision and efficacy.A principal area of investigation is the utilization of cellular carriers to enhance the delivery and distribution of OVs within tumor microenvironments,thereby optimizing immune system activation and maximizing anti-tumor effects.This review offers a comprehensive overview of the current strategies that are being used to enhance the delivery of OVs via cellular carriers with the goal of improving the clinical impact of OVT in cancer therapy.展开更多
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 nece...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.展开更多
Objective To study related guidelines such as“Guidelines for Clinical Trial Design of Oncolytic Viruses”“Technical Guidelines for Non-clinical Research and Evaluation of Gene Therapy Products”and“Technical Guidel...Objective To study related guidelines such as“Guidelines for Clinical Trial Design of Oncolytic Viruses”“Technical Guidelines for Non-clinical Research and Evaluation of Gene Therapy Products”and“Technical Guidelines for Pharmacological Research and Evaluation of Oncolytic Viruses(OVs)Products”issued by the Center for Drug Evaluation(CDE)on OV and offer some suggestions for further improvement of the policies and regulations.Methods Literature comparison and questionnaire survey were used in this paper to investigate the difficulties encountered in the practical work of domestic companies that have conducted clinical trials,thus drawing some lessons to help the subsequent implementation of the guidelines.Results and Conclusion According to the characteristics of specific varieties and the published laws,regulations and guidelines,companies can adopt more suitable and scientific strategies to accelerate the development of anti-cancer drugs.In the future,as more clinical studies and product development for various cancers expand,regulatory requirements are expected to become more specialized and complex.Learning from the regulatory experience of developed countries and regions,we can improve the regulatory system by adapting it to national conditions and development status of China.Additionally,some ideas and useful inspirations can be provided after reviewing the content of the relevant guidelines and the obstacles in the practice of corporate R&D process can be addressed.These efforts will facilitate the speed of R&D and allow enterprises to work more smoothly and efficiently.展开更多
Oncolytic viruses(OVs),a kind of emerging therapeutics for treating tumors,are characterized by high replication efficiency,superior killing effects,and few adverse reactions,which have shown great application prospec...Oncolytic viruses(OVs),a kind of emerging therapeutics for treating tumors,are characterized by high replication efficiency,superior killing effects,and few adverse reactions,which have shown great application prospects in preclinical tumor treatment trials.To overcome the limitations of OV monotherapy,recent studies have found that combination therapy with other anti-tumor therapeutics,especially with immunotherapy,yields promising outcomes in tumor eradication.Due to the advancements in genetic engineering,the combination of OVs with novel immunotherapy,including cellular immunotherapy,adoptive cellular immunotherapy,immune checkpoint inhibitors,cancer vaccines,cytokines,and bi-or tri-specific T cell engagers,has greatly improved clinical outcomes and quality of life of tumor patients.In this review,we systematically summarize the latest progress of OVs combined with immunotherapy in tumor treatment and highlight the future directions of the combination strategies,which will promote the clinical application of OVs in tumor therapy.展开更多
Anoikis is a specialized form of programmed cell death triggered by the detachment of cells from the extracellular matrix(ECM).Tumor cells that develop resistance to anoikis acquire the ability to detach,migrate,and c...Anoikis is a specialized form of programmed cell death triggered by the detachment of cells from the extracellular matrix(ECM).Tumor cells that develop resistance to anoikis acquire the ability to detach,migrate,and colonize distant sites,ultimately leading to the formation of metastatic tumors.Bit1(Bcl-2 inhibitor of transcription 1),a key effector of anoikis,is released into the cytoplasm upon loss of cell attachment and activates a caspase-independent pathway of apoptosis.Newcastle disease virus(NDV),a pathogen that poses a significant threat to the poultry industry,has also emerged as a promising oncolytic virus capable of selectively targeting and killing tumor cells.However,whether NDV can induce the death of anoikis-resistant tumor cells by activating Bit1 remains unclear.In this study,we utilized physical methods to induce cell suspension as a positive control for anoikis and further examined the expression and cellular localization of Bit1 following NDV infection in tumor cells.The results indicated that both viral infection and cell suspension resulted in partial cell death,accompanied by the translocation of Bit1 from the mitochondria to the cytoplasm and a reduction in its protein levels.Notably,Bit1 expression was found not to significantly affect viral replication.These findings suggest that NDV infection promotes tumor cell death by activating Bit1 translocation,mirroring the effects observed during cell suspension-induced anoikis.In addition,in vivo experiments demonstrated that NDV effectively inhibits the metastasis and growth of melanoma in mice,and that overexpression of Bit1 in tumor cells accelerates this process.This study provides novel insights into NDV-induced tumor cell death and identifies potential targets for understanding the mechanisms of oncolytic virus action.展开更多
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...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.展开更多
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 sa...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.展开更多
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 immunosuppres...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.展开更多
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 traditiona...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.展开更多
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 ...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.展开更多
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...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.展开更多
Oncolytic alphavirus M1 has been shown to selectively target and kill cancer cells,but cytopathic morphologies induced by M1 virus and the life cycle of the M1 strain in cancer cells remain unclear.Here,we study the k...Oncolytic alphavirus M1 has been shown to selectively target and kill cancer cells,but cytopathic morphologies induced by M1 virus and the life cycle of the M1 strain in cancer cells remain unclear.Here,we study the key stages of M1 virus infection and replication in the M1 virus-sensitive HepG2 liver cancer cell line by transmission electron microscopy,specifically examining viral entry,assembly,maturation and release.We found that M1 virus induces vacuolization of cancer cells during infection and ultimately nuclear marginalization,a typical indicator of apoptosis.Specifically,our results suggest that the endoplasmic reticulum participates in the assembly of nucleocapsids.In the early and late stage of infection,three kinds of special cytopathic vacuoles are formed and appear to be involved in the replication,maturation and release of the virus.Taken together,our data displayed the process of M1 virus infection of tumor cells and provide the structural basis for the study of M1 virus-host interactions.展开更多
Oncolytic virus is an emerging anti-cancer strategy. However, extracellular matrix(ECM), as a physical barrier, limits virus spread within the tumor. To overcome the obstacle, we constructed a recombinant Newcastle di...Oncolytic virus is an emerging anti-cancer strategy. However, extracellular matrix(ECM), as a physical barrier, limits virus spread within the tumor. To overcome the obstacle, we constructed a recombinant Newcastle disease virus(NDV) expressing matrix metalloproteinase(MMP8)(NDV-MMP8) using with reverse genetic technology. In vitro, NDV-MMP8 was identified and verified by WB and ELISA. Cell viability was detected by CCK-8 assay. In vivo, we established two liver cancer xenograft models. NDV-MMP8 was injected into the tumor to observe the tumor volume and survival of mice. The changes in extracellular matrix were observed by Masson’s trichrome staining. Virus expression in tumor tissues was detected by immunofluorescence assay. The virus titer in tumor tissues was detected by TCID50. Histopathological changes were detected by hematoxylin and eosin(HE) and terminal deoxynucleotidyl transferase d UTP nick end labeling(TUNEL) staining. Intratumoral administration of NDV-MMP8 can effectively degrade ECM, promote the spread of the virus within the tumor, and reduce tumor growth rate. Therefore, the method of increasing intratumoral virus accumulation by degradation of the ECM to enhance the oncolytic effect has great potential for clinical application.展开更多
Oncolytic virus(OV)is increasingly being recognized as a novel vector in cancer immunotherapy.Increasing evidence suggests that OV has the ability to change the immune status of tumor microenvironment,so called transf...Oncolytic virus(OV)is increasingly being recognized as a novel vector in cancer immunotherapy.Increasing evidence suggests that OV has the ability to change the immune status of tumor microenvironment,so called transformation of‘cold’tumors into‘hot’tumors.The improved anti-tumor immunity can be induced by OV and further enhanced through the combination of various immunomodulators.The Neo-2/15 is a newly de novo synthesized cytokine that functions as both IL-2 and IL-15.However,it specifically lacks the binding site of IL-2 receptorαsubunit(CD25),therefore unable to induce the Treg proliferation.In present study,a recombinant vesicular stomatitis virus expressing the Neo-2/15(VSVM51R-Neo-2/15)was generated.Intratumoral delivery of VSVM51R-Neo-2/15 efficiently inhibited tumor growth in mice without causing the IL-2-related toxicity previously observed in clinic.Moreover,treatment with VSVM51R-Neo-2/15 increased the number of activated CD8t T cells but not Treg cells in tumors.More tumor-bearing mice were survival with VSVM51R-Neo-2/15 treatment,and the surviving mice displayed enhanced protection against tumor cell rechallenge due to the induced anti-tumor immunity.In addition,combination therapy of OV and anti-PD-L1 immune checkpoint inhibitors further enhanced the anti-tumor immune response.These findings suggest that our novel VSVM51R-Neo-2/15 can effectively inhibit the tumor growth and enhance the sensitivity to immune checkpoint inhibitors,providing promising attempts for further clinical trials.展开更多
基金supported by the National Key R&D Program of China(No.2022YFC2403401)the National Natural Science Foundation of China(Nos.82073368,82303766)+2 种基金the Liaoning Revitalization Talents Program(No.XLYC2007071)the China Postdoctoral Science Foundation(No.2023M743908)the Joint Program of Science and Technology Program of Liaoning Province(No.2023JH2/101700094).
文摘Interstitial hypertension and extracellular matrix(ECM)barriers imposed by cancer-associated fibroblasts(CAFs)at the tumor site significantly impede the retention of intratumorally administered oncolytic viruses(OVs)as well as their efficacy in infecting and eradicating tumor cells.Herein,a stable,controllable,and easily prepared hydrogel was developed for employing a differential release strategy to deliver OVs.The oncolytic herpes simplex virus-2(oH2)particles were loaded within sodium alginate(ALG),together with the small molecule drug PT-100 targeting CAFs.The rapid release of PT-100 functions as an anti-CAFs agent,reducing ECM,and alleviating interstitial pressure at the tumor site.Consequently,the delayed release of oH2 could more effectively invade and eradicate tumor cells while also facilitating enhanced infiltration of immune cells into the tumor microenvironment,thereby establishing an immunologically favorable milieu against tumors.This approach holds significant potential for achieving highly efficient oncolytic virus therapy with minimal toxicity,particularly in tumors rich in stromal components.
基金supported by the National Key R&D Program of China(No.2022YFC2403401)the National Natural Science Foundation of China(nos.82073368,82303766)+2 种基金the Liaoning Revitalization Talents Program(No.XLYC2007071)the China Postdoctoral Science Foundation(No.2023M743908)the Joint Program of Science and Technology Program of Liaoning Province(No.2023JH2/101700094).
文摘Though oncolytic viruses(OVs)hold significant potential for comprehensive treatment of malignant tumors,their systemic administration faces substantial challenges such as insufficient circulation time,inadequate tumor targeting,and spontaneous antiviral immune response of the body,which seriously limits the clinical application of OVs.Herein,we proposed a tumor targeting strategy of tumor cell membrane biomimetic liposomes to encapsulate OVs for intravenous delivery,which enables OVs to target the homotypic tumor lesions and exert their oncolytic effect.On the one hand,this cell membrane biomimetic carrier enhanced the encapsulation of OVs by the hybrid lipid membranes,concealed the viral capsid proteins,and diminished the neutralization and clearance of the virions from the bloodstream.On the other hand,enhanced tumor targeted delivery can be achieved through the utilization of homologous adhesion molecules on the surface of tumor cell membrane.In addition,this strategy also promoted the tumor infiltration of CD4^(+),CD8^(+)T cells mediated by the oncolytic effect of OVs and increased the levels of inflammatory factors such as tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6)in the tumor,thereby effectively enhancing the anti-tumor effect of intravenous administration of OVs.The findings of our study demonstrate that T-L@Ad11 offers a handy and efficient approach for targeting tumors,thereby enhancing the antitumor efficacy of intravenous administration of OVs.
基金the National Natural Science Foundation of China(No.82204447)National Key R&D Program of China,2021YFA0909800+2 种基金the Natural Science Foundation of Guangdong Province(No.2022A1515011056)the Guangzhou Science and Technology Plan Project(Nos.2024A04J4711,and 2023A03J0200)the Guangdong Basic and Applied Basic Research Foundation(2022B1515020056)。
文摘Liver cancer is the fifth most common cancer in the world,with China bearing a disproportionate burden of cases.Typically diagnosed at advanced stages,liver cancer often utilizes surgical treatments such as resection,transcatheter hepatic artery chemoembolization(TACE),and radiofrequency ablation.However,advancements in genetic engineering and tumor immunology have unveiled the distinct potential of targeted oncolytic virus therapy.Oncolytic virus,in particular,can selectively destroy tumor cells without harming normal cells,offering a promising avenue for liver cancer treatment through immune system activation,tumor microenvironment modulation,and other mechanisms.This review describes the mechanism of action of oncolytic viruses,the new development of several common oncolytic viruses,and the combination with traditional therapies,aiming to provide directions for the subsequent therapeutic research on hepatocellular carcinoma(HCC).
基金by the National Natural Science Foundation of China(No.81700453).
文摘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.
基金supported by grants from the National Key R&D Program of China(Grant Nos.2021YFA0909900,X.Z.2022YFC2403401,F.L.)+3 种基金the National Natural Science Foundation of China(Grant Nos.32222045 and 32171384,X.Z.82073368,F.L.)the Liaoning Revitalization Talents Program(Grant No.XLYC2007071,F.L.)the Top-notch Talents Project of 2022“Kunlun Yingcai Advanced Innovation and Entrepreneurship”in Qinghai Province(Y.X.)。
文摘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.
文摘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.
基金supported by the National Cancer Institute(1R37CA251318-01,1R01CA248111-01A1,R01CA258477-01,R01CA278911,and R01CA288403)the CPRIT Scholar Award(RR210067).
文摘Oncolytic virotherapy(OVT)is a promising option for cancer treatment.OVT involves selective oncolytic virus(OV)replication within cancer cells,which triggers anti-tumor responses and immunostimulation.Despite promising potential,OVT faces critical challenges,including insufficient tumor-specific targeting,which results in limited tumor penetration and variability in therapeutic efficacy.These challenges are particularly pronounced in solid tumors with complex microenvironments and heterogeneous vascularization.A comprehensive research program is currently underway to develop and refine innovative delivery methods to address these issues to enhance OVT precision and efficacy.A principal area of investigation is the utilization of cellular carriers to enhance the delivery and distribution of OVs within tumor microenvironments,thereby optimizing immune system activation and maximizing anti-tumor effects.This review offers a comprehensive overview of the current strategies that are being used to enhance the delivery of OVs via cellular carriers with the goal of improving the clinical impact of OVT in cancer therapy.
文摘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.
文摘Objective To study related guidelines such as“Guidelines for Clinical Trial Design of Oncolytic Viruses”“Technical Guidelines for Non-clinical Research and Evaluation of Gene Therapy Products”and“Technical Guidelines for Pharmacological Research and Evaluation of Oncolytic Viruses(OVs)Products”issued by the Center for Drug Evaluation(CDE)on OV and offer some suggestions for further improvement of the policies and regulations.Methods Literature comparison and questionnaire survey were used in this paper to investigate the difficulties encountered in the practical work of domestic companies that have conducted clinical trials,thus drawing some lessons to help the subsequent implementation of the guidelines.Results and Conclusion According to the characteristics of specific varieties and the published laws,regulations and guidelines,companies can adopt more suitable and scientific strategies to accelerate the development of anti-cancer drugs.In the future,as more clinical studies and product development for various cancers expand,regulatory requirements are expected to become more specialized and complex.Learning from the regulatory experience of developed countries and regions,we can improve the regulatory system by adapting it to national conditions and development status of China.Additionally,some ideas and useful inspirations can be provided after reviewing the content of the relevant guidelines and the obstacles in the practice of corporate R&D process can be addressed.These efforts will facilitate the speed of R&D and allow enterprises to work more smoothly and efficiently.
基金funded by the National Natural Science Foundation of China(No.82270200,82070203,81770210,82400231)Taishan Scholars Program of Shandong Province,China+5 种基金Shandong Provincial Engineering Research Center of Lymphoma(China)Key Research and Development Program of Shandong Province,China(No.2018CXGC1213)Academic Promotion Programme of Shandong First Medical University(China)(No.2019QL018)Translational Research Grant of the National Clinical Research Center for Hematologic Diseases(NCRCH)(China)(No.2021WWB02,2020ZKMB01)China Postdoctoral Science Foundation(No.2023M741506)Shandong Provincial Natural Science Foundation(China)(No.ZR2023QH193).
文摘Oncolytic viruses(OVs),a kind of emerging therapeutics for treating tumors,are characterized by high replication efficiency,superior killing effects,and few adverse reactions,which have shown great application prospects in preclinical tumor treatment trials.To overcome the limitations of OV monotherapy,recent studies have found that combination therapy with other anti-tumor therapeutics,especially with immunotherapy,yields promising outcomes in tumor eradication.Due to the advancements in genetic engineering,the combination of OVs with novel immunotherapy,including cellular immunotherapy,adoptive cellular immunotherapy,immune checkpoint inhibitors,cancer vaccines,cytokines,and bi-or tri-specific T cell engagers,has greatly improved clinical outcomes and quality of life of tumor patients.In this review,we systematically summarize the latest progress of OVs combined with immunotherapy in tumor treatment and highlight the future directions of the combination strategies,which will promote the clinical application of OVs in tumor therapy.
基金supported by the National Key Research and Development Program of China(2022YFD1801500)the International Cooperation Project of National Natural Science Foundation of China(32220103012)the Innovation Program of Chinese Academy of Agricultural Sciences(CAAS-CSLPDCP-202402).
文摘Anoikis is a specialized form of programmed cell death triggered by the detachment of cells from the extracellular matrix(ECM).Tumor cells that develop resistance to anoikis acquire the ability to detach,migrate,and colonize distant sites,ultimately leading to the formation of metastatic tumors.Bit1(Bcl-2 inhibitor of transcription 1),a key effector of anoikis,is released into the cytoplasm upon loss of cell attachment and activates a caspase-independent pathway of apoptosis.Newcastle disease virus(NDV),a pathogen that poses a significant threat to the poultry industry,has also emerged as a promising oncolytic virus capable of selectively targeting and killing tumor cells.However,whether NDV can induce the death of anoikis-resistant tumor cells by activating Bit1 remains unclear.In this study,we utilized physical methods to induce cell suspension as a positive control for anoikis and further examined the expression and cellular localization of Bit1 following NDV infection in tumor cells.The results indicated that both viral infection and cell suspension resulted in partial cell death,accompanied by the translocation of Bit1 from the mitochondria to the cytoplasm and a reduction in its protein levels.Notably,Bit1 expression was found not to significantly affect viral replication.These findings suggest that NDV infection promotes tumor cell death by activating Bit1 translocation,mirroring the effects observed during cell suspension-induced anoikis.In addition,in vivo experiments demonstrated that NDV effectively inhibits the metastasis and growth of melanoma in mice,and that overexpression of Bit1 in tumor cells accelerates this process.This study provides novel insights into NDV-induced tumor cell death and identifies potential targets for understanding the mechanisms of oncolytic virus action.
基金This work was supported by the National Key R&D Program of China(No.2019YFC1316104)the National Natural Science Foundation of China(Nos.81871960,82073368,and 82073777)+2 种基金Liaoning Revitalization Talents Program(Nos.XLYC2007071 and XLYC1808017)China Postdoctoral Science Foundation(No.2020M680986)General Project of Liaoning Provincial Department of Education(No.JKZ0927).
文摘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.
基金supported by the National Natural Science Foundation of China (22222509,52025035,51973215,22375198,52103194)Bureau of International Cooperation Chinese Academy of Sciences (121522KYSB20200029)+5 种基金Jilin Province Science and Technology DevelopmentPlan (YDZJ202101ZYTS131,20220402037GH,20210508049RQ)Jilin Provincial International Cooperation Key Laboratory of Biomedical Polymers (20210504001GH)Changchun Science and Technology Development Plan (21ZY09,21ZGY30)the China Postdoctoral Science Foundation (E21S2101)the Youth Talents Promotion Project of Jilin Province (QT202103)the Youth Innovation Promotion Association of Chinese Academy of Sciences (2020232)。
文摘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.
基金supported by the National Natural Science Foundation of China(No.32100732).
文摘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.
基金supported by National Key R&D Program of China(No.2021YFA0909800,China)Guangdong Basic and Applied Basic Research Foundation(Nos.2022B1515020056,2021A1515011881,2023A1515010737,China)+3 种基金Leading team for entrepreneurship in Guangzhou,Guangdong Province(No.201809020004,China)Fundamental Research Funds for the Central Universities(No.22ykqb12,China)Pioneering talents project of Guangzhou Development Zone,Guangdong Province(2020-L036,China)Natural Science Foundation of Guangdong Province(No.2022A1515011056,China).
文摘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.
文摘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.
基金The work was financial supported by the National Science Foundation and South Carolina Experimental Program to Stimulate Competitive Research and Institutional Development Awards(SC EPSCoR IDeA)program under NSF Award.
文摘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.
基金This research was supported by the Science and Technology Program of Guangzhou(201707020003)the Pioneering Talents Project of Guangzhou Development Zone,Guangdong Province(CY2018-012)+2 种基金the Guangzhou People's Livelihood Science and Technology Tackling Key Project(201803010113)the Young Teacher Training Program of Sun Yat-sen University(20ykpy22)the National Natural Science Foundation of China(No.81802536).
文摘Oncolytic alphavirus M1 has been shown to selectively target and kill cancer cells,but cytopathic morphologies induced by M1 virus and the life cycle of the M1 strain in cancer cells remain unclear.Here,we study the key stages of M1 virus infection and replication in the M1 virus-sensitive HepG2 liver cancer cell line by transmission electron microscopy,specifically examining viral entry,assembly,maturation and release.We found that M1 virus induces vacuolization of cancer cells during infection and ultimately nuclear marginalization,a typical indicator of apoptosis.Specifically,our results suggest that the endoplasmic reticulum participates in the assembly of nucleocapsids.In the early and late stage of infection,three kinds of special cytopathic vacuoles are formed and appear to be involved in the replication,maturation and release of the virus.Taken together,our data displayed the process of M1 virus infection of tumor cells and provide the structural basis for the study of M1 virus-host interactions.
基金supported by the Scientific and Technological Innovation Major Base of Guangxi (No. 2018–15-Z04)Guangxi Key Research and Development Project (No. AB20117001)+1 种基金Guangxi Science and Technology Bases and Talent Special Project (No. AD17129062)Guangxi Natural Science Foundation (No. 2018JJA140524)。
文摘Oncolytic virus is an emerging anti-cancer strategy. However, extracellular matrix(ECM), as a physical barrier, limits virus spread within the tumor. To overcome the obstacle, we constructed a recombinant Newcastle disease virus(NDV) expressing matrix metalloproteinase(MMP8)(NDV-MMP8) using with reverse genetic technology. In vitro, NDV-MMP8 was identified and verified by WB and ELISA. Cell viability was detected by CCK-8 assay. In vivo, we established two liver cancer xenograft models. NDV-MMP8 was injected into the tumor to observe the tumor volume and survival of mice. The changes in extracellular matrix were observed by Masson’s trichrome staining. Virus expression in tumor tissues was detected by immunofluorescence assay. The virus titer in tumor tissues was detected by TCID50. Histopathological changes were detected by hematoxylin and eosin(HE) and terminal deoxynucleotidyl transferase d UTP nick end labeling(TUNEL) staining. Intratumoral administration of NDV-MMP8 can effectively degrade ECM, promote the spread of the virus within the tumor, and reduce tumor growth rate. Therefore, the method of increasing intratumoral virus accumulation by degradation of the ECM to enhance the oncolytic effect has great potential for clinical application.
文摘Oncolytic virus(OV)is increasingly being recognized as a novel vector in cancer immunotherapy.Increasing evidence suggests that OV has the ability to change the immune status of tumor microenvironment,so called transformation of‘cold’tumors into‘hot’tumors.The improved anti-tumor immunity can be induced by OV and further enhanced through the combination of various immunomodulators.The Neo-2/15 is a newly de novo synthesized cytokine that functions as both IL-2 and IL-15.However,it specifically lacks the binding site of IL-2 receptorαsubunit(CD25),therefore unable to induce the Treg proliferation.In present study,a recombinant vesicular stomatitis virus expressing the Neo-2/15(VSVM51R-Neo-2/15)was generated.Intratumoral delivery of VSVM51R-Neo-2/15 efficiently inhibited tumor growth in mice without causing the IL-2-related toxicity previously observed in clinic.Moreover,treatment with VSVM51R-Neo-2/15 increased the number of activated CD8t T cells but not Treg cells in tumors.More tumor-bearing mice were survival with VSVM51R-Neo-2/15 treatment,and the surviving mice displayed enhanced protection against tumor cell rechallenge due to the induced anti-tumor immunity.In addition,combination therapy of OV and anti-PD-L1 immune checkpoint inhibitors further enhanced the anti-tumor immune response.These findings suggest that our novel VSVM51R-Neo-2/15 can effectively inhibit the tumor growth and enhance the sensitivity to immune checkpoint inhibitors,providing promising attempts for further clinical trials.
