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
Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-t...Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-tumor efficacy of intratumoral injection of H101 or/and intraperitoneal injection of Camrelizumab were evaluated in an immune system humanized NOD Prkdc^(scid) Il2rg^(-/-)mice subcutaneous(S.C.)tumor model,established with human glioblastoma of unknown origin cell line U87-MG,and human bladder cancer cell line T24 and YTS-1.The mechanism by which H101 induced anti-tumor immunity were also investigated.Results:Combining H101 with Camrelizumab demonstrated more potent anti-tumor effects than monotherapy in mouse S.C.tumor model.Increased tumor-infiltrating T cells were observed in the combined treatment group.H101 infection decreased the expression of CD47 in cancer cells,thereby promoting macrophages to phagocytose cancer cells.Following the H101-mediated activation of macrophages,increased levels of cytokines,including TNF,IL-12 and IFN-γwere observed.Moreover,when induced THP-1 cells were co-cultured with H101-treated cancer cells,expression of IFN-γwas increased in T cells.Elimination of IL-12 using an anti-IL-12 antibody abolished IFN-γproduction from T cells.In addition,infection with H101 increased PD-L1 expression in YTS-1 cells.These results suggested that H101 may act synergistically to enhance the therapeutic efficacy of PD-1 blockade in cancer via suppressing CD47 signaling,which may promote macrophages to phagocytose tumor cells and activate CD8^(+)T cells.Conclusion:The combination of H101 with PD-1 blockade exhibits potential as a novel strategy for the treatment of cancer.展开更多
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
Oncolytic virus therapy is a promising strategy for cancer treatment.Herpes simplex virus type 1(HSV-1)has been successfully used in oncolytic virotherapy.In the present research,we applied an HSV-1 synthetic genomics...Oncolytic virus therapy is a promising strategy for cancer treatment.Herpes simplex virus type 1(HSV-1)has been successfully used in oncolytic virotherapy.In the present research,we applied an HSV-1 synthetic genomics platform to construct two oncolytic viruses,oHSV-1.1 and oHSV-1.2.oHSV-1.1 had the virulence gene ICP34.5 and ICP47 deleted for attenuation,and oHSV-1.2 was additionally armed with murine granulocyte macrophage-colony stimulating factor(GM-CSF)and interleukin-12(IL-12).The oncolytic viruses were evaluated in vitro and in an immunocompetent murine melanoma model.The animal experiments confirmed that both oncolytic viruses displayed antitumor efficacy,including inhibiting tumor growth and prolonging overall survival.Compared with oHSV-1.1,oHSV-1.2 demonstrated superior tumor growth suppression and enhanced antitumor efficacies,as evidenced by increased tumor cell apoptosis,cytotoxic T cells and macrophages infiltration,IFN-γ production,and upregulation of inflammatory-related gene expression.Our research highlights the potential of oncolytic HSV-1 expressing both GM-CSF and IL-12 for melanoma therapy,and provides a promising strategy for further development of oncolytic virotherapy.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
Immune checkpoint inhibitor(ICI)has limited efficacy in the treatment of immune“cold”tumors.Due to insufficient T cell infiltration and heterogeneous programmed death ligand 1(PD-L1)expression,the ORR is only 5%–8%...Immune checkpoint inhibitor(ICI)has limited efficacy in the treatment of immune“cold”tumors.Due to insufficient T cell infiltration and heterogeneous programmed death ligand 1(PD-L1)expression,the ORR is only 5%–8%compared with 30%–40%of“hot”tumors.This article reviews the synergistic mechanism,clinical efficacy and optimization strategy of oncolytic virus(OVs)combined with ICIs in the treatment of refractory malignant tumors.Systematic analysis of mechanistic interactions across tumor types and clinical trial data demonstrates that OVs transform the immunosuppressive microenvironment by inducing immunogenic cell death and activating innate immunity.Concurrently,ICIs enhance adaptive immunity by reversing T-cell exhaustion and expanding T-cell diversity.Clinical trials in melanoma,head and neck cancer and breast cancer showed superior efficacy.The Objective Response Rate(ORR)of combination therapy was 39%–62%,while the ORR of ICI monotherapy was 18%.Treatment heterogeneity is mainly attributed to virus-related factors,including targeting specificity and replication efficiency,tumor characteristics,such as antigen presenting ability and mutation load,and host immune status,including preexisting antiviral antibodies and microbiome composition.This combined approach represents a paradigm shift in cancer immunotherapy,which effectively transforms immune“cold”tumors into“hot”tumors through the continuous activation of innate and adaptive immune responses.In the future,it is expected to improve the therapeutic effect of treatment-resistant malignant tumors through the integration of immune regulatory molecules,accurate biomarkers to guide the treatment scheme and triple combination strategy by a new generation of engineering viruses.展开更多
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 microen...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.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
ONYX-015 is an attractive therapeutic adenovirus for cancer because it can selectively replicate in tumor cells and kill them. To date, clinical trials of this adenovirus have demonstrated marked safety but not potent...ONYX-015 is an attractive therapeutic adenovirus for cancer because it can selectively replicate in tumor cells and kill them. To date, clinical trials of this adenovirus have demonstrated marked safety but not potent enough when it was used alone. In this paper, we put forward a novel concept of Gene-ViroTherapy strategy and in this way, we constructed an armed therapeutic oncolytic adenovirus system, ZD55-gene, which is not only deleted of ElB 55-kD gene similar to ONYX-015, but also armed with foreign antitumor gene. ZD55-gene exhibited similar cytopathic effects and replication kinetics to that of ONYX-015 in vitro. Importantly, the carried gene is expressed and the expression level can increase with the replication of virus. Consequently, a significant antitumoral efficacy was observed when ZD55-CD/5-FU was used as an example in nude mice with subcutaneous human SW620 colon cancer. Our data demonstrated that ZD55-gene, which utilizing the Gene-ViroTherapy strategy, is more efficacious than each individual component in vivo.展开更多
AIM: To construct a tumor-selective replication-competent adenovirus (RCAd), SG300, using a modified promoter of human telomerase reverse transcriptase (hTERT). METHODS: The antitumor efficacy of SG300 in hepatocellul...AIM: To construct a tumor-selective replication-competent adenovirus (RCAd), SG300, using a modified promoter of human telomerase reverse transcriptase (hTERT). METHODS: The antitumor efficacy of SG300 in hepatocellular carcinoma was assessed in vitro and in vivo. In vitro cell viability by MTT assay was used to assess the tumor-selective oncolysis and safety features of SG300, and in vivo antitumor activity of SG300 was assessed in established hepatocellular carcinoma models in nude mice. RESULTS: SG300 could lyse hepatocellular carcinoma cells at a low multiplicity of infection (MOI), but could not affect growth of normal cells even at a high MOI. Both in Hep3B and SMMC-7721 xenograft models of hepatocellular carcinoma, SG300 had an obvious antitumor effect, resulting in a decrease in tumor volume. Its selective oncolysis to tumor cells and safety to normal cells was also superior to that of ONYX-015. Pathological examination of tumor specimens showed that SG300 replicated selectively in cancer cells and resulted in apoptosis and necrosis of cancer cells. CONCLUSION: hTERT promoter-regulated replicativeadenovirus SG300 has a better cancer-selective replication-competent ability, and can specifically kill a wide range of cancer cells with positive telomerase activity, and thus has better potential for targeting therapy of hepatocellular carcinoma.展开更多
Vascular endothelial cell growth inhibitor （VEGI） is a member of the tumor necrosis factor superfamily and plays an important role in vascular homeostasis. In this study, to investigate the anticancer therapeutic po...Vascular endothelial cell growth inhibitor （VEGI） is a member of the tumor necrosis factor superfamily and plays an important role in vascular homeostasis. In this study, to investigate the anticancer therapeutic potential of this gene, a secreted isoform of VEGI （VEGI-251） was inserted into a selectively replicating adenovirus with E1B 55 kDa gene deletion （ZD55） to construct ZD55-VEGI-251. We report here that secreted VEGI-251 produced from ZD55- VEGI-251-infected cancer cells potently inhibits endothelial cell proliferation, tube formation in vitro and angiogen- esis of chick chorioallantoic membrane in vivo. Additionally, ZD55-VEGI-251 infection leads to a much more severe cytopathic effect than control viruses on several human cancer cell lines, including cervical cancer cell line HeLa, hepatoma cell line SMMC-7721 and colorectal cancer cell line SW620. Further study reveals that the increased cytotoxicity is a result of VEGI-251 autocrine-dependent, mitochondria-mediated apoptosis accompanied by caspase-9 activation, enhanced caspase-3 activation and PARP cleavage. Moreover, ZD55-VEGI-251-treatment of athymic nude mice bearing human cervical and colorectal tumor xenografts markedly suppressed tumor growth. Our findings indicate that the combined effect of antiangiogenesis and apoptosis-induction activity makes the VEGI-251-armed oncolytic adenovirus a promising therapeutic agent for cancer.展开更多
Gastrointestinal cancer has been one of the five most commonly diagnosed and leading causes of cancer mortality over the past few decades. Great progress in traditional therapies has been made, which prolonged surviva...Gastrointestinal cancer has been one of the five most commonly diagnosed and leading causes of cancer mortality over the past few decades. Great progress in traditional therapies has been made, which prolonged survival in patients with early cancer, yet tumor relapse and drug resistance still occurred, which is explained by the cancer stem cell(CSC) theory. Oncolytic virotherapy has attracted increasing interest in cancer because of its ability to infect and lyse CSCs. This paper reviews the basic knowledge, CSC markers and therapeutics of gastrointestinal cancer(liver, gastric, colon and pancreatic cancer), as well as research advances and possible molecular mechanisms of various oncolytic viruses against gastrointestinal CSCs. This paper also summarizes the existing obstacles to oncolytic virotherapy and proposes several alternative suggestions to overcome the therapeutic limitations.展开更多
BACKGROUND: Melanoma differentiation-associated gene-7 (MDA-7)/interleukin-24 (IL-24) is a novel tumor suppressor gene, which has suppressor activity in a broad spectrum of human cancer cells. We investigated the effe...BACKGROUND: Melanoma differentiation-associated gene-7 (MDA-7)/interleukin-24 (IL-24) is a novel tumor suppressor gene, which has suppressor activity in a broad spectrum of human cancer cells. We investigated the effect of the replication-competent oncolytic adenovirus SG600-IL24 and replication-incompetent adenovirus Ad.IL-24, both expressing human MDA-7/IL-24 on the hepatocellular carcinoma cell lines HepG2, Hep3B, SMMC-7721, HCCLM3, and the normal liver cell line L02. METHODS: Hepatocellular carcinoma cell lines and the normal liver cell line were infected with SG600-IL24 and Ad.IL-24. The mRNA and protein expression of MDA-7/IL-24 in infected cells was confirmed by RT-PCR, ELISA, and Western blotting. MTT assay was used to investigate the proliferation effect. Hoechst staining and Annexin-V and PI staining were performed to study the MDA-7/IL-24 gene expressed in HCC cell lines and the normal liver cell line. Flow cytometry was used to analyse the cell cycle. RESULTS: RT-PCR, ELISA and Western blotting confirmed that the exogenous MDA-7/IL-24 gene was highly expressed in cells infected with SG600-IL24. MTT and apoptosis detection indicated that SG600-IL24 induced growth suppression, promoted apoptosis, and blocked cancer cell lines in the G2/M phase in hepatocellular carcinoma cell lines but not in the normal liver cell line. CONCLUSIONS: SG600-IL24 selectively induces growth suppression and apoptosis in hepatocellular carcinoma cell lines in vitro but not in the normal liver cell line L02. Compared with Ad.IL-24, SG600-IL24 dramatically enhances antitumor activity in hepatocellular carcinoma cell lines. (Hepatobiliary Pancreat Dis Int 2010; 9:615-621)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
Reovirus is a double-stranded RNA virus with demonstrated oncolysis or preferential replication in cancer cells. The oncolytic properties of reovirus appear to be dependent, in part, on activated Ras signaling. In add...Reovirus is a double-stranded RNA virus with demonstrated oncolysis or preferential replication in cancer cells. The oncolytic properties of reovirus appear to be dependent, in part, on activated Ras signaling. In addition, Ras-transformation promotes reovirus oncolysis by affecting several steps of the viral life cycle. Reovirusmediated immune responses can present barriers to tumor targeting, serve protective functions against reovirus systemic toxicity, and contribute to therapeutic efficacy through antitumor immune-mediated effects via innate and adaptive responses. Preclinical studies have demonstrated the broad anticancer activity of wild-type, unmodified type 3 Dearing strain reovirus（Reolysin） across a spectrum of malignancies. The development of reovirus as an anticancer agent and available clinical data reported from 22 clinical trials will be reviewed.展开更多
AIM: To investigate the effect of oncolytic adenovirus SG600-IL24 and replication-incompetent adenovirus Ad.IL-24 on hepatocellular carcinoma (HCC) cell lines and normal liver cell line. METHODS: HCC cell lines (HepG2...AIM: To investigate the effect of oncolytic adenovirus SG600-IL24 and replication-incompetent adenovirus Ad.IL-24 on hepatocellular carcinoma (HCC) cell lines and normal liver cell line. METHODS: HCC cell lines (HepG2, Hep3B and MHCC97L) and normal liver cell line (L02) with a different p53 status were infected with SG600-IL24 and Ad.IL-24, respectively. Melanoma differentiation-associated (MDA)-7/interleukin (IL)-24 mRNA and protein expressions in infected cells were detected by reverse transcription-polymerase chain reaction (RT-PCR), enzymelinked immunosorbent assay (ELISA), and Western blotting, respectively. Apoptosis of HCC cells and normal liver cells was detected by cytometric assay with Hoechst33258 staining. 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) assay was used to investigate proliferation of HCC cells and normal liver cells, and cell cycle was assayed by flow cytometry. RESULTS: RT-PCR, ELISA and Western blotting showed that the exogenous MDA-7/IL-24 gene was highly expressed in cells infected with SG600-IL24. MTT indicated that SG600-IL24 could suppress the growth of HepG2, Hep3B, MHCC97L, with an inhibition rate of 75% ± 2.5%, 85% ± 2.0%, 72% ± 1.8%, respectively (P < 0.01), promote the apoptosis of HepG2, Hep3B, MHCC97L, with an apoptosis rate of 56.59% ± 4.0%, 78.36% ± 3.5%, 43.39% ± 2.5%, respectively (P < 0.01), and block the HCC cell lines in the G2/M phase with a blocking rate of 35.4% ± 4.2%, 47.3% ± 6.2%, 42% ± 5.0%, respectively (P < 0.01) but not the normal liver cell line in a p53-independent manner. CONCLUSION: SG600-IL24 can selectively suppress the proliferation and apoptosis of HCC cell lines in vitro but not normal liver cell line L02 in a p53-independent manner. Compared with Ad.IL-24, SG600-IL24 can significantly enhance the antitumor activity in HCC cell lines.展开更多
Oncolytic measles virus(OMV) is a promising antitumor agent. However, the presence of anti-measles neutralizing antibodies(NAbs) against the hemagglutinin(H) protein of OMV is a major barrier to the therapeutic applic...Oncolytic measles virus(OMV) is a promising antitumor agent. However, the presence of anti-measles neutralizing antibodies(NAbs) against the hemagglutinin(H) protein of OMV is a major barrier to the therapeutic application of OMV in clinical practice. In order to overcome this challenge, specific types of cells have been used as carriers for OMV.Differential loading strategies appear to result in different therapeutic outcomes; despite this, only few studies have reported practical ex vivo loading strategies required for effective treatment. To this end, we systematically evaluated the antitumor efficacy of OMV using different loading strategies; this involved varying the in vitro loading duration and loading dose of OMV. We found that improved oncolysis of carrier cells was achieved by a prolonged loading duration in the absence of NAbs. However, the enhanced oncolytic effect was abrogated in the presence of NAbs. Further, we found that the expression of H protein on the surface of carrier cells was predominantly determined by the loading duration rather than the loading dose. Finally, we showed that NAbs blocked viral transfer by targeting H protein prior to the occurrence of cell-to-cell interactions. Our results provide comprehensive information on the determinants of an effective loading strategy for carrier cell-based virotherapy; these results may be useful for guiding the application of OMV as an antitumor agent in clinical practice.展开更多
Objective： Chemotherapy is an effective means of treating breast cancer, and cancer-specific replicative adenovirus is also a promising antitumor agent in recent years. Our investigation aims to demonstrate that CNHK...Objective： Chemotherapy is an effective means of treating breast cancer, and cancer-specific replicative adenovirus is also a promising antitumor agent in recent years. Our investigation aims to demonstrate that CNHK300 can mediate selective antitumor efficacy and produce synergistic cytotoxicity with chemotherapy on HER-2 over-expressing breast cancer. Methods： We engineered the telomerase-dependent replicative adenovirus CNHK300 by placing the E1A gene under the control of the human hTERT promoter. By analysis of E1A expression, we proved the fidelity of hTERT promoter in adenovirus genome and the selective expression of E1A in telomerase-positive breast cancer cells but not in normal fibroblast cells. By proliferation test, we further showed efficient replication of CNHK300 in breast cancer cells with apparently attenuated proliferation in normal fibroblast cells. Finally, we demonstrated by MTT methods that CNHK300 virus caused potent cytolysis and produced synergistic cytotoxicity with chemotherapy in breast cancer cells with attenuated cytotoxicity on normal cells. Results： In this virus, the E1A gene is successfully placed under the control of the human hTERT promoter. CNHK300 virus replicated as efficiently as the wild-type adenovirus and caused intensive cell killing in HER-2 over-expressing breast cancer cells in vitro. In contrast, telomerase-negative normal fibroblast cells, which expressed no hTERT activity, were not able to support CNHK300 replication. Combined treatment of CNHK300 with paclitaxel improved cytotoxicity on cancer cells. Conclusion： We conclude that CNHK300 can produce selective antitumor efficacy and enhance the in vitro response of chemotherapy on HER-2 overexpressing breast cancer.展开更多
Objective: To evaluate the inhibitory role of a novel oncolytic adenovirus(OA), GP73-SphK1 sR-Ad5, on the growth of hepatocellular carcinoma(HCC). Methods: GP73-SphK1 sR-Ad5 was constructed by integrating Golgi protei...Objective: To evaluate the inhibitory role of a novel oncolytic adenovirus(OA), GP73-SphK1 sR-Ad5, on the growth of hepatocellular carcinoma(HCC). Methods: GP73-SphK1 sR-Ad5 was constructed by integrating Golgi protein 73(GP73) promoter and sphingosine kinase 1(SphK1)-short hairpin RNA(shRNA) into adenovirus serotype 5(Ad5), and transfecting into HCC Huh7 cells and normal human liver HL-7702 cells. The expression of SphK1 and adenovirus early region 1(E1 A) was detected by quantitative real-time PCR(qRT-PCR) and western blot, respectively. Cell viability was detected by methylthiazolyldiphenyl-tetrazolium bromide(MTT) assay, and apoptotic rate was determined by flow cytometry. An Huh7 xenograft model was established in mice injected intratumorally with GP73-SphK 1 sR-Ad5. Twenty days after injection, the tumor volume and weight, and the survival time of the mice were recorded. The histopathological changes in tumor tissues were observed by hematoxylin-eosin(HE) staining and transmission electron microscopy(TEM). Results: Transfection of GP73-SphK1 sR-Ad5 significantly upregulated E1 A and downregulated SphK1 in Huh7 cells, but not in HL7702 cells. GP73-SphK1 sR-Ad5 transfection significantly decreased the viability and increased the apoptotic rate of Huh7 cells, but had no effect on HL7702 cells. Intratumoral injection of GP73-SphK1 sR-Ad5 into the Huh7 xenograft mouse model significantly decreased tumor volume and weight, and prolonged survival time. It also significantly decreased the tumor infiltration area and blood vessel density, and increased the percentages of cells with nucleus deformation and cells with condensed chromatin in tumor tissues. Conclusions: GP73-SphK1 sR-Ad5 serves as a novel OA and can inhibit HCC progression with high specificity and efficacy.展开更多
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supported by Techpool Bio-Pharma Co.,Ltd.(grant no.AKR-S005).
文摘Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-tumor efficacy of intratumoral injection of H101 or/and intraperitoneal injection of Camrelizumab were evaluated in an immune system humanized NOD Prkdc^(scid) Il2rg^(-/-)mice subcutaneous(S.C.)tumor model,established with human glioblastoma of unknown origin cell line U87-MG,and human bladder cancer cell line T24 and YTS-1.The mechanism by which H101 induced anti-tumor immunity were also investigated.Results:Combining H101 with Camrelizumab demonstrated more potent anti-tumor effects than monotherapy in mouse S.C.tumor model.Increased tumor-infiltrating T cells were observed in the combined treatment group.H101 infection decreased the expression of CD47 in cancer cells,thereby promoting macrophages to phagocytose cancer cells.Following the H101-mediated activation of macrophages,increased levels of cytokines,including TNF,IL-12 and IFN-γwere observed.Moreover,when induced THP-1 cells were co-cultured with H101-treated cancer cells,expression of IFN-γwas increased in T cells.Elimination of IL-12 using an anti-IL-12 antibody abolished IFN-γproduction from T cells.In addition,infection with H101 increased PD-L1 expression in YTS-1 cells.These results suggested that H101 may act synergistically to enhance the therapeutic efficacy of PD-1 blockade in cancer via suppressing CD47 signaling,which may promote macrophages to phagocytose tumor cells and activate CD8^(+)T cells.Conclusion:The combination of H101 with PD-1 blockade exhibits potential as a novel strategy for the treatment of cancer.
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supported by grant from the National Key R&D Program of China(2023YFC2306600)the Hubei Natural Science Foundation for Distinguished Young Scholars(2021CFA050).
文摘Oncolytic virus therapy is a promising strategy for cancer treatment.Herpes simplex virus type 1(HSV-1)has been successfully used in oncolytic virotherapy.In the present research,we applied an HSV-1 synthetic genomics platform to construct two oncolytic viruses,oHSV-1.1 and oHSV-1.2.oHSV-1.1 had the virulence gene ICP34.5 and ICP47 deleted for attenuation,and oHSV-1.2 was additionally armed with murine granulocyte macrophage-colony stimulating factor(GM-CSF)and interleukin-12(IL-12).The oncolytic viruses were evaluated in vitro and in an immunocompetent murine melanoma model.The animal experiments confirmed that both oncolytic viruses displayed antitumor efficacy,including inhibiting tumor growth and prolonging overall survival.Compared with oHSV-1.1,oHSV-1.2 demonstrated superior tumor growth suppression and enhanced antitumor efficacies,as evidenced by increased tumor cell apoptosis,cytotoxic T cells and macrophages infiltration,IFN-γ production,and upregulation of inflammatory-related gene expression.Our research highlights the potential of oncolytic HSV-1 expressing both GM-CSF and IL-12 for melanoma therapy,and provides a promising strategy for further development of oncolytic virotherapy.
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supported in part by grants from the National Natural Science Foundation ofChina(Nos.82260462,82460606,32360046)Yunnan Fundamental Research Kunming Medical University Joint Projects(Nos.202201AY0700001-144,202301AY070001-115)+2 种基金Yunnan Fundamental Research Projects(No.202201AT070269)Yunnan health training project of high level talents(Nos.D-2024007,H-2024023)Graduate Innovation Fund of Kunming Medical University(No.2025S100).
文摘Immune checkpoint inhibitor(ICI)has limited efficacy in the treatment of immune“cold”tumors.Due to insufficient T cell infiltration and heterogeneous programmed death ligand 1(PD-L1)expression,the ORR is only 5%–8%compared with 30%–40%of“hot”tumors.This article reviews the synergistic mechanism,clinical efficacy and optimization strategy of oncolytic virus(OVs)combined with ICIs in the treatment of refractory malignant tumors.Systematic analysis of mechanistic interactions across tumor types and clinical trial data demonstrates that OVs transform the immunosuppressive microenvironment by inducing immunogenic cell death and activating innate immunity.Concurrently,ICIs enhance adaptive immunity by reversing T-cell exhaustion and expanding T-cell diversity.Clinical trials in melanoma,head and neck cancer and breast cancer showed superior efficacy.The Objective Response Rate(ORR)of combination therapy was 39%–62%,while the ORR of ICI monotherapy was 18%.Treatment heterogeneity is mainly attributed to virus-related factors,including targeting specificity and replication efficiency,tumor characteristics,such as antigen presenting ability and mutation load,and host immune status,including preexisting antiviral antibodies and microbiome composition.This combined approach represents a paradigm shift in cancer immunotherapy,which effectively transforms immune“cold”tumors into“hot”tumors through the continuous activation of innate and adaptive immune responses.In the future,it is expected to improve the therapeutic effect of treatment-resistant malignant tumors through the integration of immune regulatory molecules,accurate biomarkers to guide the treatment scheme and triple combination strategy by a new generation of engineering viruses.
基金supported by the National Natural Science Foundation of China(Grant No.81830006)the Science Technology Department of Zhejiang Province(Grant No.2021C03117).
文摘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.
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.
基金supported by the Key Project of the Chinese Academy of Sciences(No.KSCX2-3-06)the National Natural Science Foundation of China(No.30120160823)the Chinese National“863”High Tech Project Foundation grant(No.2002AA216021).
文摘ONYX-015 is an attractive therapeutic adenovirus for cancer because it can selectively replicate in tumor cells and kill them. To date, clinical trials of this adenovirus have demonstrated marked safety but not potent enough when it was used alone. In this paper, we put forward a novel concept of Gene-ViroTherapy strategy and in this way, we constructed an armed therapeutic oncolytic adenovirus system, ZD55-gene, which is not only deleted of ElB 55-kD gene similar to ONYX-015, but also armed with foreign antitumor gene. ZD55-gene exhibited similar cytopathic effects and replication kinetics to that of ONYX-015 in vitro. Importantly, the carried gene is expressed and the expression level can increase with the replication of virus. Consequently, a significant antitumoral efficacy was observed when ZD55-CD/5-FU was used as an example in nude mice with subcutaneous human SW620 colon cancer. Our data demonstrated that ZD55-gene, which utilizing the Gene-ViroTherapy strategy, is more efficacious than each individual component in vivo.
基金Supported by the Natural Science Foundation of China, No. 30572149 the National 863 High Technology R&D Project of China, No. 2003AA216030
文摘AIM: To construct a tumor-selective replication-competent adenovirus (RCAd), SG300, using a modified promoter of human telomerase reverse transcriptase (hTERT). METHODS: The antitumor efficacy of SG300 in hepatocellular carcinoma was assessed in vitro and in vivo. In vitro cell viability by MTT assay was used to assess the tumor-selective oncolysis and safety features of SG300, and in vivo antitumor activity of SG300 was assessed in established hepatocellular carcinoma models in nude mice. RESULTS: SG300 could lyse hepatocellular carcinoma cells at a low multiplicity of infection (MOI), but could not affect growth of normal cells even at a high MOI. Both in Hep3B and SMMC-7721 xenograft models of hepatocellular carcinoma, SG300 had an obvious antitumor effect, resulting in a decrease in tumor volume. Its selective oncolysis to tumor cells and safety to normal cells was also superior to that of ONYX-015. Pathological examination of tumor specimens showed that SG300 replicated selectively in cancer cells and resulted in apoptosis and necrosis of cancer cells. CONCLUSION: hTERT promoter-regulated replicativeadenovirus SG300 has a better cancer-selective replication-competent ability, and can specifically kill a wide range of cancer cells with positive telomerase activity, and thus has better potential for targeting therapy of hepatocellular carcinoma.
基金We thank Lanying Sun, Yang Xiao, Yuelei Chen, Hua Zhou and Cell Analysis Center （Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences） for professional technical assistance. This work was supported in part by grants from Hi-Tech Research Development Program of China （863 Program, No. 2007AA021006） the Key Project of the Chinese Academy of Sciences （No. KSCX2-YW- R-09）+1 种基金 the 973 Project （No. 2004CB518804） Grant 30623003 from National Nature Science Foundation of China and Grant 06DZ22032 from Science and Technology Commission of Shang- hai Municipality.
文摘Vascular endothelial cell growth inhibitor （VEGI） is a member of the tumor necrosis factor superfamily and plays an important role in vascular homeostasis. In this study, to investigate the anticancer therapeutic potential of this gene, a secreted isoform of VEGI （VEGI-251） was inserted into a selectively replicating adenovirus with E1B 55 kDa gene deletion （ZD55） to construct ZD55-VEGI-251. We report here that secreted VEGI-251 produced from ZD55- VEGI-251-infected cancer cells potently inhibits endothelial cell proliferation, tube formation in vitro and angiogen- esis of chick chorioallantoic membrane in vivo. Additionally, ZD55-VEGI-251 infection leads to a much more severe cytopathic effect than control viruses on several human cancer cell lines, including cervical cancer cell line HeLa, hepatoma cell line SMMC-7721 and colorectal cancer cell line SW620. Further study reveals that the increased cytotoxicity is a result of VEGI-251 autocrine-dependent, mitochondria-mediated apoptosis accompanied by caspase-9 activation, enhanced caspase-3 activation and PARP cleavage. Moreover, ZD55-VEGI-251-treatment of athymic nude mice bearing human cervical and colorectal tumor xenografts markedly suppressed tumor growth. Our findings indicate that the combined effect of antiangiogenesis and apoptosis-induction activity makes the VEGI-251-armed oncolytic adenovirus a promising therapeutic agent for cancer.
基金Supported by the National Natural Science Foundation of China,No.81272687the Natural Science Foundation of Zhejiang Province of China,No.LZ13H160004 and No.LY16H160056the 521 Talent Project of Zhejiang Sci-Tech University
文摘Gastrointestinal cancer has been one of the five most commonly diagnosed and leading causes of cancer mortality over the past few decades. Great progress in traditional therapies has been made, which prolonged survival in patients with early cancer, yet tumor relapse and drug resistance still occurred, which is explained by the cancer stem cell(CSC) theory. Oncolytic virotherapy has attracted increasing interest in cancer because of its ability to infect and lyse CSCs. This paper reviews the basic knowledge, CSC markers and therapeutics of gastrointestinal cancer(liver, gastric, colon and pancreatic cancer), as well as research advances and possible molecular mechanisms of various oncolytic viruses against gastrointestinal CSCs. This paper also summarizes the existing obstacles to oncolytic virotherapy and proposes several alternative suggestions to overcome the therapeutic limitations.
基金supported by a grant from the National Natural Science Foundation of China(30872510)
文摘BACKGROUND: Melanoma differentiation-associated gene-7 (MDA-7)/interleukin-24 (IL-24) is a novel tumor suppressor gene, which has suppressor activity in a broad spectrum of human cancer cells. We investigated the effect of the replication-competent oncolytic adenovirus SG600-IL24 and replication-incompetent adenovirus Ad.IL-24, both expressing human MDA-7/IL-24 on the hepatocellular carcinoma cell lines HepG2, Hep3B, SMMC-7721, HCCLM3, and the normal liver cell line L02. METHODS: Hepatocellular carcinoma cell lines and the normal liver cell line were infected with SG600-IL24 and Ad.IL-24. The mRNA and protein expression of MDA-7/IL-24 in infected cells was confirmed by RT-PCR, ELISA, and Western blotting. MTT assay was used to investigate the proliferation effect. Hoechst staining and Annexin-V and PI staining were performed to study the MDA-7/IL-24 gene expressed in HCC cell lines and the normal liver cell line. Flow cytometry was used to analyse the cell cycle. RESULTS: RT-PCR, ELISA and Western blotting confirmed that the exogenous MDA-7/IL-24 gene was highly expressed in cells infected with SG600-IL24. MTT and apoptosis detection indicated that SG600-IL24 induced growth suppression, promoted apoptosis, and blocked cancer cell lines in the G2/M phase in hepatocellular carcinoma cell lines but not in the normal liver cell line. CONCLUSIONS: SG600-IL24 selectively induces growth suppression and apoptosis in hepatocellular carcinoma cell lines in vitro but not in the normal liver cell line L02. Compared with Ad.IL-24, SG600-IL24 dramatically enhances antitumor activity in hepatocellular carcinoma cell lines. (Hepatobiliary Pancreat Dis Int 2010; 9:615-621)
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.
文摘Reovirus is a double-stranded RNA virus with demonstrated oncolysis or preferential replication in cancer cells. The oncolytic properties of reovirus appear to be dependent, in part, on activated Ras signaling. In addition, Ras-transformation promotes reovirus oncolysis by affecting several steps of the viral life cycle. Reovirusmediated immune responses can present barriers to tumor targeting, serve protective functions against reovirus systemic toxicity, and contribute to therapeutic efficacy through antitumor immune-mediated effects via innate and adaptive responses. Preclinical studies have demonstrated the broad anticancer activity of wild-type, unmodified type 3 Dearing strain reovirus（Reolysin） across a spectrum of malignancies. The development of reovirus as an anticancer agent and available clinical data reported from 22 clinical trials will be reviewed.
基金Supported by National Natural Science Foundation of China,No. 30872510Natural Science Foundation of Hubei Province,No. 2008CDB127
文摘AIM: To investigate the effect of oncolytic adenovirus SG600-IL24 and replication-incompetent adenovirus Ad.IL-24 on hepatocellular carcinoma (HCC) cell lines and normal liver cell line. METHODS: HCC cell lines (HepG2, Hep3B and MHCC97L) and normal liver cell line (L02) with a different p53 status were infected with SG600-IL24 and Ad.IL-24, respectively. Melanoma differentiation-associated (MDA)-7/interleukin (IL)-24 mRNA and protein expressions in infected cells were detected by reverse transcription-polymerase chain reaction (RT-PCR), enzymelinked immunosorbent assay (ELISA), and Western blotting, respectively. Apoptosis of HCC cells and normal liver cells was detected by cytometric assay with Hoechst33258 staining. 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) assay was used to investigate proliferation of HCC cells and normal liver cells, and cell cycle was assayed by flow cytometry. RESULTS: RT-PCR, ELISA and Western blotting showed that the exogenous MDA-7/IL-24 gene was highly expressed in cells infected with SG600-IL24. MTT indicated that SG600-IL24 could suppress the growth of HepG2, Hep3B, MHCC97L, with an inhibition rate of 75% ± 2.5%, 85% ± 2.0%, 72% ± 1.8%, respectively (P < 0.01), promote the apoptosis of HepG2, Hep3B, MHCC97L, with an apoptosis rate of 56.59% ± 4.0%, 78.36% ± 3.5%, 43.39% ± 2.5%, respectively (P < 0.01), and block the HCC cell lines in the G2/M phase with a blocking rate of 35.4% ± 4.2%, 47.3% ± 6.2%, 42% ± 5.0%, respectively (P < 0.01) but not the normal liver cell line in a p53-independent manner. CONCLUSION: SG600-IL24 can selectively suppress the proliferation and apoptosis of HCC cell lines in vitro but not normal liver cell line L02 in a p53-independent manner. Compared with Ad.IL-24, SG600-IL24 can significantly enhance the antitumor activity in HCC cell lines.
基金supported in part by the National Natural Science Foundation of China (81472820, 81773255, 81071860 and 81602702)Jiangsu Special Program for Clinical Medical Science and Technology (BL2014054)+2 种基金the Natural Science Foundation of Jiangsu Province of China (BK20160126)the Fundamental Research Funds for the Central Universities (021414380223 and 14380336/1-2)Six talent peaks project in Jiangsu Province to JW
文摘Oncolytic measles virus(OMV) is a promising antitumor agent. However, the presence of anti-measles neutralizing antibodies(NAbs) against the hemagglutinin(H) protein of OMV is a major barrier to the therapeutic application of OMV in clinical practice. In order to overcome this challenge, specific types of cells have been used as carriers for OMV.Differential loading strategies appear to result in different therapeutic outcomes; despite this, only few studies have reported practical ex vivo loading strategies required for effective treatment. To this end, we systematically evaluated the antitumor efficacy of OMV using different loading strategies; this involved varying the in vitro loading duration and loading dose of OMV. We found that improved oncolysis of carrier cells was achieved by a prolonged loading duration in the absence of NAbs. However, the enhanced oncolytic effect was abrogated in the presence of NAbs. Further, we found that the expression of H protein on the surface of carrier cells was predominantly determined by the loading duration rather than the loading dose. Finally, we showed that NAbs blocked viral transfer by targeting H protein prior to the occurrence of cell-to-cell interactions. Our results provide comprehensive information on the determinants of an effective loading strategy for carrier cell-based virotherapy; these results may be useful for guiding the application of OMV as an antitumor agent in clinical practice.
基金the National Natural Science Foundation of China (No. 30120160824)the State 863 High Technology R&D Project of China (No. 2001AA217031)
文摘Objective： Chemotherapy is an effective means of treating breast cancer, and cancer-specific replicative adenovirus is also a promising antitumor agent in recent years. Our investigation aims to demonstrate that CNHK300 can mediate selective antitumor efficacy and produce synergistic cytotoxicity with chemotherapy on HER-2 over-expressing breast cancer. Methods： We engineered the telomerase-dependent replicative adenovirus CNHK300 by placing the E1A gene under the control of the human hTERT promoter. By analysis of E1A expression, we proved the fidelity of hTERT promoter in adenovirus genome and the selective expression of E1A in telomerase-positive breast cancer cells but not in normal fibroblast cells. By proliferation test, we further showed efficient replication of CNHK300 in breast cancer cells with apparently attenuated proliferation in normal fibroblast cells. Finally, we demonstrated by MTT methods that CNHK300 virus caused potent cytolysis and produced synergistic cytotoxicity with chemotherapy in breast cancer cells with attenuated cytotoxicity on normal cells. Results： In this virus, the E1A gene is successfully placed under the control of the human hTERT promoter. CNHK300 virus replicated as efficiently as the wild-type adenovirus and caused intensive cell killing in HER-2 over-expressing breast cancer cells in vitro. In contrast, telomerase-negative normal fibroblast cells, which expressed no hTERT activity, were not able to support CNHK300 replication. Combined treatment of CNHK300 with paclitaxel improved cytotoxicity on cancer cells. Conclusion： We conclude that CNHK300 can produce selective antitumor efficacy and enhance the in vitro response of chemotherapy on HER-2 overexpressing breast cancer.
基金Project supported by the Shandong Provincial Science and Technology Development Plan Project(No.2013GSF11853),China
文摘Objective: To evaluate the inhibitory role of a novel oncolytic adenovirus(OA), GP73-SphK1 sR-Ad5, on the growth of hepatocellular carcinoma(HCC). Methods: GP73-SphK1 sR-Ad5 was constructed by integrating Golgi protein 73(GP73) promoter and sphingosine kinase 1(SphK1)-short hairpin RNA(shRNA) into adenovirus serotype 5(Ad5), and transfecting into HCC Huh7 cells and normal human liver HL-7702 cells. The expression of SphK1 and adenovirus early region 1(E1 A) was detected by quantitative real-time PCR(qRT-PCR) and western blot, respectively. Cell viability was detected by methylthiazolyldiphenyl-tetrazolium bromide(MTT) assay, and apoptotic rate was determined by flow cytometry. An Huh7 xenograft model was established in mice injected intratumorally with GP73-SphK 1 sR-Ad5. Twenty days after injection, the tumor volume and weight, and the survival time of the mice were recorded. The histopathological changes in tumor tissues were observed by hematoxylin-eosin(HE) staining and transmission electron microscopy(TEM). Results: Transfection of GP73-SphK1 sR-Ad5 significantly upregulated E1 A and downregulated SphK1 in Huh7 cells, but not in HL7702 cells. GP73-SphK1 sR-Ad5 transfection significantly decreased the viability and increased the apoptotic rate of Huh7 cells, but had no effect on HL7702 cells. Intratumoral injection of GP73-SphK1 sR-Ad5 into the Huh7 xenograft mouse model significantly decreased tumor volume and weight, and prolonged survival time. It also significantly decreased the tumor infiltration area and blood vessel density, and increased the percentages of cells with nucleus deformation and cells with condensed chromatin in tumor tissues. Conclusions: GP73-SphK1 sR-Ad5 serves as a novel OA and can inhibit HCC progression with high specificity and efficacy.
