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1.
Br J Cancer ; 130(7): 1187-1195, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38316993

ABSTRACT

BACKGROUND: Pancreatic cancer is an aggressive, immunologically "cold" tumor. Oncolytic virotherapy is a promising treatment to overcome this problem. We developed a telomerase-specific oncolytic adenovirus armed with p53 gene (OBP-702). METHODS: We investigated the efficacy of OBP-702 for pancreatic cancer, focusing on its long-term effects via long-lived memory CD8 + T cells including tissue-resident memory T cells (TRMs) and effector memory T cells (TEMs) differentiated from effector memory precursor cells (TEMps). RESULTS: First, in vitro, OBP-702 significantly induced adenosine triphosphate (ATP), which is important for memory T cell establishment. Next, in vivo, OBP-702 local treatment to murine pancreatic PAN02 tumors increased TEMps via ATP induction from tumors and IL-15Rα induction from macrophages, leading to TRM and TEM induction. Activation of these memory T cells by OBP-702 was also maintained in combination with gemcitabine+nab-paclitaxel (GN) in a PAN02 bilateral tumor model, and GN + OBP-702 showed significant anti-tumor effects and increased TRMs in OBP-702-uninjected tumors. Finally, in a neoadjuvant model, in which PAN02 cells were re-inoculated after resection of treated-PAN02 tumors, GN + OBP-702 provided long-term anti-tumor effects even after tumor resection. CONCLUSION: OBP-702 can be a long-term immunostimulant with sustained anti-tumor effects on immunologically cold pancreatic cancer.


Subject(s)
Oncolytic Virotherapy , Oncolytic Viruses , Pancreatic Neoplasms , Telomerase , Humans , Animals , Mice , Adenoviridae/genetics , Adenoviridae/metabolism , Tumor Suppressor Protein p53/genetics , Telomerase/genetics , Telomerase/metabolism , Cell Line, Tumor , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/therapy , Adenosine Triphosphate , Oncolytic Viruses/genetics , Oncolytic Viruses/metabolism
2.
Int J Mol Sci ; 25(4)2024 Feb 16.
Article in English | MEDLINE | ID: mdl-38397030

ABSTRACT

Oncolytic Newcastle disease virus is a new type of cancer immunotherapy drug. This paper proposes a scheme for delivering oncolytic viruses using hydrogel microneedles. Gelatin methacryloyl (GelMA) was synthesized by chemical grafting, and GelMA microneedles encapsulating oncolytic Newcastle disease virus (NDV) were prepared by micro-molding and photocrosslinking. The release and expression of NDV were tested by immunofluorescence and hemagglutination experiments. The experiments proved that GelMA was successfully synthesized and had hydrogel characteristics. NDV was evenly dispersed in the allantoic fluid without agglomeration, showing a characteristic virus morphology. NDV particle size was 257.4 ± 1.4 nm, zeta potential was -13.8 ± 0.5 mV, virus titer TCID50 was 107.5/mL, and PFU was 2 × 107/mL, which had a selective killing effect on human liver cancer cells in a dose and time-dependent manner. The NDV@GelMA microneedles were arranged in an orderly cone array, with uniform height and complete needle shape. The distribution of virus-like particles was observed on the surface. GelMA microneedles could successfully penetrate 5% agarose gel and nude mouse skin. Optimal preparation conditions were freeze-drying. We successfully prepared GelMA hydrogel microneedles containing NDV, which could effectively encapsulate NDV but did not detect the release of NDV.


Subject(s)
Methacrylates , Oncolytic Virotherapy , Oncolytic Viruses , Animals , Mice , Humans , Oncolytic Viruses/genetics , Oncolytic Viruses/metabolism , Newcastle disease virus , Gelatin/metabolism , Hydrogels/metabolism
3.
Mol Cancer ; 23(1): 38, 2024 02 20.
Article in English | MEDLINE | ID: mdl-38378555

ABSTRACT

Most soft-tissue sarcomas (STS) exhibit an immunosuppressive tumor microenvironment (TME), leading to resistance against immune checkpoint inhibitors (ICIs) and limited therapeutic response. Preclinical data suggest that oncolytic viral therapy can remodel the TME, facilitating T cell accumulation and enhancing the immunogenicity of these tumors.We conducted the METROMAJX, a phase II clinical trial, to investigate the combination of JX-594, an oncolytic vaccinia virus engineered for selective tumor cell replication, with metronomic cyclophosphamide and the PD-L1 inhibitor avelumab in patients with advanced, 'cold' STS, characterized by an absence of tertiary lymphoid structures. The trial employed a two-stage Simon design. JX-594 was administered intratumorally at a dose of 1.109 pfu every 2 weeks for up to 4 intra-tumoral administrations. Cyclophosphamide was given orally at 50 mg twice daily in a week-on, week-off schedule, and avelumab was administered at 10 mg/kg biweekly. The primary endpoint was the 6-month non-progression rate.Fifteen patients were enrolled, with the most frequent toxicities being grade 1 fatigue and fever. Fourteen patients were assessable for efficacy analysis. At 6 months, only one patient remained progression-free, indicating that the trial did not meet the first stage endpoint of Simon's design. Analysis of sequential tissue biopsies and plasma samples revealed an increase in CD8 density and upregulation of immune-related protein biomarkers, including CXCL10.Intra-tumoral administration of JX-594 in combination with cyclophosphamide and avelumab is safe and capable of modulating the TME in cold STS. However, the limited efficacy observed warrants further research to define the therapeutic potential of oncolytic viruses, particularly in relation to specific histological subtypes of STS.


Subject(s)
Antibodies, Monoclonal, Humanized , Oncolytic Virotherapy , Oncolytic Viruses , Sarcoma , Humans , Tumor Microenvironment , Oncolytic Virotherapy/adverse effects , Oncolytic Viruses/genetics , Oncolytic Viruses/metabolism , Sarcoma/therapy , Cyclophosphamide/therapeutic use , Cyclophosphamide/metabolism
4.
J Am Coll Surg ; 238(4): 436-447, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38214445

ABSTRACT

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeting the B-cell antigen CD19 are standard therapy for relapsed or refractory B-cell lymphoma and leukemia. CAR T cell therapy in solid tumors is limited due to an immunosuppressive tumor microenvironment and a lack of tumor-restricted antigens. We recently engineered an oncolytic virus (CF33) with high solid tumor affinity and specificity to deliver a nonsignaling truncated CD19 antigen (CD19t), allowing targeting by CD19-CAR T cells. Here, we tested this combination against pancreatic cancer. STUDY DESIGN: We engineered CF33 to express a CD19t (CF33-CD19t) target. Flow cytometry and ELISA were performed to quantify CD19t expression, immune activation, and killing by virus and CD19-CAR T cells against various pancreatic tumor cells. Subcutaneous pancreatic human xenograft tumor models were treated with virus, CAR T cells, or virus+CAR T cells. RESULTS: In vitro, CF33-CD19t infection of tumor cells resulted in >90% CD19t cell-surface expression. Coculturing CD19-CAR T cells with infected cells resulted in interleukin-2 and interferon gamma secretion, upregulation of T-cell activation markers, and synergistic cell killing. Combination therapy of virus+CAR T cells caused significant tumor regression (day 13): control (n = 16, 485 ± 20 mm 3 ), virus alone (n = 20, 254 ± 23 mm 3 , p = 0.0001), CAR T cells alone (n = 18, 466 ± 25 mm 3 , p = NS), and virus+CAR T cells (n = 16, 128 ± 14 mm 3 , p < 0.0001 vs control; p = 0.0003 vs virus). CONCLUSIONS: Engineered CF33-CD19t effectively infects and expresses CD19t in pancreatic tumors, triggering cell killing and increased immunogenic response by CD19-CAR T cells. Notably, CF33-CD19t can turn cold immunologic tumors hot, enabling solid tumors to be targetable by agents designed against liquid tumor antigens.


Subject(s)
Oncolytic Viruses , Pancreatic Neoplasms , Receptors, Chimeric Antigen , Humans , Receptors, Chimeric Antigen/genetics , Oncolytic Viruses/genetics , Oncolytic Viruses/metabolism , T-Lymphocytes/metabolism , T-Lymphocytes/transplantation , Antigens, CD19/metabolism , Pancreatic Neoplasms/therapy , Tumor Microenvironment
5.
Mol Ther ; 32(1): 241-256, 2024 Jan 03.
Article in English | MEDLINE | ID: mdl-37927036

ABSTRACT

Oncolytic virotherapy aims to activate host antitumor immunity. In responsive tumors, intratumorally injected herpes simplex viruses (HSVs) have been shown to lyse tumor cells, resulting in local inflammation, enhanced tumor antigen presentation, and boosting of antitumor cytotoxic lymphocytes. In contrast to HSV, cytomegalovirus (CMV) is nonlytic and reprograms infected myeloid cells, limiting their antigen-presenting functions and protecting them from recognition by natural killer (NK) cells. Here, we show that when co-injected into mouse tumors with an oncolytic HSV, mouse CMV (mCMV) preferentially targeted tumor-associated myeloid cells, promoted the local release of proinflammatory cytokines, and enhanced systemic antitumor immune responses, leading to superior control of both injected and distant contralateral tumors. Deletion of mCMV genes m06, which degrades major histocompatibility complex class I (MHC class I), or m144, a viral MHC class I homolog that inhibits NK activation, was shown to diminish the antitumor activity of the HSV/mCMV combination. However, an mCMV recombinant lacking the m04 gene, which escorts MHC class I to the cell surface, showed superior HSV adjuvanticity. CMV is a potentially promising agent with which to reshape and enhance antitumor immune responses following oncolytic HSV therapy.


Subject(s)
Cytomegalovirus Infections , Herpesvirus 1, Human , Neoplasms , Oncolytic Virotherapy , Oncolytic Viruses , Animals , Mice , Herpesvirus 1, Human/genetics , Cytomegalovirus , Neoplasms/therapy , Oncolytic Virotherapy/methods , Antigen Presentation , Oncolytic Viruses/genetics , Oncolytic Viruses/metabolism
6.
Nat Commun ; 14(1): 6781, 2023 10 25.
Article in English | MEDLINE | ID: mdl-37880243

ABSTRACT

IDH1 mutations frequently occur early in human glioma. While IDH1 mutation has been shown to promote gliomagenesis via DNA and histone methylation, little is known regarding its regulation in antiviral immunity. Here, we discover that IDH1 mutation inhibits virus-induced interferon (IFN) antiviral responses in glioma cells. Mechanistically, D2HG produced by mutant IDH1 enhances the binding of DNMT1 to IRF3/7 promoters such that IRF3/7 are downregulated, leading to impaired type I IFN response in glioma cells, which enhances the susceptibility of gliomas to viral infection. Furthermore, we identify DNMT1 as a potential biomarker predicting which IDH1mut gliomas are most likely to respond to oncolytic virus. Finally, both D2HG and ectopic mutant IDH1 can potentiate the replication and oncolytic efficacy of VSVΔ51 in female mouse models. These findings reveal a pivotal role for IDH1 mutation in regulating antiviral response and demonstrate that IDH1 mutation confers sensitivity to oncolytic virotherapy.


Subject(s)
Brain Neoplasms , Glioma , Oncolytic Virotherapy , Oncolytic Viruses , Animals , Female , Humans , Mice , Brain Neoplasms/genetics , Brain Neoplasms/therapy , Glioma/genetics , Glioma/therapy , Glioma/metabolism , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , Methylation , Mutation , Oncolytic Viruses/genetics , Oncolytic Viruses/metabolism
7.
Cancer Biol Med ; 20(9)2023 08 23.
Article in English | MEDLINE | ID: mdl-37615308

ABSTRACT

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.


Subject(s)
Neoplasms , Oncolytic Virotherapy , Oncolytic Viruses , Humans , Immunotherapy , Neoplasms/therapy , Oncolytic Viruses/genetics , Oncolytic Viruses/metabolism , Tumor Microenvironment , Vaccinia virus/genetics , Vaccinia virus/metabolism , Clinical Trials as Topic
8.
Methods Mol Biol ; 2684: 319-327, 2023.
Article in English | MEDLINE | ID: mdl-37410244

ABSTRACT

Oncolytic viruses are biological agents which can easily be delivered at high doses directly to the bladder through a catheter (intravesical), with low risk of systemic uptake and toxicity. To date, a number of viruses have been delivered intravesically in patients and in murine models with bladder cancer and antitumour effects demonstrated. Here, we describe in vitro methods to evaluate Coxsackie virus, CVA21, as an oncolytic virus for the treatment of human bladder cancer by determining the susceptibility of bladder cancer cell lines expressing differing levels of ICAM-1 surface receptor to CVA21.


Subject(s)
Carcinoma , Oncolytic Virotherapy , Oncolytic Viruses , Urinary Bladder Neoplasms , Humans , Animals , Mice , Oncolytic Viruses/genetics , Oncolytic Viruses/metabolism , Oncolytic Virotherapy/methods , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/metabolism , Urinary Bladder/metabolism , Cell Line , Urinary Bladder Neoplasms/therapy , Urinary Bladder Neoplasms/pathology , Cell Line, Tumor
9.
Nat Commun ; 14(1): 4367, 2023 07 20.
Article in English | MEDLINE | ID: mdl-37474548

ABSTRACT

The codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in male mice, we identify that codependent cholesterol metabolism in tumors induces phagocytic dysfunction in monocyte-derived tumor-associated macrophages (TAMs), resulting in disease progression. Manipulating cholesterol efflux with apolipoprotein A1 (ApoA1), a cholesterol reverse transporter, restores TAM phagocytosis and reactivates TAM-T cell antitumor immunity. Cholesterol metabolomics analysis of in vivo-sorted TAMs further reveals that ApoA1 mediates lipid-related metabolic remodeling and lowers 7-ketocholesterol levels, which directly inhibits tumor necrosis factor signaling in TAMs through mitochondrial translation inhibition. An ApoA1-armed oncolytic adenovirus is also developed, which restores antitumor immunity and elicits long-term tumor-specific immune surveillance. Our findings provide insight into the mechanisms by which cholesterol metabolism impairs antitumor immunity in GBM and offer an immunometabolic approach to target cholesterol disturbances in GBM.


Subject(s)
Glioblastoma , Oncolytic Viruses , Male , Mice , Animals , Glioblastoma/genetics , Glioblastoma/therapy , Glioblastoma/metabolism , Oncolytic Viruses/genetics , Oncolytic Viruses/metabolism , Tumor-Associated Macrophages/metabolism , Phagocytosis , Cholesterol/metabolism , Tumor Microenvironment
10.
J Immunother Cancer ; 11(6)2023 06.
Article in English | MEDLINE | ID: mdl-37270180

ABSTRACT

BACKGROUND: Arginine (Arg) is a semiessential amino acid whose bioavailability is required for the in vitro replication of several oncolytic viruses. In vivo, Arg bioavailability is regulated by a combination of dietary intake, protein catabolism, and limited biosynthesis through portions of the urea cycle. Interestingly, despite the importance of bioavailable Arg to support cellular proliferation, many forms of cancer are functionally auxotrophic for this amino acid due to the epigenetic silencing of argininosuccinate synthetase 1 (ASS1), an enzyme responsible for the conversion of citrulline and aspartate into the Arg precursor argininosuccinate. The impact of this silencing on oncolytic virotherapy (OV), however, has never been examined. METHODS: To address this gap in knowledge, we generated tumor cells lacking ASS1 and examined how loss of this enzyme impacted the in vivo replication and therapeutic efficacy of oncolytic myxoma virus (MYXV). We also generated a series of recombinant MYXV constructs expressing exogenous ASS1 to evaluate the therapeutic benefit of virally reconstituting Arg biosynthesis in ASS1-/- tumors. RESULTS: Our results show that the in vitro replication of oncolytic MYXV is dependent on the presence of bioavailable Arg. This dependence can be overcome by the addition of the metabolic precursor citrulline, however, this rescue requires expression of ASS1. Because of this, tumors formed from functionally ASS1-/- cells display significantly reduced MYXV replication as well as poorer therapeutic responses. Critically, both defects could be partially rescued by expressing exogenous ASS1 from recombinant oncolytic MYXVs. CONCLUSIONS: These results demonstrate that intratumoral defects to Arg metabolism can serve as a novel barrier to virally induced immunotherapy and that the exogenous expression of ASS1 can improve the efficacy of OV in Arg-auxotrophic tumors.


Subject(s)
Myxoma virus , Neoplasms , Oncolytic Viruses , Humans , Oncolytic Viruses/metabolism , Myxoma virus/genetics , Citrulline , Neoplasms/pathology , Arginine/metabolism
11.
Eur J Cell Biol ; 102(2): 151328, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37321037

ABSTRACT

Lipocalin-2 (LCN2) performs pleiotropic and tumor context-dependent functions in cancers of diverse etiologies. In prostate cancer (PCa) cells, LCN2 regulates distinct phenotypic features, including cytoskeleton organization and expression of inflammation mediators. Oncolytic virotherapy uses oncolytic viruses (OVs) to kill cancer cells and induce anti-tumor immunity. A main source of specificity of OVs towards tumor cells stems from cancer-induced defects in interferon (IFN)-based cell autonomous immune responses. However, the molecular underpinnings of such defects in PCa cells are only partially understood. Moreover, LCN2 effects on IFN responses of PCa cells and their susceptibility to OVs are unknown. To examine these issues, we queried gene expression databases for genes coexpressed with LCN2, revealing co-expression of IFN-stimulated genes (ISGs) and LCN2. Analysis of human PCa cells revealed correlated expression of LCN2 and subsets of IFNs and ISGs. CRISPR/Cas9-mediated stable knockout of LCN2 in PC3 cells or transient overexpression of LCN2 in LNCaP cells revealed LCN2-mediated regulation of IFNE (and IFNL1) expression, activation of JAK/STAT pathway, and expression of selected ISGs. Accordingly, and dependent on a functional JAK/STAT pathway, LCN2 reduced the susceptibility of PCa cells to infection with the IFN-sensitive OV, EHDV-TAU. In PC3 cells, LCN2 knockout increased phosphorylation of eukaryotic initiation factor 2α (p-eIF2α). Inhibition of PKR-like ER kinase (PERK) in PC3-LCN2-KO cells reduced p-eIF2α while increasing constitutive IFNE expression, phosphorylation of STAT1, and ISG expression; and decreasing EHDV-TAU infection. Together, these data propose that LCN2 regulates PCa susceptibility to OVs through attenuation of PERK activity and increased IFN and ISG expression.


Subject(s)
Oncolytic Viruses , Prostatic Neoplasms , Virus Diseases , Humans , Male , Interferons/genetics , Interferons/metabolism , Janus Kinases/metabolism , Lipocalin-2/genetics , Lipocalin-2/metabolism , Oncolytic Viruses/genetics , Oncolytic Viruses/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/therapy , Prostatic Neoplasms/pathology , Signal Transduction/physiology , STAT Transcription Factors/metabolism
12.
J Virol ; 97(6): e0037223, 2023 06 29.
Article in English | MEDLINE | ID: mdl-37199666

ABSTRACT

Viral oncolytic immunotherapy is a nascent field that is developing tools to direct the immune system to find and eliminate cancer cells. Safety is improved by using cancer-targeted viruses that infect or grow poorly on normal cells. The recent discovery of the low-density lipoprotein (LDL) receptor as the major vesicular stomatitis virus (VSV) binding site allowed for the creation of a Her2/neu-targeted replicating recombinant VSV (rrVSV-G) by eliminating the LDL receptor binding site in the VSV-G glycoprotein (gp) and adding a sequence coding for a single chain antibody (SCA) to the Her2/neu receptor. The virus was adapted by serial passage on Her2/neu-expressing cancer cells resulting in a virus that yielded a 15- to 25-fold higher titer following in vitro infection of Her2/neu+-expressing cell lines than that of Her2/neu-negative cells (~1 × 108/mL versus 4 × 106 to 8 × 106/mL). An essential mutation resulting in a higher titer virus was a threonine-to-arginine change that produced an N-glycosylation site in the SCA. Infection of Her2/neu+ subcutaneous tumors yielded >10-fold more virus on days 1 and 2 than Her2/neu- tumors, and virus production continued for 5 days in Her2/neu+ tumors compared with 3 days that of 3 days in Her2/neu- tumors. rrVSV-G cured 70% of large 5-day peritoneal tumors compared with a 10% cure by a previously targeted rrVSV with a modified Sindbis gp. rrVSV-G also cured 33% of very large 7-day tumors. rrVSV-G is a new targeted oncolytic virus that has potent antitumor capabilities and allows for heterologous combination with other targeted oncolytic viruses. IMPORTANCE A new form of vesicular stomatitis virus (VSV) was created that specifically targets and destroys cancer cells that express the Her2/neu receptor. This receptor is commonly found in human breast cancer and is associated with a poor prognosis. In laboratory tests using mouse models, the virus was highly effective at eliminating implanted tumors and creating a strong immune response against cancer. VSV has many advantages as a cancer treatment, including high levels of safety and efficacy and the ability to be combined with other oncolytic viruses to enhance treatment results or to create an effective cancer vaccine. This new virus can also be easily modified to target other cancer cell surface molecules and to add immune-modifying genes. Overall, this new VSV is a promising candidate for further development as an immune-based cancer therapy.


Subject(s)
Breast Neoplasms , Glycoproteins , Oncolytic Virotherapy , Oncolytic Viruses , Vesiculovirus , Animals , Female , Humans , Mice , Breast Neoplasms/therapy , Cell Line, Tumor , Glycoproteins/genetics , Glycoproteins/metabolism , Oncolytic Virotherapy/methods , Oncolytic Viruses/genetics , Oncolytic Viruses/metabolism , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Vesiculovirus/genetics , Vesiculovirus/metabolism , Virus Replication , Survival Analysis
13.
Int Immunopharmacol ; 120: 110323, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37207446

ABSTRACT

OBJECTIVE: To evaluate targeted killing of hepatocellular carcinoma (HCC) cells by a recombinant oncolytic influenza virus expressing a PD-L1 antibody (rgFlu/PD-L1) and to develop a novel immunotherapy for HCC. METHODS: Using influenza virus reverse genetics, a recombinant oncolytic virus was generated in the background of the A/Puerto Rico/8/34 (PR8) virus, then identified via screening and passage in specific pathogen-free chicken embryos. Hepatocellular carcinoma cell killing by rgFlu/PD-L1 was confirmed in vitro and in vivo. Transcriptome analyses were used to explore PD-L1 expression and function. Western blotting revealed that PD-L1 activated the cGas-STING pathway. RESULTS: rgFlu/PD-L1 expressed the PD-L1 heavy and light chain in PB1 and PA, respectively; PR8 served as the backbone. The hemagglutinin titer of rgFlu/PD-L1 was 29, and the virus titer was 9-10 logTCID50/mL. Electron microscopy revealed that the rgFlu/PD-L1 morphology and size were consistent with wild-type influenza virus. The MTS assay showed that rgFlu/PD-L1 induced significant killing of HCC cells but not normal cells. rgFlu/PD-L1 inhibited PD-L1 expression and induced apoptosis in HepG2 cells. Notably, rgFlu/PD-L1 controlled the viability and function of CD8+ T cells by activating the cGas-STING pathway. CONCLUSION: rgFlu/PD-L1 activated the cGas-STING pathway in CD8+ T cells, causing them to kill HCC cells. This approach represents a novel immunotherapy for liver cancer.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Oncolytic Viruses , Orthomyxoviridae , Chick Embryo , Animals , Mice , CD8-Positive T-Lymphocytes , Oncolytic Viruses/genetics , Oncolytic Viruses/metabolism , B7-H1 Antigen/metabolism , Antibodies
14.
Anticancer Res ; 43(3): 1185-1191, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36854523

ABSTRACT

BACKGROUND/AIM: Attempts have been made to enhance treatment with vesicular stomatitis virus (VSV) for osteosarcoma. We have previously shown that VSV incorporated with miRNA143 enhanced the antitumor effect at some doses; however, the range of the doses was narrow. This has not been evaluated in vivo, and the synergistic effect of this antitumor effect in animals is unknown. The purpose of the study was to evaluate the oncolytic effect of VSV-miRNA on osteosarcoma cells in vivo. MATERIALS AND METHODS: A novel oncolytic VSV was developed by incorporating the tumor-suppressor microRNA143 (rVSV-miR143). In order to compare the antitumor effects of administration methods (intravenous and intratumoral administration) of rVSV-miR143 with those of VSV, a comparative analysis of primary tumor volume, metastatic lesions and survival rate was performed in mouse models of osteosarcoma. RESULTS: Following intratumoral injection, rVSV-miR143 showed a significant reduction in primary tumor volume, but no significant difference was observed in metastatic lesions and survival rate compared to VSV. Following intravenous injection, rVSV-miR143 revealed no significant difference in primary tumor volume, metastatic lesion and survival rate compared to VSV. CONCLUSION: VSV incorporating tumor-suppressor miRNA143 demonstrated a slightly synergistic antitumor effect on osteosarcoma in vivo.


Subject(s)
Bone Neoplasms , MicroRNAs , Oncolytic Viruses , Osteosarcoma , Vesiculovirus , Animals , Mice , Bone Neoplasms/genetics , Bone Neoplasms/therapy , Disease Models, Animal , MicroRNAs/genetics , MicroRNAs/therapeutic use , Osteosarcoma/genetics , Osteosarcoma/therapy , Vesicular Stomatitis/virology , Oncolytic Viruses/metabolism
15.
Hum Gene Ther ; 34(1-2): 68-77, 2023 01.
Article in English | MEDLINE | ID: mdl-36503264

ABSTRACT

A prototype strain of Coxsackievirus A21 (CVA21) is being evaluated as an oncolytic virus immunotherapy. CVA21 preferentially lyses cells that upregulate the expression of intercellular adhesion molecule 1, which includes some types of tumor cells. CVA21 has an icosahedral capsid structure made up of 60 protein subunits encapsidating a viral RNA genome with a particle diameter size of 30 nm. Rapid and robust analytical methods to quantify CVA21 total, empty, and full virus particles are important to support the process development, meet regulatory requirements, and validate manufacturing processes. In this study, we demonstrate the detection of all four CVA21 capsid proteins, VP1, VP2, VP3, and VP4, as well as VP0, a surrogate for empty particles, using in-house-generated antibodies. An automated and quantitative capillary Western blot assay, Simple Western, was developed using these antibodies to quantify CVA21 total particles through VP1, empty particles through VP0, relative ratio of empty to full particles through VP0 and VP4, and the absolute ratio of empty to total particles through VP0 and VP1. Finally, this Simple Western method was used to support CVA21 cell culture and purification process optimization as a high-throughput analytical tool to make rapid process decisions.


Subject(s)
Capsid , Oncolytic Viruses , Capsid/metabolism , Oncolytic Viruses/metabolism , Viral Proteins , Capsid Proteins/genetics , Capsid Proteins/metabolism
16.
Biomed Pharmacother ; 157: 114035, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36434955

ABSTRACT

The conventional treatment strategy for glioblastoma multiforme (GBM) is surgical resection followed by radiotherapy and chemotherapy. Oncolytic adenovirotherapy is a promising alternative to conventional treatment. It provides a strategic combination of direct tumor-specific cell lysis and antitumor immune promotion. Despite advances in oncolytic adenovirotherapy, limitations remain, including the host's antiviral immune response and insufficient viral infiltration into the tumor. Mesenchymal stem cells (MSCs) have emerged as innovative vehicles due to their ability to home to tumors and protect oncolytic adenovirus (oAd) from the host antiviral immune system. We developed an Ad5-Ki67/IL-15 driven by the Ki67 promoter and armed with IL-15. Using this construction, viral replication is related to Ki67 expression in GBM cells. Thus, MSCs with background Ki67 expression can help deliver higher levels of oncolytic viruses and can strike a balance between viral load and cell viability. Using in vitro assay, MSCs loaded with Ad5-Ki67/IL-15 (MSC-Ad5) were shown to exert anti-glioblastoma efficacy. Compared to previous attempts at direct intratumoral injection of high doses of viruses, MSCs loaded with lower doses of viruses exerted stronger therapeutic effects and promoted macrophage/microglia infiltration in a Vivo model. Collectively, our results suggest that the use of MSCs as vehicles of oAd is a promising strategy and deserves further investigation for the treatment of GBM.


Subject(s)
Glioblastoma , Mesenchymal Stem Cells , Oncolytic Virotherapy , Oncolytic Viruses , Humans , Oncolytic Virotherapy/methods , Interleukin-15/metabolism , Cell Line, Tumor , Oncolytic Viruses/genetics , Oncolytic Viruses/metabolism , Glioblastoma/therapy , Glioblastoma/metabolism , Mesenchymal Stem Cells/metabolism , Adenoviridae/genetics , Adenoviridae/metabolism , Xenograft Model Antitumor Assays
17.
Biomed Pharmacother ; 158: 114094, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36502755

ABSTRACT

As an emerging tumor therapy, ideal oncolytic viruses preferentially replicate in malignant cells, reverse the immunosuppressive tumor microenvironment, and eventually can be eliminated by the patient. It is of great significance for cancer treatment to discover new excellent oncolytic viruses. Here, we found that WNV live attenuated vaccine WNV-poly(A) could be developed as a novel ideal oncolytic agent against several types of cancers. Mechanistically, due to its high sensitivity to type Ι interferon (IFN-Ι), WNV-poly(A) could specifically kill tumor cells rather than normal cells. At the same time, WNV-poly(A) could activate Dendritic cells (DCs) and trigger tumor antigen specific response mediated by CD8 + T cell, which contributed to inhibit the propagation of original and distal tumor cells. Like intratumoral injection, intravenous injection with WNV-poly(A) also markedly delays Huh7 hepatic carcinoma (HCC) transplanted tumor progression. Most importantly, in addition to an array of mouse xenograft tumor models, WNV-poly(A) also has a significant inhibitory effect on many different types of patient-derived tumor tissues and HCC patient-derived xenograft (PDX) tumor models. Our studies reveal that WNV-poly(A) is a potent and excellent oncolytic agent against many types of tumors and may have a role in metastatic and recurrent tumors.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Oncolytic Viruses , Animals , Mice , CD8-Positive T-Lymphocytes , Cell Line, Tumor , Immunity , Liver Neoplasms/therapy , Neoplasm Recurrence, Local , Oncolytic Viruses/metabolism , Tumor Microenvironment , Virus Replication
18.
Int J Mol Sci ; 23(23)2022 Dec 06.
Article in English | MEDLINE | ID: mdl-36499754

ABSTRACT

Oncolytic adenoviruses are promising new anticancer agents. To realize their full anticancer potential, they are being engineered to express therapeutic payloads. Tumor suppressor p53 function contributes to oncolytic adenovirus activity. Many cancer cells carry an intact TP53 gene but express p53 inhibitors that compromise p53 function. Therefore, we hypothesized that oncolytic adenoviruses could be made more effective by suppressing p53 inhibitors in selected cancer cells. To investigate this concept, we attenuated the expression of the established p53 inhibitor synoviolin (SYVN1) in A549 lung cancer cells by RNA interference. Silencing SYVN1 inhibited p53 degradation, thereby increasing p53 activity, and promoted adenovirus-induced A549 cell death. Based on these observations, we constructed a new oncolytic adenovirus that expresses a short hairpin RNA against SYVN1. This virus killed A549 cells more effectively in vitro and inhibited A549 xenograft tumor growth in vivo. Surprisingly, increased susceptibility to adenovirus-mediated cell killing by SYVN1 silencing was also observed in A549 TP53 knockout cells. Hence, while the mechanism of SYVN1-mediated inhibition of adenovirus replication is not fully understood, our results clearly show that RNA interference technology can be exploited to design more potent oncolytic adenoviruses.


Subject(s)
Oncolytic Virotherapy , Oncolytic Viruses , Humans , Adenoviridae/physiology , Oncolytic Viruses/genetics , Oncolytic Viruses/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Oncolytic Virotherapy/methods , Virus Replication/genetics , Cell Line, Tumor , Xenograft Model Antitumor Assays , Ubiquitin-Protein Ligases/metabolism
19.
Int J Mol Sci ; 23(21)2022 Oct 27.
Article in English | MEDLINE | ID: mdl-36361831

ABSTRACT

An apparent paradox exists between the evidence for spontaneous systemic T cell- mediated anti-tumor immune responses in cancer patients, observed particularly in their bone marrow, and local tumor growth in the periphery. This phenomenon, known as "concomitant immunity" suggests that the local tumor and its tumor microenvironment (TME) prevent systemic antitumor immunity to become effective. Oncolytic Newcastle disease virus (NDV), an agent with inherent anti-neoplastic and immune stimulatory properties, is capable of breaking therapy resistance and immunosuppression. This review updates latest information about immunosuppression by the TME and discusses mechanisms of how oncolytic viruses, in particular NDV, and cellular immunotherapy can counteract the immunosuppressive effect of the TME. With regard to cellular immunotherapy, the review presents pre-clinical studies of post-operative active-specific immunotherapy and of adoptive T cell-mediated therapy in immunocompetent mice. Memory T cell (MTC) transfer in tumor challenged T cell-deficient nu/nu mice demonstrates longevity and functionality of these cells. Graft-versus-leukemia (GvL) studies in mice demonstrate complete remission of late-stage disease including metastases and cachexia. T cell based immunotherapy studies with human cells in human tumor xenotransplanted NOD/SCID mice demonstrate superiority of bone marrow-derived as compared to blood-derived MTCs. Results from clinical studies presented include vaccination studies using two different types of NDV-modified cancer vaccine and a pilot adoptive T-cell mediated therapy study using re-activated bone marrow-derived cancer-reactive MTCs. As an example for what can be expected from clinical immunotherapy against tumors with an immunosuppressive TME, results from vaccination studies are presented from the aggressive brain tumor glioblastoma multiforme. The last decades of basic research in virology, oncology and immunology can be considered as a success story. Based on discoveries of these research areas, translational research and clinical studies have changed the way of treatment of cancer by introducing and including immunotherapy.


Subject(s)
Neoplasms , Oncolytic Virotherapy , Oncolytic Viruses , Humans , Mice , Animals , Oncolytic Viruses/genetics , Oncolytic Viruses/metabolism , Newcastle disease virus , Tumor Microenvironment , Oncolytic Virotherapy/methods , Mice, SCID , Mice, Inbred NOD , Immunotherapy/methods , Neoplasms/therapy , Immunosuppression Therapy
20.
Angew Chem Int Ed Engl ; 61(45): e202210487, 2022 11 07.
Article in English | MEDLINE | ID: mdl-36117387

ABSTRACT

T lymphocytes (T cells) are essential for tumor immunotherapy. However, the insufficient number of activated T cells greatly limits the efficacy of tumor immunotherapy. Herein, we proposed an oncolytic virus-mimicking strategy to enhance T cell recruitment and activation for tumor treatment. We constructed an oncolytic virus-like nanoplatform (PolyIC@ZIF-8) that was degraded in the acidic tumor environment to release PolyIC and Zn2+ . The released PolyIC exhibited an oncolytic virus-like function that induced tumor cell apoptosis and promoted T cell recruitment and activation through a tumor antigen-dependent manner. More importantly, the released Zn2+ not only enhanced T cell recruitment by inducing CXCL9/10/11 expression but also promoted T cell activation to increase interferon-γ (INF-γ) expression by inducing the phosphorylation of ZAP-70 via a tumor antigen-independent manner. This Zn2+ -enhanced oncolytic virus-mimicking strategy provides a new approach for tumor immunotherapy.


Subject(s)
Nanoparticles , Neoplasms , Oncolytic Virotherapy , Oncolytic Viruses , Humans , Oncolytic Viruses/metabolism , Immunotherapy , Neoplasms/therapy , Antigens, Neoplasm , Cell Line, Tumor
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