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Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here, we describe the application of virus-like vesicles (VLV) for delivery of three immunomodulators alone and in combination, as a promising approach for cancer immunotherapy. VLV vectors were designed to deliver single chain interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA) as a single payload or as a combination payload. Intralesional delivery of the VLV vector expressing IL-12 alone, as well as the trivalent vector (designated CARG-2020) eradicated large established tumors. However, only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice, indicating a benefit of the combined immunomodulation. The abscopal effects of CARG-2020 on the non-injected contralateral tumors, as well as protection from the tumor cell re-challenge, suggest immune-mediated mechanism of protection and establishment of immunological memory. Mechanistically, CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.
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@#In recent years, the chimeric antigen receptor T-cell (CAR-T) therapy has achieved breakthrough progress in the treatment of hematologic malignancies. However, when it comes to solid tumors, numerous challenges persist.These include limited CAR-T cell infiltration, susceptibility to T cell exhaustion, off-target effects, and more.Thus, novel therapeutic strategies are imperative to enhance the efficacy of CAR-T therapy for solid tumors. In comparison to standalone CAR-T approaches, the combination of CAR-T with other tumor treatment modalities has demonstrated remarkable effectiveness in both preclinical and clinical research.This review article summarizes the advancements in combining CAR-T with various solid tumor treatments: antibody drugs, oncolytic viruses, tumor vaccines, and nanomedicines.The objective is to furnish a theoretical foundation and novel perspectives for the development of innovative CAR-T combination strategies tailored for solid tumor therapy.
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Since the oncolytic herpes simplex virus T-VEC was approved in the United States for the treatment of malignant melanoma in 2015, there has been increasing interests in the oncolytic virus therapy. The oncolytic virus therapy also occupies a certain position in the treatment research process of non-small cell lung cancer(NSCLC). Based on the rapid development of genetic engineering and protein engineering, researchers have designed many recombinant oncolytic viruses targeting various specific sites to further improve their targeting and oncolytic effect in order to alleviate symptoms and even cure NSCLC patients. This review introduces the two major classifications of oncolytic viruses, wild type and gene-edited, and how they achieve tumor lysis by specifically targeting and killing tumor cells. We focus on the research progress of oncolytic virus applied alone to treat NSCLC, or combined with chemotherapy, immunotherapies such as chimeric antigen receptor (CAR)-T cell therapy, immune checkpoint inhibitors and other current hot research to treat NSCLC. At the same time, we summarize and discuss the issue of targeted transport, which is of high concern in the academic field of oncolytic virus therapy, and point out that the use of extracellular vesicles as drug carriers has a good potential for development. Finally, we analyze the existing problems and future application prospects in the context of existing basic and clinical studies, to expend new approaches for the treatment of NSCLC, so that it is no longer limited to traditional therapies.
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Pancreatic cancer is one of the most common tumors in digestive system, which is characterized by insidious clinical symptoms, strong invasion, easy metastasis and high mortality. In recent years, immunotherapy is a new direction to the treatment of solid tumors, but its applica-tion in pancreatic cancer is limited by tumor microenvironment of pancreatic cancer. The authors systematically analyze the tumor microenvironment of pancreatic cancer, summarize the clinical researches related to pancreatic cancer immunotherapy, and discuss the prospect of pancreatic cancer immunotherapy.
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Objective To explore whether PI3K inhibitor combined with oncolytic virus can play an effective oncolytic effect on osteosarcoma. Methods The cytotoxicity to tumor cells was detected by MTT method, and the mechanism of enhancing the anti-tumor activity was explored by observation of the swelling of endoplasmic reticulum using electron microscope and the expression of apoptosis-related proteins using Western blotting. The tumor clearance ability of the combination of the PI3k inhibitor ZSTK474 and vesicular stomatitis virus A51 (VSVA51) was verified by anti-tumor experiment in vivo. The apoptosis of tumor cells was verified by immunohistochemistry. Results PI3K inhibitor could be used as sensitizers of oncolytic VSVA51, and confirmed that the)' promoted the strong apoptosis of osteosarcoma cells by aggravating the stress of endoplasmic reticulum in tumor cells (P < 0 . 01). In vivo experiments also showed that PI3K inhibitors combined with VSVA51 could significantly promote the oncolytic effect of osteosarcoma (P<0.001), and this combination therapy enhanced the infiltration of immune cells in the tumor (P<0.001). Conclusion PI3K inhibitors combined with oncolytic virus is a potential therapy for osteosarcoma.
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OBJECTIVE：To study the effects and mechanism of oncolytic virus M 1（called M 1 virus for short ）inducing the apoptosis of cervical cancer C-33A cells. METHODS ：MTT assay was used to detect survival rate of C- 33A cells that were treated with different titers （0，0.001，0.01，0.1，1，10 PFU/cell）of M 1 virus. C- 33A cells were divided into control group （0 PFU/cell）， low-dose，medium-dose and high-dose groups of M 1 virus（0.001，0.01，0.1 PFU/cell）. After treated with corresponding titers of M1 virus for 48 h，flow cytometry was used to detect the apoptotic rate and infection rate of cells；Western blot was performed to detect the protein expression of C/EBP homologous proteins （CHOP），caspase-12，caspase-3 and cleaved-caspase- 3. RESULTS ： After treated with different titers of M 1 virus，the survival rate of C- 33A cells decreased significantly （P＜0.01），and showed a dose-dependent tr end. Compared with control group ，the apoptotic rate and infection rate of cells in M 1 virus groups as well as the protein expression of CHOP ，caspase-12 and cleaved-caspase- 3（except for medium-dose group ）in M 1 virus medium-dose and high-dose groups were increased significantly （P＜0.01）. CONCLUSIONS ：M1 virus can induce the apoptosis of cervical cancer C-33A cells ，and its mechanism may be related to the activation of endoplasmic reticulum stress pathway.
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Insufficiency of standard cancer therapeutic agents and a high degree of toxicity associated with chemotherapy and radiotherapy have created a dearth of therapeutic options for metastatic cancers. Oncolytic viruses (OVs) are an emerging therapeutic option for the treatment of various human cancers. Several OVs, including poxviruses, are currently in preclinical and clinical studies and have shown to be effective in treating metastatic cancer types. Tanapoxvirus (TANV), a member of the Poxviridae family, is being developed as an OV for different human cancers due to its desirable safety and efficacy features. TANV causes a mild self-limiting febrile disease in humans, does not spread human to human, and its large genome makes it a relatively safer OV for use in humans. TANV is relatively well characterized at both molecular and clinical levels. Some of the TANV-encoded proteins that are a part of the virus' immune evasion strategy are also characterized. TANV replicates considerably slower than vaccinia virus. TANV has been shown to replicate in different human cancer cells in vitro and regresses human tumors in a nude mouse model. TANV is currently being developed as a therapeutic option for several human cancers including breast cancer, ovarian cancer, colorectal cancer, pancreatic cancer, retinoblastoma, and melanoma. This review provides a comprehensive summary from the discovery to the development of TANV as an OV candidate for a wide array of human cancers
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AIM:To establish a TaqMan RT-qPCR method for surveiling the spread of oncolytic virus M1 in tissue,helping control the dosage and assessing the safety of virus. METHODS:A TaqMan-based one-step RT-qPCR method for the detection and quantification of oncolytic virus M1 in the tissues was established. The virus load and distri-bution in the tissues of SD rats,cynomolgus monkeys and nude mice were also investigated. RESULTS:A pair of specific primers(Q3)and the standard viral RNA for SYBR Green RT-qPCR were screened and selected with the best specificity and amplification efficiency. By optimizing the experiment conditions,we found that the annealing temperature above 62℃reduced matrix effect but affected the amplification efficiency. So we established a one-step TaqMan RT-qPCR method and redesigned a pair of Q3 short primers(Q3S). Using the one-step TaqMan RT-qPCR and Q3S primer,the stan-dard RNA with low copy numbers was specifically detected under the background of mixed matrix RNA of SD rats or cyno-molgus monkeys. Furthermore,the method was verified to be suitable for detecting tissue distribution of M1 virus in the mice,SD rats and cynomolgus monkeys. CONCLUSION:The TaqMan-based one-step RT-qPCR constructed with Q3S primer can be used for M1 virus quantification in various tissue samples of different animals with better specificity and sen-sitivity,and may be further applied to the detection of clinical samples.
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Morbidity and mortality rates of bladder cancer (BC) are still rising with a poor prognosis. Therefore, better biomarkers are urgently needed to advance the accurate diagnosis and treatment of BC. The limitations of the different detection techniques of circulating tumor cell (CTC) cause that the CTC as biomarkers of point of view of diagnosis and treatment of BC is not yet clear. This review first compares and analyzes the current CTC detection technology methods, and then reviews the five aspects of screening, diagnosis, staging, curative effect monitoring, prognostic evaluation, and personalized treatment of patients with malignant tumors with oncolytic virus and CTC. The application of oncolytic virus detection CTC in BC was evaluated. The results suggest that oncolytic virus with fluorescent protein combined with fluorescence microscopy and flow cytometer are used to detect CTC. This method can be only used to detect live CTCs, instead of dead CTCs. The CTC count is more accurate, efficient with high sensitivity and specificity. It can also perform phenotypic analysis of CTC and single-cell sequencing. It can be used for screening, diagnosis, and guidance of targeted therapy for bladder cancer, assessing efficacy and judging prognosis which has a very broad clinical application prospect for advancing the accurate diagnosis and treatment of BC.
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Morbidity and mortality rates of bladder cancer (BC) are still rising with a poor prognosis. Therefore, better biomarkers are urgently needed to advance the accurate diagnosis and treatment of BC. The limitations of the different detection techniques of circulating tumor cell (CTC) cause that the CTC as biomarkers of point of view of diagnosis and treatment of BC is not yet clear. This review first compares and analyzes the current CTC detection technology methods, and then reviews the five aspects of screening, diagnosis, staging, curative effect monitoring, prognostic evaluation, and personalized treatment of patients with malignant tumors with oncolytic virus and CTC. The application of oncolytic virus detection CTC in BC was evaluated. The results suggest that oncolytic virus with fluorescent protein combined with fluorescence microscopy and flow cytometer are used to detect CTC. This method can be only used to detect live CTCs, instead of dead CTCs. The CTC count is more accurate, efficient with high sensitivity and specificity. It can also perform phenotypic analysis of CTC and single-cell sequencing. It can be used for screening, diagnosis, and guidance of targeted therapy for bladder cancer, assessing efficacy and judging prognosis which has a very broad clinical application prospect for advancing the accurate diagnosis and treatment of BC.
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Malignant glioma is the most common primary tumor of the central nervous system in adults, and it exhibits complex biological behavior and high malignancy. However, current therapies for malignant glioma are limited. Despite standard radiation therapy, maximal safe surgical resection, and combined radiochemotherapy, clinical outcomes remain dismal. Patients diagnosed with GBM only have a median survival of approximately 15 months. Several molecular targets and immunotherapies have recently emerged, and the field has made great progress, particularly with respect to oncolytic virus, which has received extensive attention among researchers because of its unique targeting, security, and antitumor effects. Oncolytic virus therapy has demonstrated considerable efficacy in basic and clinical research of various cancers. Furthermore, relevant investigations of malignant glioma are being conducted for its better understanding. Here, we review the recent clinical research progress in oncolytic virus therapy for treating malignant glioma.
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Autophagy is a physiological process of normal cells that is activated in response to accumulation of abnormal proteins, damaged organelles, and cell starvation and involves their transport to lysosomes for degradation and recycling, enabling the mainte-nance of cellular homeostasis. Oncolytic viruses, which are obtained from naturally occurring or genetically modified viruses, specifical-ly target and kill tumor cells. Despite receiving much attention, the mechanisms underlying this process remain unclear, although re-cent studies have implicated autophagy in the phenomenon. Here we outline how oncolytic viruses cause cell death via autophagy and how they can be exploited for the treatment of cancer.
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Gastric cancer is one of the malignant tumors with high morbidity and high mortality in China.Research has shown that viral infection is closely related to the occurrence of gastric cancer.EpsteinBarr virus-associated gastric cancer characterized by EB virus infection has been classified as a subtype of gastric cancer,whose epidemiology,pathogenesis,clinical and histopathologic features have been studied in detail.At the same time,oncolytic viruses reveal the inhibitory effect of the virus on tumors,and their ability to target and kill tumor cells is used in the treatment of some advanced cancers.This article will review the research advances about relevance to gastric cancer of several viruses that have been reported and the latest progress in anticancer mechanisms and combined therapies for oncolytic viruses.
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In recent years, the incidence of hematological malignancies has increased year by year, although with the progress of chemotherapy, targeted therapy and hematopoietic stem cell transplantation, the efficacy of some types of lymphoma and leukemia has been greatly improved.However, the prognosis is still poor and the fatality rate is high.Finding new strategies to improve the curative effect has become an urgent problem to be solved.Oncolytic virus can promote anti-tumor response by selectively destroying tumor cells and inducing specific anti-tumor immune response.At present, oncolytic virus has become an effective strategy for the treatment of a variety of malignant tumors.A lot of breakthrough progress has also been made in the treatment of hematological malignant tumors.In this paper, the latest research progress of oncolytic virus in the treatment of hematological malignant tumors in recent years is reviewed.
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Systemic target therapeutic drugs, such as sorafenib, lenvatinib, or regorafenib are the only drugs that are known to be effective against advanced hepatocellular carcinoma (HCC). However, these agents show a limited efficacy in killing residual tumors. Immunotherapy is an alternative approach to this treatment and has been used to successfully treat different cancers, including HCC. HCC is an inflammation-induced cancer and represents a very interesting target for immunotherapeutics. Immunotherapies aim to reverse the immune tolerance and suppression found in tumor microenvironments and include approaches, such as adoptive cell therapy, immune checkpoint inhibition, and cancer vaccination. Adoptive cell therapy uses autologous natural killer or cytokine-induced killer cells by cultivating them ex vivo and subsequently reinfusing them into the patient. Immune checkpoint inhibitors reactivate tumor-specific T cells by suppressing checkpoint-mediated inhibitory signaling. Cancer vaccination induces a tumor-specific immune response by activating effector T lymphocytes. A wide range of potential immunotherapy-related adverse events occur; therefore, a multidisciplinary collaborative management is required across the clinical spectrum. This review summarizes the current status of immunotherapy for HCC and provides a perspective on its future applications.
Subject(s)
Humans , Carcinoma, Hepatocellular , Cell- and Tissue-Based Therapy , Cytokine-Induced Killer Cells , Homicide , Immune Tolerance , Immunotherapy , Neoplasm, Residual , Oncolytic Viruses , T-Lymphocytes , Tumor Microenvironment , VaccinationABSTRACT
In recent years,the incidence of hematological malignancies has increased year by year,although with the progress of chemotherapy,targeted therapy and hematopoietic stem cell transplantation,the efficacy of some types of lymphoma and leukemia has been greatly improved.However,the prognosis is still poor and the fatality rate is high.Finding new strategies to improve the curative effect has become an urgent problem to be solved.Oncolytic virus can promote anti-tumor response by selectively destroying tumor cells and inducing specific anti-tumor immune response.At present,oncolytic virus has become an effective strategy for the treatment of a variety of malignant tumors.A lot of breakthrough progress has also been made in the treatment of hematological malignant tumors.In this paper,the latest research progress of oncolytic virus in the treatment of hematological malignant tumors in recent years is reviewed.
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Cancer is the first cause of death in China. From traditional treatment to targeted therapy and again to immunotherapy, each step forward has brought us a new hope and some challenges as well. Effective antitumor immunotherapy relies on two aspects, breakdown of immunotolerance and maintenance of system immune homeostasis. Oncolytic viruses (OVs) are capable of selective replication in malignant cells and induction of their lysis and death. With a characterization of OVs, this review introduces the mechanisms of oncolytic immunotherapy and the Results of related studies.
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Objective@#To evaluate the oncolytic effect of herpes simplex virus type 1 which carried recombined human granulocyte-macrophage colony-stimulating factor (HSV1-hGM-CSF) on the mouse breast cancer cell line 4T1 and compare the anticancer effects of HSV1-hGM-CSF, doxorubicin alone or combination on the breast cancer in mice.@*Methods@#We investigated the cytotoxic effect on 4T1 cells in vitro, the cell growth, cell apoptosis and cell cycle of 4T1 cells treated with oncolytic HSV1-hGM-CSF at different MOIs (0, 0.5, 1 and 2) and doxorubicin at different concentrations (0, 2, 4 and 8 μg/ml). The effects of oncolytic HSV1-hGM-CSF and doxorubicin on the tumor growth, survival time and their side effects on the mouse breast cancer model were observed.@*Results@#Both oncolytic HSV1-hGM-CSF and doxorubicin significantly inhibited the proliferation of 4T1 cells in vitro. Doxorubicin induced the G2/M phase arrest of 4T1 cells, while the cytotoxicity of oncolytic HSV1-hGM-CSF was no cell cycle-dependent.At day 16 after treatment with doxorubicin and HSV1-hGM-CSF, the tumor volume of 4T1 tumor bearing mice were (144.40±27.68)mm3, (216.80±57.18)mm3, (246.10±21.90)mm3, (327.50±44.24)mm3, (213.30±32.31)mm3 and (495.80±75.87)mm3 in the groups of doxorubicin combined with high dose HSV1-hGM-CSF, doxorubicin combined with low dose HSV1-hGM-CSF, doxorubicin alone, high dose HSV1-hGM-CSF alone, low dose HSV1-hGM-CSF alone and control, respectively.Compared with the control group, both doxorubicin and HSV1-hGM-CSF treatment exhibited significant reduction of primary tumor volume in vivo (P<0.001). The median survival times were 48, 50, 40, 42, 43 and 37 days in the six groups mentioned above, respectively. The median survival period of doxorubicin alone, high dose HSV1-hGM-CSF alone and low dose HSV1-hGM-CSF alone were significantly longer than that of control (P<0.05).@*Conclusion@#Synergistic effect of sequential treatment with doxorubicin and oncolytic HSV1-hGM-CSF is observed in 4T1 mouse breast cancer.
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Oncolytic virus therapy is becoming a new direction for cancer treatment, which could take the advantage of the characteristic of oncolytic virus selectively replicating in cancer cells, and killing tumor cells without damaging normal cells. Compared with conventional chemotherapy or radiotherapy, it has higher specificity, fewer side effects and the ability resisting various kinds of malignant tumors. Newcastle disease virus, a typical oncolytic virus, can cause Newcastle disease in poultry. However, no serious symptoms occurred after human being infected with NDV. With the development of reverse genetics technology, it is possible to enhance the anti-tumor activity of NDV by promoting membrane fusion and apoptosis with gene recombination. The review is about the recent research progress in vitro and in vivo oncolytic experiments and clinical application of NDV at home and abroad, which aimed at providing scientific reference for the anti-tumor study of NDV in the future.
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Objective To construct a recombinant oncolytic virus vvmIL33 that can steadily se-crete mouse IL-33 protein (mIL-33) in targeted tumor cells and to study its synergistic inhibitory effect on tumor. Methods Mouse IL-33 gene sequence was amplified by PCR and inserted into the eukaryotic ex-pression vector pCMS1. The constructed pCMS1-mIL33 was transfected into the parent virus (vJS6)-infected cells by Lipofactamine. Recombinant oncolytic virus vvmIL33 was purified by cell flow sorting. Enzyme-linked immunosorbent assay ( ELISA) was used to detect the level of mIL-33 protein in the culture superna-tant of vvmIL33-infected tumor cells. Recombinant oncolytic virus vvmIL33 and parental virus vJS6 were re-spectively used to infect tumor cells, and then analyzed by plaque formation assay and MTS kit. T cell co-culture experiments were performed to examine the anti-tumor ability of T cells induced by vvmIL33-infected tumor cells. Results Electrophoresis results of the recombinant plasmid pCMS1-mIL33 showed that mIL-33 gene was inserted successfully. Compared with the control group, vvmIL33 could steadily secrete high levels of mIL-33 protein in MC38 cells after infection (P<0. 001). Results of the plaque formation assay showed that vvmIL33-or vJS6-infected CV1 and MC38 cells produced similar amounts of virus at various time points without statistical difference (P>0. 05). Under different multiplicity of infection (MOI), the lytic ability of vvmIL33 against tumor cells was similar to that of vJS6 without statistical difference (P>0. 05). In the T cell co-culture experiments, the concentration of INF-γ protein produced by T cells in the vvmIL33-infected MC38 cell group was significantly increased as compared with that of the vJS6 group (P<0. 05). Moreover, the cytotoxic effect of induced T cells on tumor cells was also significantly increased (P<0. 05). Conclusion The recombinant oncolytic virus vvmIL33 was successfully constructed without damaging its ability to repli-cate and induce tumor cell lysis. Oncolytic virus carrying mIL-33 enhanced the immune effect of T cells and increased anti-tumor effect.