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
Hepatocellular carcinoma(HCC)arises on the background of chronic liver disease.Despite the development of effective anti-viral therapeutics HCC is continuing to rise,in part driven by the epidemic of non-alcoholic fat...Hepatocellular carcinoma(HCC)arises on the background of chronic liver disease.Despite the development of effective anti-viral therapeutics HCC is continuing to rise,in part driven by the epidemic of non-alcoholic fatty liver disease.Many patients present with advanced disease out with the criteria for transplant,resection or even locoregional therapy.Currently available therapeutics for HCC are effective in a small minority of individuals.However,there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers,great opportunities now exist for treating HCC with newer and more sophisticated agents.Whilst checkpoint inhibitors are at the forefront of this revolution,other therapeutics such as inhibitory cytokine blockade,oncolytic viruses,adoptive cellular therapies and vaccines are emerging.Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response.Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy,either in combination with one another or in combination with treatment modalities such as locoregional therapy.Together these agents are likely to generate new and exciting opportunities for treating HCC,which are summarized in this review.展开更多
With rapid advances in understanding molecular pathogenesis of human diseases in the era of genome sciences and systems biology,it is anticipated that increasing numbers of therapeutic genes or targets will become ava...With rapid advances in understanding molecular pathogenesis of human diseases in the era of genome sciences and systems biology,it is anticipated that increasing numbers of therapeutic genes or targets will become available for targeted therapies.Despite numerous setbacks,efficacious gene and/or cell-based therapies still hold the great promise to revolutionize the clinical management of human diseases.It is wildly recognized that poor gene delivery is the limiting factor for most in vivo gene therapies.There has been a long-lasting interest in using viral vectors,especially adenoviral vectors,to deliver therapeutic genes for the past two decades.Among all currently available viral vectors,adenovirus is the most efficient gene delivery system in a broad range of cell and tissue types.The applications of adenoviral vectors in gene delivery have greatly increased in number and efficiency since their initial development.In fact,among over 2000 gene therapy clinical trials approved worldwide since 1989,a significant portion of the trials have utilized adenoviral vectors.This review aims to provide a comprehensive overview on the characteristics of adenoviral vectors,including adenoviral biology,approaches to engineering adenoviral vectors,and their applications in clinical and preclinical studies with an emphasis in the areas of cancer treatment,vaccination and regenerative medicine.Current challenges and future directions regarding the use of adenoviral vectors are also discussed.It is expected that the continued improvements in adenoviral vectors should provide great opportunities for cell and gene therapies to live up to its enormous potential in personalized medicine.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
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
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
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the world with an extremely poor prognosis. The major etiologic risk factors for HCC development include hepatitis B virus (HB...Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the world with an extremely poor prognosis. The major etiologic risk factors for HCC development include hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, toxins (alcohol, aflatoxin BI) and various inherited metabolic liver diseases, such as hemochromatosis and alpha-1-antitrypsin deficiency. Central to the molecular pathogenesis of HCC are mutations of various genes and genetic/chromosomal instability that result from chronic liver disease and the associated enhanced liver cell regeneration and mitotic activity. Alterations in the structure or expression of several tumor suppressor genes and oncogenes have been described. In addition, mechanisms leading to genetic instability due to mismatch repair deficiency or chromosomal instability and aneuploidy due to defective chromosomal segregation appear to be involved. The prognosis of HCC patients is generally very poor. Most studies have shown a five-year survival rate of less than 5% in symptomatic patients. HCC has been found to be quite resistant to radio- or chemotherapy. Investigations of the natural history and clinical course of HCC revealed a long-term survival of patients only with small asymptomatic HCC that could be treated surgically or nonsurgically. For patients with advanced symptomatic HCC, novel therapeutic strategies such as gene therapy are urgently needed. Apart from exploring and refining new HCC treatment strategies, the implementation of the existing measures or the development of novel measures to prevent HCC is most important. Primary HCC prevention could have a major impact on the incidence of HCC. Further, secondary prevention of a local recurrence or of new HCC lesions in patients after successful surgical or nonsurgical HCC treatment is of paramount importance and is expected to significantly improve disease-free and overall survival rates of patients. Based on rapid scientific advances, molecular diagnosis, gene therapy and molecu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
Pancreatic ductal adenocarcinoma(PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients wh...Pancreatic ductal adenocarcinoma(PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses(TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1(PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer.展开更多
Colorectal cancer (CRC) is one of the main reasons of tumor-related deaths worldwide.At present,the main treatment is surgery,but the results are unsatisfactory,and the prognosis is poor.The majority of patients die d...Colorectal cancer (CRC) is one of the main reasons of tumor-related deaths worldwide.At present,the main treatment is surgery,but the results are unsatisfactory,and the prognosis is poor.The majority of patients die due to liver or lung metastasis or recurrence.In recent years,great progress has been made in the field of tumor gene therapy,providing a new treatment for combating CRC.As oncolytic viruses selectively replicate almost exclusively in the cytoplasm of tumor cells and do not require integration into the host genome,they are safer,more effective and more attractive as oncolytic agents.Newcastle disease virus (NDV) is a natural RNA oncolytic virus.After NDV selectively infects tumor cells,the immune response induced by NDV’s envelope protein and intracellular factors can effectively kill the tumor without affecting normal cells.Reverse genetic techniques make NDV a vector for gene therapy.Arming the virus by inserting various exogenous genes or using NDV in combination with immunotherapy can also improve the anti-CRC capacity of NDV,and good results have been achieved in animal models and clinical treatment trials.This article reviews the molecular biological characteristics and oncolytic mechanism of NDV and discusses in vitro and in vivo experiments on NDV anti-CRC capacity and clinical treatment.In conclusion,NDV is an excellent candidate for cancer treatment,but more preclinical studies and clinical trials are needed to ensure its safety and efficacy.展开更多
The knowledge that the body possesses natural defenses to combat cancer existed long before the modern period,with multiple anecdotal reports of tumors miraculously disappearing,sometimes spontaneously or after a febr...The knowledge that the body possesses natural defenses to combat cancer existed long before the modern period,with multiple anecdotal reports of tumors miraculously disappearing,sometimes spontaneously or after a febrile or infectious episode.Spontaneous tumor regression of untreated malignant tumors is currently a well-accepted albeit rare phenomenon,and it is recognized that immunosuppression is associated with a higher cancer risk.The treatment of bladder carcinoma by intravesical administration of live attenuated Bacillus Calmette-Guérin bacteria was shown to be very effective in 1976 and is now standard treatment.Effective immunity against cancer involves complex interactions between the tumor,the host,and the environment.Cancer immunotherapy uses various strategies to augment tumor immunity and represents a paradigm shift in treating cancer,since attention has become more focused on the“biologic passport”of the individual tumor rather than the site of origin of the tumor.The different types of cancer immunotherapies discussed here include biologic modifiers,such as cytokines and vaccines,adoptive cell therapies,oncolytic viruses,and antibodies against immune checkpoint inhibitors,such as the co-inhibitory T-cell receptor PD-1 and one of its ligands,programmed death-ligand 1.展开更多
Background Oncolytic herpes simplex virus (HSV) vectors can be used for cancer therapy as direct cytotoxic agents, inducers of anti-tumor immune responses, and as expressers of anti-cancer genes. In this study, the ef...Background Oncolytic herpes simplex virus (HSV) vectors can be used for cancer therapy as direct cytotoxic agents, inducers of anti-tumor immune responses, and as expressers of anti-cancer genes. In this study, the efficacy of HSV vectors, G47Delta and NV1023 were examined for the treatment of the human breast cancer. Methods Human breast cancer MDA-MB-435 cells were cultured or implanted subcutaneously in BALB/c nude mice. The cells or tumors were inoculated with G47Delta or NV1023, and cell killing or inhibition of tumor growth determined. Both viruses contained the LacZ gene and expression in infected cells was detected with X-gal histochemistry. Results G47Delta and NV1023 were highly cytotoxic to MDA-MB-435 cells in vitro at very low multiplicities of infection. X-gal staining of infected tumor cells in vitro and in vivo illustrated the replication and spread of both viruses. G47Delta and NV1023 inoculation inhibited tumor growth and prolonged mouse survival. Both vectors behaved similarly. Conclusions Oncolytic HSV vectors, G47Delta and NV1023, were extremely effective at killing human breast cancer cells in vitro and in tumor xenografts in vivo. This novel form of cancer therapy warrants further investigation and consideration of clinical application.展开更多
Acral melanoma(AM)is the most common histologic subtype of melanoma in dark-skinned patients and is associated with a worse prognosis and a high mortality rate,largely due to the inconspicuous nature of early-stage le...Acral melanoma(AM)is the most common histologic subtype of melanoma in dark-skinned patients and is associated with a worse prognosis and a high mortality rate,largely due to the inconspicuous nature of early-stage lesions,which can lead to late diagnosis.Because of the overlapping clinical and histopathological features of AM with other forms of cutaneous melanomas,early detection of AM requires a multidisciplinary approach that integrates various diagnostic modalities,including clinical examination,dermoscopy,histopathology,molecular testing,radiological imaging,and blood tests.While surgery is the preferred method of treatment for AM,other therapeutic options may be employed based on the stage and underlying etiology of the disease.Immune checkpoint inhibitors,molecular targeted therapy,radiotherapy,chemotherapy,and oncolytic virotherapy represent promising advanced treatment options for AM.In this review,we provide an overview of the latest advancements in diagnostic and therapeutic methods for AM,highlighting the importance of early detection and the prompt,individualized management of this challenging disease.展开更多
Colorectal cancer(CRC)affects 1 in 23 males and 1 in 25 females,making it the third most common cancer.With roughly 608000 deaths worldwide,CRC accounts for 8%of all cancer-related deaths,making it the second most com...Colorectal cancer(CRC)affects 1 in 23 males and 1 in 25 females,making it the third most common cancer.With roughly 608000 deaths worldwide,CRC accounts for 8%of all cancer-related deaths,making it the second most common cause of death due to cancer.Standard and conventional CRC treatments include surgical expurgation for resectable CRC and radiotherapy,chemotherapy,immunotherapy,and their combinational regimen for non-resectable CRC.Despite these tactics,nearly half of patients develop incurable recurring CRC.Cancer cells resist the effects of chemotherapeutic drugs in a variety of ways,including drug inactivation,drug influx and efflux modifications,and ATPbinding cassette transporter overexpression.These constraints necessitate the development of new target-specific therapeutic strategies.Emerging therapeutic approaches,such as targeted immune boosting therapies,non-coding RNA-based therapies,probiotics,natural products,oncolytic viral therapies,and biomarkerdriven therapies,have shown promising results in preclinical and clinical studies.We tethered the entire evolutionary trends in the development of CRC treatments in this review and discussed the potential of new therapies and how they might be used in conjunction with conventional treatments as well as their advantages and drawbacks as future medicines.展开更多
In accordance with the World Health Organization data,cancer remains at the forefront of fatal diseases.An upward trend in cancer incidence and mortality has been observed globally,emphasizing that efforts in developi...In accordance with the World Health Organization data,cancer remains at the forefront of fatal diseases.An upward trend in cancer incidence and mortality has been observed globally,emphasizing that efforts in developing detection and treatment methods should continue.The diagnostic path typically begins with learning the medical history of a patient;this is followed by basic blood tests and imaging tests to indicate where cancer may be located to schedule a needle biopsy.Prompt initiation of diagnosis is crucial since delayed cancer detection entails higher costs of treatment and hospitalization.Thus,there is a need for novel cancer detection methods such as liquid biopsy,elastography,synthetic biosensors,fluorescence imaging,and reflectance confocal microscopy.Conventional therapeutic methods,although still common in clinical practice,pose many limitations and are unsatisfactory.Nowadays,there is a dynamic advancement of clinical research and the development of more precise and effective methods such as oncolytic virotherapy,exosome-based therapy,nanotechnology,dendritic cells,chimeric antigen receptors,immune checkpoint inhibitors,natural product-based therapy,tumor-treating fields,and photodynamic therapy.The present paper compares available data on conventional and modern methods of cancer detection and therapy to facilitate an understanding of this rapidly advancing field and its future directions.As evidenced,modern methods are not without drawbacks;there is still a need to develop new detection strategies and therapeutic approaches to improve sensitivity,specificity,safety,and efficacy.Nevertheless,an appropriate route has been taken,as confirmed by the approval of some modern methods by the Food and Drug Administration.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
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
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.
文摘Hepatocellular carcinoma(HCC)arises on the background of chronic liver disease.Despite the development of effective anti-viral therapeutics HCC is continuing to rise,in part driven by the epidemic of non-alcoholic fatty liver disease.Many patients present with advanced disease out with the criteria for transplant,resection or even locoregional therapy.Currently available therapeutics for HCC are effective in a small minority of individuals.However,there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers,great opportunities now exist for treating HCC with newer and more sophisticated agents.Whilst checkpoint inhibitors are at the forefront of this revolution,other therapeutics such as inhibitory cytokine blockade,oncolytic viruses,adoptive cellular therapies and vaccines are emerging.Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response.Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy,either in combination with one another or in combination with treatment modalities such as locoregional therapy.Together these agents are likely to generate new and exciting opportunities for treating HCC,which are summarized in this review.
基金Research in the authors’laboratories was supported in part by research grants from the National Institutes of Health(AT004418,DE020140 to TCH and RRR)the US Department of Defense(OR130096 to JMW)+3 种基金the Scoliosis Research Society(TCH and MJL)the 973 Program of the Ministry of Science and Technology(MOST)of China(#2011CB707906 to TCH)The reported work was also supported in part by The University of Chicago Cancer Center Support Grant(P30CA014599)the National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number UL1 TR000430.
文摘With rapid advances in understanding molecular pathogenesis of human diseases in the era of genome sciences and systems biology,it is anticipated that increasing numbers of therapeutic genes or targets will become available for targeted therapies.Despite numerous setbacks,efficacious gene and/or cell-based therapies still hold the great promise to revolutionize the clinical management of human diseases.It is wildly recognized that poor gene delivery is the limiting factor for most in vivo gene therapies.There has been a long-lasting interest in using viral vectors,especially adenoviral vectors,to deliver therapeutic genes for the past two decades.Among all currently available viral vectors,adenovirus is the most efficient gene delivery system in a broad range of cell and tissue types.The applications of adenoviral vectors in gene delivery have greatly increased in number and efficiency since their initial development.In fact,among over 2000 gene therapy clinical trials approved worldwide since 1989,a significant portion of the trials have utilized adenoviral vectors.This review aims to provide a comprehensive overview on the characteristics of adenoviral vectors,including adenoviral biology,approaches to engineering adenoviral vectors,and their applications in clinical and preclinical studies with an emphasis in the areas of cancer treatment,vaccination and regenerative medicine.Current challenges and future directions regarding the use of adenoviral vectors are also discussed.It is expected that the continued improvements in adenoviral vectors should provide great opportunities for cell and gene therapies to live up to its enormous potential in personalized medicine.
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 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.
文摘Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the world with an extremely poor prognosis. The major etiologic risk factors for HCC development include hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, toxins (alcohol, aflatoxin BI) and various inherited metabolic liver diseases, such as hemochromatosis and alpha-1-antitrypsin deficiency. Central to the molecular pathogenesis of HCC are mutations of various genes and genetic/chromosomal instability that result from chronic liver disease and the associated enhanced liver cell regeneration and mitotic activity. Alterations in the structure or expression of several tumor suppressor genes and oncogenes have been described. In addition, mechanisms leading to genetic instability due to mismatch repair deficiency or chromosomal instability and aneuploidy due to defective chromosomal segregation appear to be involved. The prognosis of HCC patients is generally very poor. Most studies have shown a five-year survival rate of less than 5% in symptomatic patients. HCC has been found to be quite resistant to radio- or chemotherapy. Investigations of the natural history and clinical course of HCC revealed a long-term survival of patients only with small asymptomatic HCC that could be treated surgically or nonsurgically. For patients with advanced symptomatic HCC, novel therapeutic strategies such as gene therapy are urgently needed. Apart from exploring and refining new HCC treatment strategies, the implementation of the existing measures or the development of novel measures to prevent HCC is most important. Primary HCC prevention could have a major impact on the incidence of HCC. Further, secondary prevention of a local recurrence or of new HCC lesions in patients after successful surgical or nonsurgical HCC treatment is of paramount importance and is expected to significantly improve disease-free and overall survival rates of patients. Based on rapid scientific advances, molecular diagnosis, gene therapy and molecu
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 United Kingdom Charity pancreatic Cancer Research Fundpancreatic Cancer Research United Kingdom+1 种基金Ministry of Sciences and Technology of ChinaNo.2013DFG32080
文摘Pancreatic ductal adenocarcinoma(PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses(TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1(PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer.
文摘Colorectal cancer (CRC) is one of the main reasons of tumor-related deaths worldwide.At present,the main treatment is surgery,but the results are unsatisfactory,and the prognosis is poor.The majority of patients die due to liver or lung metastasis or recurrence.In recent years,great progress has been made in the field of tumor gene therapy,providing a new treatment for combating CRC.As oncolytic viruses selectively replicate almost exclusively in the cytoplasm of tumor cells and do not require integration into the host genome,they are safer,more effective and more attractive as oncolytic agents.Newcastle disease virus (NDV) is a natural RNA oncolytic virus.After NDV selectively infects tumor cells,the immune response induced by NDV’s envelope protein and intracellular factors can effectively kill the tumor without affecting normal cells.Reverse genetic techniques make NDV a vector for gene therapy.Arming the virus by inserting various exogenous genes or using NDV in combination with immunotherapy can also improve the anti-CRC capacity of NDV,and good results have been achieved in animal models and clinical treatment trials.This article reviews the molecular biological characteristics and oncolytic mechanism of NDV and discusses in vitro and in vivo experiments on NDV anti-CRC capacity and clinical treatment.In conclusion,NDV is an excellent candidate for cancer treatment,but more preclinical studies and clinical trials are needed to ensure its safety and efficacy.
文摘The knowledge that the body possesses natural defenses to combat cancer existed long before the modern period,with multiple anecdotal reports of tumors miraculously disappearing,sometimes spontaneously or after a febrile or infectious episode.Spontaneous tumor regression of untreated malignant tumors is currently a well-accepted albeit rare phenomenon,and it is recognized that immunosuppression is associated with a higher cancer risk.The treatment of bladder carcinoma by intravesical administration of live attenuated Bacillus Calmette-Guérin bacteria was shown to be very effective in 1976 and is now standard treatment.Effective immunity against cancer involves complex interactions between the tumor,the host,and the environment.Cancer immunotherapy uses various strategies to augment tumor immunity and represents a paradigm shift in treating cancer,since attention has become more focused on the“biologic passport”of the individual tumor rather than the site of origin of the tumor.The different types of cancer immunotherapies discussed here include biologic modifiers,such as cytokines and vaccines,adoptive cell therapies,oncolytic viruses,and antibodies against immune checkpoint inhibitors,such as the co-inhibitory T-cell receptor PD-1 and one of its ligands,programmed death-ligand 1.
基金ThisstudywassupportedinpartbyagrantfromtheU S ArmyMedicalResearchMaterielCommand(DAMD17 99 1 9202)
文摘Background Oncolytic herpes simplex virus (HSV) vectors can be used for cancer therapy as direct cytotoxic agents, inducers of anti-tumor immune responses, and as expressers of anti-cancer genes. In this study, the efficacy of HSV vectors, G47Delta and NV1023 were examined for the treatment of the human breast cancer. Methods Human breast cancer MDA-MB-435 cells were cultured or implanted subcutaneously in BALB/c nude mice. The cells or tumors were inoculated with G47Delta or NV1023, and cell killing or inhibition of tumor growth determined. Both viruses contained the LacZ gene and expression in infected cells was detected with X-gal histochemistry. Results G47Delta and NV1023 were highly cytotoxic to MDA-MB-435 cells in vitro at very low multiplicities of infection. X-gal staining of infected tumor cells in vitro and in vivo illustrated the replication and spread of both viruses. G47Delta and NV1023 inoculation inhibited tumor growth and prolonged mouse survival. Both vectors behaved similarly. Conclusions Oncolytic HSV vectors, G47Delta and NV1023, were extremely effective at killing human breast cancer cells in vitro and in tumor xenografts in vivo. This novel form of cancer therapy warrants further investigation and consideration of clinical application.
基金This work was supported by the Zhejiang Provincial Natural Science Foundation of China(No.LS21H060001)the Alibaba Youth Studio Project(No.ZJU-032)the Zhejiang Province Medical and Health Science and Technology Program(Nos.2022KY1455 and 2022RC136).The funding bodies had no role in the design of the study,in collection,analysis,and interpretation of data,or in drafting the manuscript.We thank Fatima ALALIWI and Ma LING for their invaluable support and encouragement.
文摘Acral melanoma(AM)is the most common histologic subtype of melanoma in dark-skinned patients and is associated with a worse prognosis and a high mortality rate,largely due to the inconspicuous nature of early-stage lesions,which can lead to late diagnosis.Because of the overlapping clinical and histopathological features of AM with other forms of cutaneous melanomas,early detection of AM requires a multidisciplinary approach that integrates various diagnostic modalities,including clinical examination,dermoscopy,histopathology,molecular testing,radiological imaging,and blood tests.While surgery is the preferred method of treatment for AM,other therapeutic options may be employed based on the stage and underlying etiology of the disease.Immune checkpoint inhibitors,molecular targeted therapy,radiotherapy,chemotherapy,and oncolytic virotherapy represent promising advanced treatment options for AM.In this review,we provide an overview of the latest advancements in diagnostic and therapeutic methods for AM,highlighting the importance of early detection and the prompt,individualized management of this challenging disease.
文摘Colorectal cancer(CRC)affects 1 in 23 males and 1 in 25 females,making it the third most common cancer.With roughly 608000 deaths worldwide,CRC accounts for 8%of all cancer-related deaths,making it the second most common cause of death due to cancer.Standard and conventional CRC treatments include surgical expurgation for resectable CRC and radiotherapy,chemotherapy,immunotherapy,and their combinational regimen for non-resectable CRC.Despite these tactics,nearly half of patients develop incurable recurring CRC.Cancer cells resist the effects of chemotherapeutic drugs in a variety of ways,including drug inactivation,drug influx and efflux modifications,and ATPbinding cassette transporter overexpression.These constraints necessitate the development of new target-specific therapeutic strategies.Emerging therapeutic approaches,such as targeted immune boosting therapies,non-coding RNA-based therapies,probiotics,natural products,oncolytic viral therapies,and biomarkerdriven therapies,have shown promising results in preclinical and clinical studies.We tethered the entire evolutionary trends in the development of CRC treatments in this review and discussed the potential of new therapies and how they might be used in conjunction with conventional treatments as well as their advantages and drawbacks as future medicines.
文摘In accordance with the World Health Organization data,cancer remains at the forefront of fatal diseases.An upward trend in cancer incidence and mortality has been observed globally,emphasizing that efforts in developing detection and treatment methods should continue.The diagnostic path typically begins with learning the medical history of a patient;this is followed by basic blood tests and imaging tests to indicate where cancer may be located to schedule a needle biopsy.Prompt initiation of diagnosis is crucial since delayed cancer detection entails higher costs of treatment and hospitalization.Thus,there is a need for novel cancer detection methods such as liquid biopsy,elastography,synthetic biosensors,fluorescence imaging,and reflectance confocal microscopy.Conventional therapeutic methods,although still common in clinical practice,pose many limitations and are unsatisfactory.Nowadays,there is a dynamic advancement of clinical research and the development of more precise and effective methods such as oncolytic virotherapy,exosome-based therapy,nanotechnology,dendritic cells,chimeric antigen receptors,immune checkpoint inhibitors,natural product-based therapy,tumor-treating fields,and photodynamic therapy.The present paper compares available data on conventional and modern methods of cancer detection and therapy to facilitate an understanding of this rapidly advancing field and its future directions.As evidenced,modern methods are not without drawbacks;there is still a need to develop new detection strategies and therapeutic approaches to improve sensitivity,specificity,safety,and efficacy.Nevertheless,an appropriate route has been taken,as confirmed by the approval of some modern methods by the Food and Drug Administration.
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.
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.
