scholarly journals Delta-24 adenoviral therapy for glioblastoma: evolution from the bench to bedside and future considerations

2021 ◽  
Vol 50 (2) ◽  
pp. E6
Author(s):  
Chibawanye I. Ene ◽  
Juan Fueyo ◽  
Frederick F. Lang
Keyword(s):  
Cancer Cells ◽  
Oncolytic Viruses ◽  
Phase Iii ◽  
Ongoing Research ◽  
Depth Analysis ◽  
Underlying Basis ◽  
Clinical Responses ◽  
Phase Iii Studies

Delta-24–based oncolytic viruses are conditional replication adenoviruses developed to selectively infect and replicate in retinoblastoma 1 (Rb)–deficient cancer cells but not normal cell with intact Rb1 pathways. Over the years, there has been a significant evolution in the design of Delta-24 based on a better understanding of the underlying basis for infection, replication, and spread within cancer. One example is the development of Delta-24-RGD (DNX-2401), where the arginine-glycine-aspartate (RGD) domain enhances the infectivity of Delta-24 for cancer cells. DNX-2401 demonstrated objective biological and clinical responses during a phase I window of opportunity clinical trial for recurrent human glioblastoma. In long-term responders (> 3 years), there was evidence of immune infiltration (T cells and macrophages) into the tumor microenvironment with minimal toxicity. Although more in-depth analysis and phase III studies are pending, these results indicate that Delta-24–based adenovirus therapy may induce an antitumor response in glioblastoma, resulting in long-term antitumor immune response. In this review, the authors discuss the preclinical and clinical development of Delta-24 oncolytic adenoviral therapy for glioblastoma and describe structural improvements to Delta-24 that have enhanced its efficacy in vivo. They also highlight ongoing research that attempts to address the remaining obstacles limiting efficacy of Delta-24 adenovirus therapy for glioblastoma.

scholarly journals HIV-Infected Macrophages Are Infected and Killed by the Interferon-Sensitive Rhabdovirus MG1

2021 ◽  
Vol 95 (9) ◽  
Author(s):  
Teslin S. Sandstrom ◽  
Nischal Ranganath ◽  
Stephanie C. Burke Schinkel ◽  
Syim Salahuddin ◽  
Oussama Meziane ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Oncolytic Viruses ◽  
Type I Interferons ◽  
Viral Reservoir ◽  
Type I ◽  
Antiviral Signaling ◽  
Infected Cells ◽  
Hiv 1

ABSTRACT The use of unique cell surface markers to target and eradicate HIV-infected cells has been a longstanding objective of HIV-1 cure research. This approach, however, overlooks the possibility that intracellular changes present within HIV-infected cells may serve as valuable therapeutic targets. For example, the identification of dysregulated antiviral signaling in cancer has led to the characterization of oncolytic viruses capable of preferentially killing cancer cells. Since impairment of cellular antiviral machinery has been proposed as a mechanism by which HIV-1 evades immune clearance, we hypothesized that HIV-infected macrophages (an important viral reservoir in vivo) would be preferentially killed by the interferon-sensitive oncolytic Maraba virus MG1. We first showed that HIV-infected monocyte-derived macrophages (MDM) were more susceptible to MG1 infection and killing than HIV-uninfected cells. As MG1 is highly sensitive to type I interferons (IFN-I), we then investigated whether we could identify IFN-I signaling differences between HIV-infected and uninfected MDM and found evidence of impaired IFN-α responsiveness within HIV-infected cells. Finally, to assess whether MG1 could target a relevant, primary cell reservoir of HIV-1, we investigated its effects in alveolar macrophages (AM) obtained from effectively treated individuals living with HIV-1. As observed with in vitro-infected MDM, we found that HIV-infected AM were preferentially eliminated by MG1. In summary, the oncolytic rhabdovirus MG1 appears to preferentially target and kill HIV-infected cells via impairment of antiviral signaling pathways and may therefore provide a novel approach to an HIV-1 cure. IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) remains a treatable, but incurable, viral infection. The establishment of viral reservoirs containing latently infected cells remains the main obstacle in the search for a cure. Cure research has also focused on only one cellular target of HIV-1 (the CD4+ T cell) while largely overlooking others (such as macrophages) that contribute to HIV-1 persistence. In this study, we address these challenges by describing a potential strategy for the eradication of HIV-infected macrophages. Specifically, we show that an engineered rhabdovirus—initially developed as a cancer therapy—is capable of preferential infection and killing of HIV-infected macrophages, possibly via the same altered antiviral signaling seen in cancer cells. As this rhabdovirus is currently being explored in phase I/II clinical trials, there is potential for this approach to be readily adapted for use within the HIV-1 cure field.

scholarly journals Growth factor–induced shedding of syndecan-1 confers glypican-1 dependence on mitogenic responses of cancer cells

2005 ◽  
Vol 171 (4) ◽  
pp. 729-738 ◽  
Author(s):  
Kan Ding ◽  
Martha Lopez-Burks ◽  
José Antonio Sánchez-Duran ◽  
Murray Korc ◽  
Arthur D. Lander
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cell Surface ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Sulfate Proteoglycan ◽  
Matrix Metalloproteinase 7 ◽  
Over Time

The cell surface heparan sulfate proteoglycan (HSPG) glypican-1 is up-regulated by pancreatic and breast cancer cells, and its removal renders such cells insensitive to many growth factors. We sought to explain why the cell surface HSPG syndecan-1, which is also up-regulated by these cells and is a known growth factor coreceptor, does not compensate for glypican-1 loss. We show that the initial responses of these cells to the growth factor FGF2 are not glypican dependent, but they become so over time as FGF2 induces shedding of syndecan-1. Manipulations that retain syndecan-1 on the cell surface make long-term FGF2 responses glypican independent, whereas those that trigger syndecan-1 shedding make initial FGF2 responses glypican dependent. We further show that syndecan-1 shedding is mediated by matrix metalloproteinase-7 (MMP7), which, being anchored to cells by HSPGs, also causes its own release in a complex with syndecan-1 ectodomains. These results support a specific role for shed syndecan-1 or MMP7–syndecan-1 complexes in tumor progression and add to accumulating evidence that syndecans and glypicans have nonequivalent functions in vivo.

scholarly journals Matrix Metalloproteinase 8 (Collagenase 2) Induces the Expression of Interleukins 6 and 8 in Breast Cancer Cells

2013 ◽  
Vol 288 (23) ◽  
pp. 16282-16294 ◽  
Author(s):  
Sally Thirkettle ◽  
Julie Decock ◽  
Hugh Arnold ◽  
Caroline J. Pennington ◽  
Diane M. Jaworski ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Matrix Metalloproteinase ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Breast Cancer Cell Lines

Matrix metalloproteinase 8 (MMP-8) is a tumor-suppressive protease that cleaves numerous substrates, including matrix proteins and chemokines. In particular, MMP-8 proteolytically activates IL-8 and, thereby, regulates neutrophil chemotaxis in vivo. We explored the effects of expression of either a WT or catalytically inactive (E198A) mutant version of MMP-8 in human breast cancer cell lines. Analysis of serum-free conditioned media from three breast cancer cell lines (MCF-7, SK-BR-3, and MDA-MB-231) expressing WT MMP-8 revealed elevated levels of IL-6 and IL-8. This increase was mirrored at the mRNA level and was dependent on MMP-8 catalytic activity. However, sustained expression of WT MMP-8 by breast cancer cells was non-permissive for long-term growth, as shown by reduced colony formation compared with cells expressing either control vector or E198A mutant MMP-8. In long-term culture of transfected MDA-MB-231 cells, expression of WT but not E198A mutant MMP-8 was lost, with IL-6 and IL-8 levels returning to base line. Rare clonal isolates of MDA-MB-231 cells expressing WT MMP-8 were generated, and these showed constitutively high levels of IL-6 and IL-8, although production of the interleukins was no longer dependent upon MMP-8 activity. These studies support a causal connection between MMP-8 activity and the IL-6/IL-8 network, with an acute response to MMP-8 involving induction of the proinflammatory mediators, which may in part serve to compensate for the deleterious effects of MMP-8 on breast cancer cell growth. This axis may be relevant to the recognized ability of MMP-8 to orchestrate the innate immune system in inflammation in vivo.

scholarly journals Multiple Mutations in Hepatitis C Virus NS5A Domain II Are Required To Confer a Significant Level of Resistance to Alisporivir

2012 ◽  
Vol 56 (10) ◽  
pp. 5113-5121 ◽  
Author(s):  
Jose A. Garcia-Rivera ◽  
Michael Bobardt ◽  
Udayan Chatterji ◽  
Sam Hopkins ◽  
Matthew A. Gregory ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Mechanism Of Action ◽  
Phase Iii ◽  
Viral Resistance ◽  
Single Mutation ◽  
Phase Iii Studies ◽  
Cyp Inhibitors

ABSTRACTAlisporivir is the most advanced host-targeting antiviral cyclophilin (Cyp) inhibitor in phase III studies and has demonstrated a great deal of promise in decreasing hepatitis C virus (HCV) viremia in infected patients. In an attempt to further elucidate the mechanism of action of alisporivir, HCV replicons resistant to the drug were selected. Interestingly, mutations constantly arose in domain II of NS5A. To demonstrate that these mutations are responsible for drug resistance, they were reintroduced into the parental HCV genome, and the resulting mutant viruses were tested for replication in the presence of alisporivir or in the absence of the alisporivir target, CypA. We also examined the effect of the mutations on NS5A binding to itself (oligomerization), CypA, RNA, and NS5B. Importantly, the mutations did not affect any of these interactions. Moreover, the mutations did not preserve NS5A-CypA interactions from alisporivir rupture. NS5A mutations alone render HCV only slightly resistant to alisporivir. In sharp contrast, when multiple NS5A mutations are combined, significant resistance was observed. The introduction of multiple mutations in NS5A significantly restored viral replication in CypA knockdown cells. Interestingly, the combination of NS5A mutations renders HCV resistant to all classes of Cyp inhibitors. This study suggests that a combination of multiple mutations in domain II of NS5A rather than a single mutation is required to render HCV significantly and universally resistant to Cyp inhibitors. This in accordance within vivodata that suggest that alisporivir is associated with a low potential for development of viral resistance.

scholarly journals EXTH-45. DELTA-24-RGDOX ACTIVATION OF THE IDO-KYN-AHR CASCADE IN GLIOBLASTOMA: OLD TARGETS FOR A NEW THERAPY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii96-ii97
Author(s):  
Teresa Nguyen ◽  
Dong Ho Shin ◽  
Hong Jiang ◽  
Derek Wainwright ◽  
Sagar Sohoni ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Oncolytic Viruses ◽  
Immune Memory ◽  
Tryptophan Depletion

Abstract Immune enhancement of virotherapy by reshaping the tumor immune landscape may improve its success rates. IDO, an IFNγ inducible tryptophan catabolizing enzyme, is upregulated in glioblastoma, correlating with poor prognoses. IDO-mediated tryptophan depletion in the tumor-microenvironment decreases proliferation and induces apoptosis of surrounding effector T-cells. Kynurenine, a metabolite of tryptophan, induces T-cell differentiation into immunosuppressive Tregs. Excess kynurenine elicits AhR-mediated lymphocyte dysfunction and immunosuppression. The immune stimulating effect of oncolytic-virus, Delta-24-RGDOX, triggers IFNγ production contributing to a positive IDO-Kynurenine-AhR feedback loop. We hypothesized that combining Delta-24-RGDOX with IDO inhibitors will synergize to effectively treat glioblastoma. We characterized IDO and AhR in Delta-24-RGDOX infected cancers using immunofluorescence, qRT-PCR, and flow cytometry and found increased expression of both proteins in vitro and in vivo. We also observed induction of AhR in CD4+ and CD8+ T-cells by Delta-24-RGDOX in vivo. Delta-24-RGDOX also increased activity of AhR in cancer cells as indicated by an AhR responsive elements transcription assay. We used a murine glioblastoma model to test the efficacy of combining Delta-24-RGDOX with IDO inhibitor, 1MT/indoximod; the combination produced 30% more long-term survivors compared Delta-24-RGDOX alone (P=0.03), which we showed, through lymphocytic depletion studies, was dependent on CD4+ T-cell activation. We observed 100% survival in the re-challenged long-term glioblastoma survivors, indicating the establishment of immune memory by the combination. Functional studies showed significant increases in anti-tumor activity of splenocytes from combination-treated mice compared to Delta-24-RGDOX-treated mice (P=0.009). Flow cytometry studies revealed that combination-treated mice yielded the highest levels of chronically activated T-cells and lowest levels of Tregs and myeloid derived suppressor cells compared to Delta-24-RGDOX single treatment (P≤0.05). This microenvironment remodeling correlated with complete tumor elimination. Altogether, Delta-24-RGDOX activates the IDO-Kyn-AhR cascade in gliomas, identifying new targets, which when inhibited have the potential to enhance the anti-glioma effect of oncolytic-viruses by reversing tumor immunosuppression.

scholarly journals Development of a selective biopharmaceutical from Herpes simplex virus type 1 glycoproteins E and I for blocking antibody mediated neutralization of oncolytic viruses

2010 ◽  
Vol 60 (4) ◽  
pp. 407-413
Author(s):  
Septimiu Bucurescu
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cancer Cells ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Oncolytic Viruses ◽  
Blocking Antibody ◽  
Simplex Virus

Development of a selective biopharmaceutical from Herpes simplex virus type 1 glycoproteins E and I for blocking antibody mediated neutralization of oncolytic virusesFuture cancer therapies will be molecular cures. They will correct, block or destroy cancer cells by targeting molecular changes that lead to carcinogenesis. Destroying cancer cells can be done using oncolytic viruses. By blocking antibody mediated neutralization of oncolytic viruses, Herpes simplex virus type 1 glycoproteins E and I could be used in the adjuvant treatment of cancer for improving the chances of oncolytic viruses to kill cancer cells in vivo.

Final follow up survey of the randomized Pbo-controlled study of oregovomab (Ov) as a consolidation treatment for advanced ovarian cancer (OC): Insights into surveillance approaches

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5079-5079 ◽  
Author(s):  
C. F. Nicodemus ◽  
J. S. Berek ◽  
B. C. Schultes ◽  
J. P. Balser ◽  
P. T. Taylor
Keyword(s):  
Phase Iii ◽  
Controlled Study ◽  
Front Line ◽  
Term Survival ◽  
Long Term Survival ◽  
Time To Relapse ◽  
Phase Iii Studies ◽  
Ongoing Phase

5079 Background: Ov is a monoclonal antibody specific for CA125 currently in two phase III studies as a consolidation immunotherapy for OC. A five year outcome follow up for patients participating in the prior randomized phase II study used to design the current pivotal trials has been completed. An assessment of survival post relapse (SPR) as a function of identifiable risk factors, and implications for long term survival survey methodology were reviewed. Methods: OC patients with no evaluable disease post front-line chemotherapy were randomized to IV infusions of OV or Pbo Q4 wks × 3, then Q12 wks. At relapse, therapy was stopped and second-line Rx was initiated without restriction. All patients were surveyed quarterly for long term outcomes for a pre-specified 5 years from initial randomization. A Kaplan-Meier (KM) analysis of overall survival and Cox multivariate analysis of SPR was completed. Results: 145 randomized participants were followed, including 67 designated as the successful front-line (SFLT) subpopulation identified to have characteristics favorable for intervention with immunotherapy (basis of ongoing phase III program). At five years, 47% of Ov (n = 73) and 37% of Pbo (n = 72) patients were alive overall, and 56% of Ov (n = 34) and 32% of Pbo (n = 33) were alive in the SFLT population. KM estimates of median survival are 57.5 mo [44.5-non-estimable (ne)] for Ov and 48.6 mo [30.9-ne] for Pbo in the overall population and ne mo [50.5-ne] for Ov and 48.6 mo [24-ne] for Pbo (p = 0.11) in the subpopulation. For relapsed patients, improved survival post relapse was most associated (Cox regression p < 0.10) with lower CA125 velocity at relapse, treatment (Ov), and longer time to relapse. Conclusions: Survival data was consistent with previously reported time to relapse data in this study. For the SFLT, the 5 yr duration of survival survey and sample size were insufficient for a definitive outcome. However, results support the hypothesis that treatment with OvaRex may provide clinical benefit. The ongoing phase III studies will include a 10 year survival survey of 354 patients to definitively assess the impact of this treatment on long term survival. [Table: see text]

scholarly journals Searching for Promoters to Drive Stable and Long-Term Transgene Expression in Fibroblasts for Syngeneic Mouse Tumor Models

2020 ◽  
Vol 21 (17) ◽  
pp. 6098
Author(s):  
Dina V. Antonova ◽  
Irina V. Alekseenko ◽  
Anastasiia K. Siniushina ◽  
Alexey I. Kuzmich ◽  
Victor V. Pleshkan
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Transgene Expression ◽  
Close Contact ◽  
Mouse Tumor ◽  
Cancer Associated Fibroblasts

Tumor is a complex system of interactions between cancer cells and other cells of the tumor microenvironment. The cancer-associated fibroblasts (CAFs) of the tumor microenvironment remain in close contact with the cancer cells and play an important role in cancer progression. Genetically, CAFs are more stable than cancer cells, making them an attractive target for genetic modification in gene therapy. However, the efficiency of various promoters for transgene expression in fibroblasts is scarcely studied. We performed a comparative analysis of transgene long-term expression under the control of strong cytomegalovirus promoter (pCMV), constitutive cell promoter of the PCNA gene (pPCNA), and the potentially fibroblast-specific promoter of the IGFBP2 gene (pIGFBP2). In vitro expression of the transgene under the control of pCMV in fibroblasts was decreased soon after transduction, whereas the expression was more stable under the control of pIGFBP2 and pPCNA. The efficiency of transgene expression was higher under pPCNA than that under pIGFBP2. Additionally, in a mouse model, pPCNA provided more stable and increased transgene expression in fibroblasts as compared to that under pCMV. We conclude that PCNA promoter is the most efficient for long-term expression of transgenes in fibroblasts both in vitro and in vivo.

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