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1
Ho, Chun-Te, Mei-Hsuan Wu, Ming-Jen Chen, Shih-Pei Lin, Yu-Ting Yen, and Shih-Chieh Hung. "Combination of Mesenchymal Stem Cell-Delivered Oncolytic Virus with Prodrug Activation Increases Efficacy and Safety of Colorectal Cancer Therapy." Biomedicines 9, no. 5 (May 13, 2021): 548. http://dx.doi.org/10.3390/biomedicines9050548.
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Although oncolytic viruses are currently being evaluated for cancer treatment in clinical trials, systemic administration is hindered by many factors that prevent them from reaching the tumor cells. When administered systemically, mesenchymal stem cells (MSCs) target tumors, and therefore constitute good cell carriers for oncolytic viruses. MSCs were primed with trichostatin A under hypoxia, which upregulated the expression of CXCR4, a chemokine receptor involved in tumor tropism, and coxsackievirus and adenovirus receptor that plays an important role in adenoviral infection. After priming, MSCs were loaded with conditionally replicative adenovirus that exhibits limited proliferation in cells with a functional p53 pathway and encodes Escherichia coli nitroreductase (NTR) enzymes (CRAdNTR) for targeting tumor cells. Primed MSCs increased tumor tropism and susceptibility to adenoviral infection, and successfully protected CRAdNTR from neutralization by anti-adenovirus antibodies both in vitro and in vivo, and specifically targeted p53-deficient colorectal tumors when infused intravenously. Analyses of deproteinized tissues by UPLC-MS/QTOF revealed that these MSCs converted the co-administered prodrug CB1954 into cytotoxic metabolites, such as 4-hydroxylamine and 2-amine, inducing oncolysis and tumor growth inhibition without being toxic for the host vital organs. This study shows that the combination of oncolytic viruses delivered by MSCs with the activation of prodrugs is a new cancer treatment strategy that provides a new approach for the development of oncolytic viral therapy for various cancers.
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Raimondi, Giulia, Sabrina Gea-Sorlí, Marc Otero-Mateo, and Cristina Fillat. "Inhibition of miR-222 by Oncolytic Adenovirus-Encoded miRNA Sponges Promotes Viral Oncolysis and Elicits Antitumor Effects in Pancreatic Cancer Models." Cancers 13, no. 13 (June 28, 2021): 3233. http://dx.doi.org/10.3390/cancers13133233.
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Oncolytic adenoviruses (OA) are envisioned as a therapeutic option for patients with cancer, designed to preferentially replicate in cancer cells. However, the high number of genetic alterations in tumors can generate a context in which adenoviruses have difficulties replicating. Abnormal miRNAs expression is a trademark of pancreatic cancer, with several oncogenic miRNAs playing essential roles in cancer-associated pathways. The perturbed miRNome induces reprogramming of gene expression in host cells that can impact the complex interplay between cellular processes and viral replication. We have studied the effects of overexpressed miRNAs on oncolytic adenoviral activity and identified miRNAs modulators of adenoviral oncolysis in pancreatic cancer cells. Inhibition of the highly upregulated miR-222 sensitized cancer cells to oncolysis. To provide a therapeutic application to this insight, we engineered the oncolytic adenovirus AdNuPARmE1A with miR-222 binding sites, working as sponges to withdraw the miRNA from the cellular environment. AdNuPAR-E-miR222-S mediated-decrease of miR-222 expression in pancreatic cancer cells strongly improved the viral yield and enhanced the adenoviral cytotoxic effects. Antitumoral studies confirmed a high activity for AdNuPARmE1A-miR222-S in vivo, controlling tumor progression more effectively than the scrambled control virus in xenografts. We demonstrated that the increased antitumor potency of the novel oncolytic virus resulted from the combinatory effects of miR-222 oncomiR inhibition and the restoration of miR-222 target genes activity enhancing viral fitness.
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Phillips, Lynette, Joy Gumin, Shoudong Li, Marc Daou, Daniel Ledbetter, Anwar Hossain, Brittany Parker Kerrigan, Candelaria Gomez-Manzano, Juan Fueyo, and Frederick Lang. "TMOD-16. A NOVEL ADENOVIRAL-PERMISSIVE, IMMUNOCOMPETENT HAMSTER GLIOMA MODEL TO EVALUATE ONCOLYTIC ADENOVIRAL THERAPY." Neuro-Oncology 22, Supplement_2 (November 2020): ii231. http://dx.doi.org/10.1093/neuonc/noaa215.967.
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Abstract Oncolytic adenoviruses, including Delta-24-RGD, target tumors by direct tumor cell oncolysis and by activation of an anti-tumor immune response. Due to the species selectivity of oncolytic adenoviruses, there is currently no single preclinical animal model of glioma that supports viral replication, tumor oncolysis, and virus-mediated immune responses. To address this gap, we took advantage of the Syrian hamster to develop the first glioma model that is both adenovirus replication-permissive and immunocompetent. Hamster glioma stem-like cells (GSCs), transformed by forced expression of hTERT, SV40 large T antigen, and h-RasV12, reproducibly form intracranial tumors in hamsters. In vitro, electron microscopy and cytopathic effect assays demonstrated that hamster GSCs supported viral replication and were susceptible to Delta-24-RGD-mediated cell death. In vivo, hamster GSCs consistently developed into highly proliferative tumors resembling high-grade gliomas. Following intratumoral delivery of Delta-24-RGD, immunohistochemistry for viral proteins demonstrated viral infectivity and replication in hamster gliomas. Flow cytometry revealed increased T cell infiltration in Delta-24-RGD-infected tumors. Delta-24-RGD treatment of tumor-bearing hamsters led to significantly increased survival compared with hamsters treated with PBS. Using this model, we evaluated the effects of corticosteroid-mediated immunosuppression on Delta-24-RGD efficacy. Dexamethasone treatment significantly decreased peripheral blood lymphocytes, decreased tumor-infiltrating lymphocytes, and suppressed the levels of serum anti-adenovirus antibodies. Dexamethasone reduced the number of long-term survivors and decreased the median survival (50 days for Delta-24-RGD + dexamethasone vs undetermined for Delta-24-RGD alone). In summary, we have developed the first adenovirus-permissive, immunocompetent hamster glioma model, addressing a critical need for a model in which to study the role of direct oncolysis in driving immune mediated viral clearance versus driving an antiglioma immune response. Understanding these mechanisms is critical to optimizing the success of oncolytic adenoviral therapy in the clinic.
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Hemminki, Akseli. "Oncolytic Immunotherapy: Where Are We Clinically?" Scientifica 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/862925.
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Following a century of preclinical and clinical work, oncolytic viruses are now proving themselves in randomized phase 3 trials. Interestingly, human data indicates that these agents have potent immunostimulatory activity, raising the possibility that the key consequence of oncolysis might be induction of antitumor immunity, especially in the context of viruses harboring immunostimulatory transgenes. While safety and efficacy of many types of oncolytic viruses, including adenovirus, herpes, reo, and vaccinia seem promising, few mechanisms of action studies have been performed with human substrates. Thus, the relative contribution of “pure” oncolysis, the immune response resulting from oncolysis, and the added benefit of adding a transgene remain poorly understood. Here, the available clinical data on oncolytic viruses is reviewed, with emphasis on immunological aspects.
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Hensen, Lobke C. M., Rob C. Hoeben, and Selas T. F. Bots. "Adenovirus Receptor Expression in Cancer and Its Multifaceted Role in Oncolytic Adenovirus Therapy." International Journal of Molecular Sciences 21, no. 18 (September 17, 2020): 6828. http://dx.doi.org/10.3390/ijms21186828.
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Oncolytic adenovirus therapy is believed to be a promising way to treat cancer patients. To be able to target tumor cells with an oncolytic adenovirus, expression of the adenovirus receptor on the tumor cell is essential. Different adenovirus types bind to different receptors on the cell, of which the expression can vary between tumor types. Pre-existing neutralizing immunity to human adenovirus species C type 5 (HAdV-C5) has hampered its therapeutic efficacy in clinical trials, hence several adenoviral vectors from different species are currently being developed as a means to evade pre-existing immunity. Therefore, knowledge on the expression of appropriate adenovirus receptors on tumor cells is important. This could aid in determining which tumor types would benefit most from treatment with a certain oncolytic adenovirus type. This review provides an overview of the known receptors for human adenoviruses and how their expression on tumor cells might be differentially regulated compared to healthy tissue, before and after standardized anticancer treatments. Mechanisms behind the up- or downregulation of adenovirus receptor expression are discussed, which could be used to find new targets for combination therapy to enhance the efficacy of oncolytic adenovirus therapy. Additionally, the utility of the adenovirus receptors in oncolytic virotherapy is examined, including their role in viral spread, which might even surpass their function as primary entry receptors. Finally, future directions are offered regarding the selection of adenovirus types to be used in oncolytic adenovirus therapy in the fight against cancer.
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Peter, Malin, and Florian Kühnel. "Oncolytic Adenovirus in Cancer Immunotherapy." Cancers 12, no. 11 (November 13, 2020): 3354. http://dx.doi.org/10.3390/cancers12113354.
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Tumor-selective replicating “oncolytic” viruses are novel and promising tools for immunotherapy of cancer. However, despite their first success in clinical trials, previous experience suggests that currently used oncolytic virus monotherapies will not be effective enough to achieve complete tumor responses and long-term cure in a broad spectrum of cancers. Nevertheless, there are reasonable arguments that suggest advanced oncolytic viruses will play an essential role as enablers of multi-stage immunotherapies including established systemic immunotherapies. Oncolytic adenoviruses (oAds) display several features to meet this therapeutic need. oAds potently lyse infected tumor cells and induce a strong immunogenic cell death associated with tumor inflammation and induction of antitumor immune responses. Furthermore, established and versatile platforms of oAds exist, which are well suited for the incorporation of heterologous genes to optimally exploit and amplify the immunostimulatory effect of viral oncolysis. A considerable spectrum of functional genes has already been integrated in oAds to optimize particular aspects of immune stimulation including antigen presentation, T cell priming, engagement of additional effector functions, and interference with immunosuppression. These advanced concepts have the potential to play a promising future role as enablers of multi-stage immunotherapies involving adoptive cell transfer and systemic immunotherapies.
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Mantwill, Klaus, Florian Gerhard Klein, Dongbiao Wang, Sruthi Vasantamadhava Hindupur, Maximilian Ehrenfeld, Per Sonne Holm, and Roman Nawroth. "Concepts in Oncolytic Adenovirus Therapy." International Journal of Molecular Sciences 22, no. 19 (September 29, 2021): 10522. http://dx.doi.org/10.3390/ijms221910522.
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Oncolytic adenovirus therapy is gaining importance as a novel treatment option for the management of various cancers. Different concepts of modification within the adenovirus vector have been identified that define the mode of action against and the interaction with the tumour. Adenoviral vectors allow for genetic manipulations that restrict tumour specificity and also the expression of specific transgenes in order to support the anti-tumour effect. Additionally, replication of the virus and reinfection of neighbouring tumour cells amplify the therapeutic effect. Another important aspect in oncolytic adenovirus therapy is the virus induced cell death which is a process that activates the immune system against the tumour. This review describes which elements in adenovirus vectors have been identified for modification not only to utilize oncolytic adenovirus vectors into conditionally replicating adenoviruses (CRAds) that allow replication specifically in tumour cells but also to confer specific characteristics to these viruses. These advances in development resulted in clinical trials that are summarized based on the conceptual design.
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Reid, Tony, Andrew Kummel, Scott Caroen, Jaimin Shah, Bryan Oronsky, and Christopher Larson. "Abstract P3-07-20: Treatment of 4T1 Breast Cancer with Liposome-Encapsulated AdAPT-001, a TGF-beta Trap Encoded Oncolytic Adenovirus Currently in a Phase 1/2 Anticancer Trial." Cancer Research 83, no. 5_Supplement (March 1, 2023): P3–07–20—P3–07–20. http://dx.doi.org/10.1158/1538-7445.sabcs22-p3-07-20.
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Abstract Adenoviral vectors have been used extensively for gene therapy. However, efficient infection of cells requires expression of the coxsackie-adenoviral receptor (CAR). Many tumor cells lack adequate expression of CAR and, hence, are not good targets for adenoviral based vectors. We have developed a unique nanoparticle (Epi-039) that can be used to efficiently introduce adenoviral vectors into tumor cells that have low or no CAR expression. We used the CAR-negative 4T1 mammary carcinoma model system, which represents a typical triple-negative breast cancer cell line (ER−, PR−, HER2−) and which is refractory to adenoviral infection to demonstrate effective transduction of an encapsulated oncolytic adenovirus. The adenovirus that was used is called AdAPT-001. This armed oncolytic virus, which is currently in a phase I/II clinical trial called BETA PRIME for the treatment of refractory cancers, expresses a TGFb receptor trap to neutralize the immunosuppressive cytokine, TGF beta. Overexpression of TGF-beta positively correlates with metastasis in breast carcinoma and thus confers a poorer prognosis. In this study, the unique Epi-039 nanoparticle carrying AdAPT-001 not only significantly enhanced the transduction efficiency of AdAPT-001 but also protected it from neutralization by natural antibodies in human whole blood. Accordingly, we demonstrate a significant increase (P value= 0.0029) in the expression of green fluorescent protein (GFP) in CAR-negative 4T1 cells infected with the encapsulated AdAPT-001 adenovirus but not the unencapsulated AdAPT-001 adenovirus. Additional in vivo studies using nanoparticle encapsulated adenoviral vectors including AdAPT-001 to treat breast cancer are underway for rapid translation to the clinic. Citation Format: Tony Reid, Andrew Kummel, Scott Caroen, Jaimin Shah, Bryan Oronsky, Christopher Larson. Treatment of 4T1 Breast Cancer with Liposome-Encapsulated AdAPT-001, a TGF-beta Trap Encoded Oncolytic Adenovirus Currently in a Phase 1/2 Anticancer Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-20.
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O'Prey, Jim, Simon Wilkinson, and Kevin M. Ryan. "Tumor Antigen LRRC15 Impedes Adenoviral Infection: Implications for Virus-Based Cancer Therapy." Journal of Virology 82, no. 12 (April 2, 2008): 5933–39. http://dx.doi.org/10.1128/jvi.02273-07.
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ABSTRACT Adenoviruses for gene or oncolytic therapy are under development. Notable among these strategies is adenoviral delivery of the tumor suppressor p53. Since all therapeutics have limitations in certain settings, we have undertaken retroviral suppressor screens to identify genes conferring resistance to adenovirus-delivered p53. These studies identified the tumor antigen LRRC15, which is frequently overexpressed in multiple tumor types, as a repressor of cell death due to adenoviral p53. LRRC15, however, does not impede p53 function per se but impedes adenoviral infection. Specifically, LRRC15 causes redistribution of the coxsackievirus-adenovirus receptor away from the cell surface. This effect is manifested in less adenoviral binding to the surfaces of LRRC15-expressing cells. This discovery, therefore, not only is important for understanding adenoviral biology but also has potentially important implications for adenovirus-based anticancer therapeutics.
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Han, Zhezhu, Yeonsoo Joo, Jihyun Lee, Suwan Ko, Rong Xu, Geun-Hyeok Oh, Soojin Choi, Jeong A. Hong, Hye Jin Choi, and Jae J. Song. "High levels of Daxx due to low cellular levels of HSP25 in murine cancer cells result in inefficient adenovirus replication." Experimental & Molecular Medicine 51, no. 10 (October 2019): 1–20. http://dx.doi.org/10.1038/s12276-019-0321-4.
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Abstract When the adenoviral protein E1B55K binds death domain-associated protein (Daxx), the proteasome-dependent degradation of Daxx is initiated, and adenoviral replication is effectively maintained. Here, we show that the cellular levels of Daxx differ between human and mouse cancer cell lines. Specifically, we observed higher cellular Daxx levels and the diminished replication of oncolytic adenovirus in mouse cancer cell lines, suggesting that cellular Daxx levels limit the replication of oncolytic adenoviruses that lack E1B55K in murine cells. Indeed, the replication of oncolytic adenoviruses that lack E1B55K was significantly increased following infection with oncolytic adenovirus expressing Daxx-specific shRNA. Cellular Daxx levels were decreased in mouse cells expressing heat shock protein 25 (HSP25; homolog of human HSP27) following heat shock or stable transfection with HSP25-bearing plasmids. Furthermore, Daxx expression in murine cell lines was primarily regulated at the transcriptional level via HSP25-mediated inhibition of the nuclear translocation of the signal transducer and activator of transcription 3 (stat3) protein, which typically upregulates Daxx transcription. Conversely, human HSP27 enhanced stat3 activity to increase Daxx transcription. Interestingly, human Daxx, but not mouse Daxx, was degraded as normal by ubiquitin-dependent lysosomal degradation; however, HSP27 downregulation induced the ubiquitin-independent proteasomal degradation of Daxx.
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Kimball, Kristopher J., Angel A. Rivera, Kurt R. Zinn, Mert Icyuz, Vaibhav Saini, Jing Li, Zeng B. Zhu, et al. "Novel Infectivity-Enhanced Oncolytic Adenovirus with a Capsid-Incorporated Dual-Imaging Moiety for Monitoring Virotherapy in Ovarian Cancer." Molecular Imaging 8, no. 5 (September 1, 2009): 7290.2009.00025. http://dx.doi.org/10.2310/7290.2009.00025.
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We sought to develop a cancer-targeted, infectivity-enhanced oncolytic adenovirus that embodies a capsid-labeling fusion for non-invasive dual-modality imaging of ovarian cancer virotherapy. A functional fusion protein composed of fluorescent and nuclear imaging tags was genetically incorporated into the capsid of an infectivity-enhanced conditionally replicative adenovirus. Incorporation of herpes simplex virus thymidine kinase (HSV-tk) and monomeric red fluorescent protein 1 (mRFP1) into the viral capsid and its genomic stability were verified by molecular analyses. Replication and oncolysis were evaluated in ovarian cancer cells. Fusion functionality was confirmed by in vitro gamma camera and fluorescent microscopy imaging. Comparison of tk-mRFP virus to single-modality controls revealed similar replication efficiency and oncolytic potency. Molecular fusion did not abolish enzymatic activity of HSV-tk as the virus effectively phosphorylated thymidine both ex vivo and in vitro. In vitro fluorescence imaging demonstrated a strong correlation between the intensity of fluorescent signal and cytopathic effect in infected ovarian cancer cells, suggesting that fluorescence can be used to monitor viral replication. We have in vitro validated a new infectivity-enhanced oncolytic adenovirus with a dual-imaging modality-labeled capsid, optimized for ovarian cancer virotherapy. The new agent could provide incremental gains toward climbing the barriers for achieving conditionally replicated adenovirus efficacy in human trials.
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Jogler, Christian, Dennis Hoffmann, Dirk Theegarten, Thomas Grunwald, Klaus Überla, and Oliver Wildner. "Replication Properties of Human Adenovirus In Vivo and in Cultures of Primary Cells from Different Animal Species." Journal of Virology 80, no. 7 (April 1, 2006): 3549–58. http://dx.doi.org/10.1128/jvi.80.7.3549-3558.2006.
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ABSTRACT Oncolytic adenoviruses have emerged as a promising approach for the treatment of tumors resistant to other treatment modalities. However, preclinical safety studies are hampered by the lack of a permissive nonhuman host. Screening of a panel of primary cell cultures from seven different animal species revealed that porcine cells support productive replication of human adenovirus type 5 (Ad5) nearly as efficiently as human A549 cells, while release of infectious virus by cells from other animal species tested was diminished by several orders of magnitude. Restriction of productive Ad5 replication in rodent and rabbit cells seems to act primarily at a postentry step. Replication efficiency of adenoviral vectors harboring different E1 deletions or mutations in porcine cells was similar to that in A549 cells. Side-by-side comparison of the viral load kinetics in blood of swine and mice injected with Ad5 or a replication-deficient adenoviral vector failed to provide clear evidence for virus replication in mice. In contrast, evidence suggests that adenovirus replication occurs in swine, since adenoviral late gene expression produced a 13.5-fold increase in viral load in an individual swine from day 3 to day 7 and 100-fold increase in viral DNA levels in the Ad5-infected swine compared to the animal receiving a replication-deficient adenovirus. Lung histology of Ad5-infected swine revealed a severe interstitial pneumonia. Although the results in swine are based on a small number of animals and need to be confirmed, our data strongly suggest that infection of swine with human adenovirus or oncolytic adenoviral vectors is a more appropriate animal model to study adenoviral pathogenicity or pharmacodynamic and toxicity profiles of adenoviral vectors than infection of mice.
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Kim, Goo-Young, Ji Yeon Son, So Jin Lee, Sang Woo Jo, Changhoon In, Sang Hoon Kim, Joon Young Park, et al. "592 Enhancing the therapeutic potential of oncolytic adenoviruses with vSENS™ technology." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A627. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0592.
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BackgroundOncolytic viro-therapeutics is a promising treatment for cancer. Among the different strains of oncolytic viruses currently being developed, potent cytolytic activity, manageable safety profiles, large genomic capacity for addition of transgenes and available advanced manufacture processes make adenovirus (Ad) a great choice.1 However, the delivery of Ad for clinical application is limited due to 1) neutralization by pre-existing neutralizing antibodies (nAb) in bloodstream and 2) receptor restricted tumor-cellular entry.2 To overcome these limitations, we developed a novel proprietary polymer nanoparticle delivery system, so called Stability Enhanced Nano Shells (SENS™) for the delivery of Virus (vSENS).MethodsSENS™ employs proprietary an ionizable cationic lipid and biodegradable and biocompatible polymers. Following complexation with replication-incompetent adenovirus serotype 5 (Ad-vSENS) or replication-competent oncolytic adenovirus serotype 5 (OAd-vSENS), the physicochemical properties of the complexes were characterized by dynamic light scattering (DLS) and electron microscopy. The benefit of vSENS in coxsackievirus and adenovirus receptor (CAR) restricted cellular transduction of adenovirus was evaluated with Ad-vSENS in CAR negative cancer cells. Pharmacokinetic profile of OAd-vSENS was examined in mice following systemic administration to assess the protective effect of vSENS in the presence of pre-existing immunity to Adenoviral proteins. Anti-tumor efficacy was evaluated in syngeneic subcutaneous tumor mice models. The serum level of alanine aminotransferase (ALT) in mice was evaluated by blood chemistry analyzer.ResultsAd-vSENS effectively infected cancer cells in CAR-independent manner, where cancer cell-killing effects of OAd-vSENS were significantly enhanced in CAR negative cancer cells compare with those of naked OAd. When vSENS is complexed with an adenovirus, it encapsulates the virus like a shell shielding the adenovirus. Consistently, in syngeneic tumor bearing mice with pre-existing Ad immunity, longer virus blood half-life and longer survival of the mice were observed when administered with OAd-vSENS compared to naked OAd. The hepatotoxicity of OAd was greatly reduced by vSENS formulation as evidenced by the absence of acute spike in serum ALT levels typically seen after systemic administration of OAd.ConclusionsThe results show the potential of vSENS as a novel platform technology for delivery of Ad to overcome challenges adeno-virotherapies face in the clinic. vSENS platform is expected to expand the efficacy of the virus from cancer patients with high CAR expression to patients with limited CAR expression often associated as the cancer progresses. The platform is likely to facilitate treatment in patients with high levels of antibodies to adenovirus by shielding the virus from neutralization and increasing the bioavailability.Ethics ApprovalThe study was approved by Samyang Biopharmaceuticals Institution’s Ethics Board, approval number SYAU2009.ReferencesTwumasi-Boateng K, Pettigrew JL, Kwok YYE, Bell JC, Nelson BH, Oncolytic viruses as engineering platforms for combination immunotherapy. Nat Rev Cancer 2018;18:419–322.Zheng M, Huang J, Tong A, Yang H, Oncolytic viruses for cancer therapy: barriers and recent advances. Mol Ther Oncolytics 2019;15:234–247.
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Tysome, James Russell, Ghassan Alusi, Nick Lemoine, and Yaohe Wang. "Oncolytic Vaccinia Virus Gene Therapy for HNSCC." Otolaryngology–Head and Neck Surgery 139, no. 2_suppl (August 2008): P92—P93. http://dx.doi.org/10.1016/j.otohns.2008.05.500.
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Problem Oncolytic viral therapy a promising new strategy for the treatment of cancer and an oncolytic adenovirus was first licensed for head and neck squamous cell carcinoma (HNSCC). However, the outcomes of clinical trials with viral monotherapy have been disappointing. Oncolytic vaccinia virus represents an attractive alternative as its replication is less dependent than adenovirus on the genetic make-up of tumor cells and it has been used safely as the smallpox vaccine in millions of patients. Methods The potency and replication of vaccinia virus and adenovirus were compared in a panel of HNSCC cell lines in vitro before assessing the tumor selectivity of systemically delivered vaccinia virus in vivo. In order to increase antitumor potency, a novel vaccinia virus expressing the angiogenesis inhibitory endostatin-angiostatin fusion protein was constructed. The expression and function of this protein was confirmed in vitro and antitumor efficacy assessed in vivo. Results Oncolytic vaccinia virus was more potent than adenovirus against all HNSCC cell lines and displayed high selectivity for cancer cells, sparing normal cells both in vitro and in animal tumour models in vivo. Vaccinia virus expressing the endostatin-angiostatin fusion protein inhibited new blood vessel formation as well as tumour growth by oncolysis. The protein was expressed in virus-infected HNSCC cells and demonstrated function by the inhibition of human umbilical vein epithelial cell proliferation and tube formation in vitro. Treatment of nude mice bearing FaDu HNSCC xenografts significantly prolonged survival when compared to the oncolytic adenovirus ONYX-015 used previously for HNSCC. Conclusion This novel vaccinia virus is a promising therapeutic agent for HNSCC, which improved survival in tumour bearing mice and requires further evaluation in vivo. Significance The combination of an oncolytic vaccinia virus that delivers tumor-specific angiogenesis inhibition may prove to be an effective treatment for patients with HNSCC, with the potential for systemic delivery to treat metastatic disease. Support Cancer Research UK, Royal College of Surgeons of England, Barts and the London Trustees.
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Gillard, Andrew, Dong Ho Shin, Virginia Laspidea, Sanjay K. Singh, Hong Jiang, Debora Kim, Xuejun Fan, et al. "IMMU-11. NONO IS A NEW ADENOVIRUS SENSOR: IMPLICATION FOR VIROTHERAPY." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii133. http://dx.doi.org/10.1093/neuonc/noac209.509.
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Abstract The median survival for GBM patients is 15 months with a five-year survival rate of less than 10%. Current conventional and experimental treatments, including immune checkpoint blockade, have not improved outcomes in the vast majority of glioma patients. Oncolytic viruses (OVs) are designed to specifically infect and lyse cancer cells to elicit an anti-tumor immune response. In a clinical trial developed by the MDACC team, 20% of GBM patients treated with the oncolytic adenovirus Delta-24-RGD showed complete response and survival longer than three years (NCT00805376). Although these studies have shown that robust immune responses can be invoked using oncolytic virotherapy, the molecular mechanisms underlying OV-mediated anti-tumor immunity remain elusive. Exposure to viruses by innate immune sensors induces protective antiviral immunity. Using bulk RNA sequencing of cells infected with adenovirus we identified the main upstream regulators of the innate immune response including IFN gamma, Interferon responsive genes 3 and 7, and STAT3. However, RNAseq unexpectedly uncovered NONO (Non-POU Domain Containing Octamer Binding) as the most relevant upstream regulator. In agreement with the RNAseq data, Protein analyses demonstrated the upregulation of NONO after adenovirus infection. In addition, immunofluorescence and confocal microscopy examination of the infected cells showed the overexpression and translocation to the nucleus of NONO upon virus infection. We are the first laboratory that has identified NONO as a sensor of adenovirus infection, which may have great significance for the future development of oncolytic viruses. Importantly, we discovered the network of proteins that are upregulated after NONO activation and, finally, we have established that changes in the expression level and subcellular localization of NONO are coincident in time during the infection of cultured cells. Future work is focused on examining the immunomodulatory functions of NONO in adenoviral infected tumors and subsequent generation of NONO-resistant oncolytic adenovirus.
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Watanabe, Maki, Yuya Nishikawaji, Hirotaka Kawakami, and Ken-ichiro Kosai. "Adenovirus Biology, Recombinant Adenovirus, and Adenovirus Usage in Gene Therapy." Viruses 13, no. 12 (December 14, 2021): 2502. http://dx.doi.org/10.3390/v13122502.
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Gene therapy is currently in the public spotlight. Several gene therapy products, including oncolytic virus (OV), which predominantly replicates in and kills cancer cells, and COVID-19 vaccines have recently been commercialized. Recombinant adenoviruses, including replication-defective adenoviral vector and conditionally replicating adenovirus (CRA; oncolytic adenovirus), have been extensively studied and used in clinical trials for cancer and vaccines. Here, we review the biology of wild-type adenoviruses, the methodological principle for constructing recombinant adenoviruses, therapeutic applications of recombinant adenoviruses, and new technologies in pluripotent stem cell (PSC)-based regenerative medicine. Moreover, this article describes the technology platform for efficient construction of diverse “CRAs that can specifically target tumors with multiple factors” (m-CRAs). This technology allows for modification of four parts in the adenoviral E1 region and the subsequent insertion of a therapeutic gene and promoter to enhance cancer-specific viral replication (i.e., safety) as well as therapeutic effects. The screening study using the m-CRA technology successfully identified survivin-responsive m-CRA (Surv.m-CRA) as among the best m-CRAs, and clinical trials of Surv.m-CRA are underway for patients with cancer. This article also describes new recombinant adenovirus-based technologies for solving issues in PSC-based regenerative medicine.
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Cerullo, Vincenzo, Cristian Capasso, Markus Vaha-Koskela, Otto Hemminki, and Akseli Hemminki. "Cancer-Targeted Oncolytic Adenoviruses for Modulation of the Immune System." Current Cancer Drug Targets 18, no. 2 (January 15, 2018): 124–38. http://dx.doi.org/10.2174/1568009617666170502152352.
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Adenovirus is one of the most commonly used vectors for gene therapy and it is the first approved virus-derived drug for treatment of cancer. As an oncolytic agent, it can induce lysis of infected cells, but it can also engage the immune system, promoting activation and maturation of antigen- presenting cells (APCs). In essence, oncolysis combined with the associated immunostimulatory actions result in a “personalized in situ vaccine” for each patient. In order to take full advantage of these features, we should try to understand how adenovirus interacts with the immune system, what are the receptors involved in triggering subsequent signals and which kind of responses they elicit. Tackling these questions will give us further insight in how to manipulate adenovirus-mediated immune responses for enhancement of anti-tumor efficacy. In this review, we first highlight how oncolytic adenovirus interacts with the innate immune system and its receptors such as Toll-like receptors, nucleotide-binding and oligomerization domain (NOD)- like receptors and other immune sensors. Then we describe the effect of these interactions on the adaptive immune system and its cells, especially B and T lymphocytes. Finally, we summarize the most significant preclinical and clinical results in the field of gene therapy where researchers have engineered adenovirus to manipulate the host immune system by expressing cytokines and signalingmediators.
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Nestić, Davor, Ksenija Božinović, Isabela Pehar, Rebecca Wallace, Alan L. Parker, and Dragomira Majhen. "The Revolving Door of Adenovirus Cell Entry: Not All Pathways Are Equal." Pharmaceutics 13, no. 10 (September 29, 2021): 1585. http://dx.doi.org/10.3390/pharmaceutics13101585.
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Adenoviruses represent exceptional candidates for wide-ranging therapeutic applications, from vectors for gene therapy to oncolytics for cancer treatments. The first ever commercial gene therapy medicine was based on a recombinant adenovirus vector, while most recently, adenoviral vectors have proven critical as vaccine platforms in effectively controlling the global coronavirus pandemic. Here, we discuss factors involved in adenovirus cell binding, entry, and trafficking; how they influence efficiency of adenovirus-based vectors; and how they can be manipulated to enhance efficacy of genetically modified adenoviral variants. We focus particularly on endocytosis and how different adenovirus serotypes employ different endocytic pathways to gain cell entry, and thus, have different intracellular trafficking pathways that subsequently trigger different host antiviral responses. In the context of gene therapy, the final goal of the adenovirus vector is to efficiently deliver therapeutic transgenes into the target cell nucleus, thus allowing its functional expression. Aberrant or inefficient endocytosis can impede this goal, therefore, it should be considered when designing and constructing adenovirus-based vectors.
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Ekeke, Chigozirim N., Kira L. Russell, Kyla Joubert, David L. Bartlett, James D. Luketich, Adam C. Soloff, Zong Sheng Guo, Michael T. Lotze, and Rajeev Dhupar. "Fighting Fire With Fire: Oncolytic Virotherapy for Thoracic Malignancies." Annals of Surgical Oncology 28, no. 5 (February 11, 2021): 2715–27. http://dx.doi.org/10.1245/s10434-020-09477-4.
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AbstractThoracic malignancies are associated with high mortality rates. Conventional therapy for many of the patients with thoracic malignancies is obviated by a high incidence of locoregional recurrence and distant metastasis. Fortunately, developments in immunotherapy provide effective strategies for both local and systemic treatments that have rapidly advanced during the last decade. One promising approach to cancer immunotherapy is to use oncolytic viruses, which have the advantages of relatively high tumor specificity, selective replication-mediated oncolysis, enhanced antigen presentation, and potential for delivery of immunogenic payloads such as cytokines, with subsequent elicitation of effective antitumor immunity. Several oncolytic viruses including adenovirus, coxsackievirus B3, herpes virus, measles virus, reovirus, and vaccinia virus have been developed and applied to thoracic cancers in preclinical murine studies and clinical trials. This review discusses the current state of oncolytic virotherapy in lung cancer, esophageal cancer, and metastatic malignant pleural effusions and considers its potential as an emergent therapeutic for these patients.
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Lu, Yi, Yu Zhang, Guimin Chang, and Jun Zhang. "Comparison of Prostate-Specific Promoters and the Use of PSP-Driven Virotherapy for Prostate Cancer." BioMed Research International 2013 (2013): 1–15. http://dx.doi.org/10.1155/2013/624632.
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Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths in men today. Although virus-based gene therapy is a promising strategy to combat advanced prostate cancer, its current effectiveness is limited partially due to inefficient cellular transductionin vivo. To overcome this obstacle, conditional oncolytic viruses (such as conditional replication adenovirus (CRAD)) are developed to specifically target prostate without (or with minimal) systemic toxicity due to viral self-replication. In this study, we have analyzed and compared three prostate-specific promoters (PSA, probasin, and MMTV LTR) for their specificity and activity bothin vitroandin vivo. Both mice model with xenograft prostate tumor model and canine model were used. The best PSP was selected to construct a prostate-specific oncolytic adenovirus (CRAD) by controlling the adenoviral E1 region. The efficacy and specificity of CRAD on prostate cancer cells were examined in cell culture and animal models.
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Romanenko, Margarita, Ivan Osipov, Sergey V. Netesov, and Julia Davydova. "Adenovirus Type 6: Subtle Structural Distinctions from Adenovirus Type 5 Result in Essential Differences in Properties and Perspectives for Gene Therapy." Pharmaceutics 13, no. 10 (October 8, 2021): 1641. http://dx.doi.org/10.3390/pharmaceutics13101641.
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Adenovirus vectors are the most frequently used agents for gene therapy, including oncolytic therapy and vaccine development. It’s hard to overestimate the value of adenoviruses during the COVID-19 pandemic as to date four out of four approved viral vector-based SARS-CoV-2 vaccines are developed on adenovirus platform. The vast majority of adenoviral vectors are based on the most studied human adenovirus type 5 (HAdV-C5), however, its immunogenicity often hampers the clinical translation of HAdV-C5 vectors. The search of less seroprevalent adenovirus types led to another species C adenovirus, Adenovirus type 6 (HAdV-C6). HAdV-C6 possesses high oncolytic efficacy against multiple cancer types and remarkable ability to induce the immune response towards carrying antigens. Being genetically very close to HAdV-C5, HAdV-C6 differs from HAdV-C5 in structure of the most abundant capsid protein, hexon. This leads to the ability of HAdV-C6 to evade the uptake by Kupffer cells as well as to distinct opsonization by immunoglobulins and other blood proteins, influencing the overall biodistribution of HAdV-C6 after systemic administration. This review describes the structural features of HAdV-C6, its interaction with liver cells and blood factors, summarizes the previous experiences using HAdV-C6, and provides the rationale behind the use of HAdV-C6 for vaccine and anticancer drugs developments.
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Robinson, Michael, Betty Li, Ying Ge, Derek Ko, Satya Yendluri, Thomas Harding, Melinda VanRoey, Katherine R. Spindler, and Karin Jooss. "Novel Immunocompetent Murine Tumor Model for Evaluation of Conditionally Replication-Competent (Oncolytic) Murine Adenoviral Vectors." Journal of Virology 83, no. 8 (February 4, 2009): 3450–62. http://dx.doi.org/10.1128/jvi.02561-08.
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ABSTRACT Oncolytic adenoviral vectors that express immunostimulatory transgenes are currently being evaluated in clinic. Preclinical testing of these vectors has thus far been limited to immunodeficient xenograft tumor models since human adenoviruses do not replicate effectively in murine tumor cells. The effect of the immunostimulatory transgene on overall virus potency can therefore not be readily assessed in these models. Here, a model is described that allows the effective testing of mouse armed oncolytic adenovirus (MAV) vectors in immunocompetent syngeneic tumor models. These studies demonstrate that the MAV vectors have a high level of cytotoxicity in a wide range of murine tumor cells. The murine oncolytic viruses were successfully armed with murine granulocyte-macrophage colony-stimulating factor (mGM-CSF) by a novel method which resulted in vectors with a high level of tumor-specific transgene expression. The mGM-CSF-armed MAV vectors showed an improved level of antitumor potency and induced a systemic antitumor immune response that was greater than that induced by unarmed parental vectors in immunocompetent syngeneic tumor models. Thus, the oncolytic MAV-1 system described here provides a murine homolog model for the testing of murine armed oncolytic adenovirus vectors in immunocompetent animals. The model allows evaluation of the impact of virus replication and the host immune response on overall virus potency and enables the generation of translational data that will be important for guiding the clinical development of these viruses.
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Gao, Jian, Wenli Zhang, and Anja Ehrhardt. "Expanding the Spectrum of Adenoviral Vectors for Cancer Therapy." Cancers 12, no. 5 (May 2, 2020): 1139. http://dx.doi.org/10.3390/cancers12051139.
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Adenoviral vectors (AdVs) have attracted much attention in the fields of vaccine development and treatment for diseases such as genetic disorders and cancer. In this review, we discuss the utility of AdVs in cancer therapies. In recent years, AdVs were modified as oncolytic AdVs (OAs) that possess the characteristics of cancer cell-specific replication and killing. Different carriers such as diverse cells and extracellular vesicles are being explored for delivering OAs into cancer sites after systemic administration. In addition, there are also various strategies to improve cancer-specific replication of OAs, mainly through modifying the early region 1 (E1) of the virus genome. It has been documented that oncolytic viruses (OVs) function through stimulating the immune system, resulting in the inhibition of cancer progression and, in combination with classical immune modulators, the anti-cancer effect of OAs can be even further enforced. To enhance the cancer treatment efficacy, OAs are also combined with other standard treatments, including surgery, chemotherapy and radiotherapy. Adenovirus type 5 (Ad5) has mainly been explored to develop vectors for cancer treatment with different modulations. Only a limited number of the more than 100 identified AdV types were converted into OAs and, therefore, the construction of an adenovirus library for the screening of potential novel OA candidates is essential. Here, we provide a state-of-the-art overview of currently performed and completed clinic trials with OAs and an adenovirus library, providing novel possibilities for developing innovative adenoviral vectors for cancer treatment.
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Yousaf, Iris, Jakob Kaeppler, Sally Frost, Len W. Seymour, and Egon J. Jacobus. "Attenuation of the Hypoxia Inducible Factor Pathway after Oncolytic Adenovirus Infection Coincides with Decreased Vessel Perfusion." Cancers 12, no. 4 (April 1, 2020): 851. http://dx.doi.org/10.3390/cancers12040851.
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The interplay between oncolytic virus infection and tumour hypoxia is particularly unexplored in vivo, although hypoxia is present in virtually all solid carcinomas. In this study, oncolytic adenovirus infection foci were found within pimonidazole-reactive, oxygen-poor areas in a colorectal xenograft tumour, where the expression of VEGF, a target gene of the hypoxia-inducible factor (HIF), was attenuated. We hypothesised that adenovirus infection interferes with the HIF-signalling axis in the hypoxic tumour niche, possibly modifying the local vascular supply. In vitro, enadenotucirev (EnAd), adenovirus 11p and adenovirus 5 decreased the protein expression of HIF-1α only during the late phase of the viral life cycle by transcriptional down-regulation and not post-translational regulation. The decreasing HIF levels resulted in the down-regulation of angiogenic factors such as VEGF, coinciding with reduced endothelial tube formation but also increased T-cell activation in conditioned media transfer experiments. Using intravital microscopy, a decreased perfused vessel volume was observed in infected tumour nodules upon systemic delivery of EnAd, encoding the oxygen-independent fluorescent reporter UnaG to a tumour xenograft grown under an abdominal window chamber. We conclude that the attenuation of the HIF pathway upon adenoviral infection may contribute to anti-vascular and immunostimulatory effects in the periphery of established infection foci in vivo.
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Sato-Dahlman, Mizuho, and Masato Yamamoto. "The Development of Oncolytic Adenovirus Therapy in the Past and Future - For the Case of Pancreatic Cancer." Current Cancer Drug Targets 18, no. 2 (January 15, 2018): 153–61. http://dx.doi.org/10.2174/1568009617666170222123925.
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Pancreatic cancer is an aggressive malignant disease and the efficacy of current treatments for unresectable diseases is quite limited despite recent advances. Gene therapy /virotherapy strategies may provide new options for the treatment of various cancers including pancreatic cancer. Oncolytic adenovirus shows an antitumoral effect via its intratumoral amplification and strong cytocidal effect in a variety of cancers and it has been employed for the development of potent oncolytic virotherapy agents for pancreatic cancer. Our ultimate goal is to develop an oncolytic adenovirus enabling the treatment of patients with advanced or spread diseases by systemic injection. Systemic application of oncolytic therapy mandates more efficient and selective gene delivery and needs to embody sufficient antitumor effect even with limited initial delivery to the tumor location. In this review, the current status of oncolytic adenoviruses from the viewpoints of vector design and potential strategies to overcome current obstacles for its clinical application will be described. We will also discuss the efforts to improve the antitumor activity of oncolytic adenovirus, in in vivo animal models, and the combination therapy of oncolytic adenovirus with radiation and chemotherapy.
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Glockzin, Gabriel, Klaus Mantwill, Karsten Jurchott, Alexandra Bernshausen, Axel Ladhoff, Hans-Dieter Royer, Bernd Gansbacher, and Per Sonne Holm. "Characterization of the Recombinant Adenovirus Vector AdYB-1: Implications for Oncolytic Vector Development." Journal of Virology 80, no. 8 (April 15, 2006): 3904–11. http://dx.doi.org/10.1128/jvi.80.8.3904-3911.2006.
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ABSTRACT Conditionally replicating adenoviruses are a promising new modality for the treatment of cancer. However, early clinical trials demonstrate that the efficacy of current vectors is limited. Interestingly, DNA replication and production of viral particles do not always correlate with virus-mediated cell lysis and virus release depending on the vector utilized for infection. However, we have previously reported that nuclear accumulation of the human transcription factor YB-1 by regulating the adenoviral E2 late promoter facilitates viral DNA replication of E1-deleted adenovirus vectors which are widely used for cancer gene therapy. Here we report the promotion of virus-mediated cell killing as a new function of the human transcription factor YB-1. In contrast to the E1A-deleted vector dl312 the first-generation adenovirus vector AdYB-1, which overexpresses YB-1 under cytomegalovirus promoter control, led to necrosis-like cell death, virus production, and viral release after infection of A549 and U2OS tumor cell lines. Our data suggest that the integration of YB-1 in oncolytic adenoviruses is a promising strategy for developing oncolytic vectors with enhanced potency against different malignancies.
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Liikanen, Ilkka, Saru Basnet, Dafne C. A. Quixabeira, Kristian Taipale, Otto Hemminki, Minna Oksanen, Matti Kankainen, et al. "Oncolytic adenovirus decreases the proportion of TIM-3+ subset of tumor-infiltrating CD8+ T cells with correlation to improved survival in patients with cancer." Journal for ImmunoTherapy of Cancer 10, no. 2 (February 2022): e003490. http://dx.doi.org/10.1136/jitc-2021-003490.
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BackgroundOncolytic viruses are a potent form of active immunotherapy, capable of invoking antitumor T-cell responses. Meanwhile, less is known about their effects on immune checkpoints, the main targets for passive immunotherapy of cancer. T-cell immunoglobulin and mucin domain-3 (TIM-3) is a coinhibitory checkpoint driving T-cell exhaustion in cancer. Here we investigated the effects of oncolytic adenovirus on the TIM-3 checkpoint on tumor-infiltrating immune cells and clinical impact in patients with cancer receiving oncolytic immunotherapy.MethodsModulation of TIM-3 expression on tumor-infiltrating immune cells was studied preclinically in B16 melanoma following intratumoral treatment with Ad5/3∆24-granulocyte-macrophage colony-stimulating factor oncolytic adenovirus. We conducted a retrospective longitudinal analysis of 15 patients with advanced-stage cancer with tumor-site biopsies before and after oncolytic immunotherapy, treated in the Advanced Therapy Access Program (ISRCTN10141600, April 5, 2011). Following patient stratification with regard to TIM-3 (increase vs decrease in tumors), overall survival and imaging/marker responses were evaluated by log-rank and Fisher’s test, while coinhibitory receptors/ligands, transcriptomic changes and tumor-reactive and tumor-infltrating immune cells in biopsies and blood samples were studied by microarray rank-based statistics and immunoassays.ResultsPreclinically, TIM-3+ tumor-infiltrating lymphocytes (TILs) in B16 melanoma showed an exhausted phenotype, whereas oncolytic adenovirus treatment significantly reduced the proportion of TIM-3+ TIL subset through recruitment of less-exhausted CD8+ TIL. Decrease of TIM-3 was observed in 60% of patients, which was associated with improved overall survival over TIM-3 increase patients (p=0.004), together with evidence of clinical benefit by imaging and blood analyses. Coinhibitory T-cell receptors and ligands were consistently associated with TIM-3 changes in gene expression data, while core transcriptional exhaustion programs and T-cell dysfunction were enriched in patients with TIM-3 increase, thus identifying patients potentially benefiting from checkpoint blockade. In striking contrast, patients with TIM-3 decrease displayed an acute inflammatory signature, redistribution of tumor-reactive CD8+ lymphocytes and higher influx of CD8+ TIL into tumors, which were associated with the longest overall survival, suggesting benefit from active immunotherapy.ConclusionsOur results indicate a key role for the TIM-3 immune checkpoint in oncolytic adenoviral immunotherapy. Moreover, our results identify TIM-3 as a potential biomarker for oncolytic adenoviruses and create rationale for combination with passive immunotherapy for a subset of patients.
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Blanchette, Paola, and Jose G. Teodoro. "A Renaissance for Oncolytic Adenoviruses?" Viruses 15, no. 2 (January 26, 2023): 358. http://dx.doi.org/10.3390/v15020358.
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In the 1990s, adenovirus became one of the first virus types to be genetically engineered to selectively destroy cancer cells. In the intervening years, the field of “oncolytic viruses” has slowly progressed and culminated in 2015 with the FDA approval of Talimogene laherparepvec, a genetically engineered herpesvirus, for the treatment of metastatic melanoma. Despite the slower progress in translating oncolytic adenovirus to the clinic, interest in the virus remains strong. Among all the clinical trials currently using viral oncolytic agents, the largest proportion of these are using recombinant adenovirus. Many trials are currently underway to use oncolytic virus in combination with immune checkpoint inhibitors (ICIs), and early results using oncolytic adenovirus in this manner are starting to show promise. Many of the existing strategies to engineer adenoviruses were designed to enhance selective tumor cell replication without much regard to interactions with the immune system. Adenovirus possesses a wide range of viral factors to attenuate both innate anti-viral pathways and immune cell killing. In this review, we summarize the strategies of oncolytic adenoviruses currently in clinical trials, and speculate how the mutational backgrounds of these viruses may impact upon the efficacy of these agents in oncolytic and immunotherapy. Despite decades of research on human adenoviruses, the interactions that these viruses have with the immune system remains one of the most understudied aspects of the virus and needs to be improved to rationally design the next generation of engineered viruses.
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Vermeulen, Christie, Tereza Brachtlova, Nikki Tol, Ida H. van der Meulen-Muileman, Jasmina Hodzic, Henri J. van de Vrugt, and Victor W. van Beusechem. "Evaluation of a Novel Oncolytic Adenovirus Silencing SYVN1." International Journal of Molecular Sciences 23, no. 23 (December 6, 2022): 15430. http://dx.doi.org/10.3390/ijms232315430.
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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.
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Farzad, Lisa, Vincenzo Cerullo, Shigeki Yagyu, Terry Bertin, Akseli Hemminki, Cliona Rooney, Brendan Lee, and Masataka Suzuki. "Combinatorial treatment with oncolytic adenovirus and helper-dependent adenovirus augments adenoviral cancer gene therapy." Molecular Therapy - Oncolytics 1 (2014): 14008. http://dx.doi.org/10.1038/mto.2014.8.
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Bots, Selas T. F., and Rob C. Hoeben. "Non-Human Primate-Derived Adenoviruses for Future Use as Oncolytic Agents?" International Journal of Molecular Sciences 21, no. 14 (July 8, 2020): 4821. http://dx.doi.org/10.3390/ijms21144821.
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Non-human primate (NHP)-derived adenoviruses have formed a valuable alternative for the use of human adenoviruses in vaccine development and gene therapy strategies by virtue of the low seroprevalence of neutralizing immunity in the human population. The more recent use of several human adenoviruses as oncolytic agents has exhibited excellent safety profiles and firm evidence of clinical efficacy. This proffers the question whether NHP-derived adenoviruses could also be employed for viral oncolysis in human patients. While vaccine vectors are conventionally made as replication-defective vectors, in oncolytic applications replication-competent viruses are used. The data on NHP-derived adenoviral vectors obtained from vaccination studies can only partially support the suitability of NHP-derived adenoviruses for use in oncolytic virus therapy. In addition, the use of NHP-derived adenoviruses in humans might be received warily given the recent zoonotic infections with influenza viruses and coronaviruses. In this review, we discuss the similarities and differences between human- and NHP-derived adenoviruses in view of their use as oncolytic agents. These include their genome organization, receptor use, replication and cell lysis, modulation of the host’s immune responses, as well as their pathogenicity in humans. Together, the data should facilitate a rational and data-supported decision on the suitability of NHP-derived adenoviruses for prospective use in oncolytic virus therapy.
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Ylösmäki, Erkko, Tanja Hakkarainen, Akseli Hemminki, Tapio Visakorpi, Raul Andino, and Kalle Saksela. "Generation of a Conditionally Replicating Adenovirus Based on Targeted Destruction of E1A mRNA by a Cell Type-Specific MicroRNA." Journal of Virology 82, no. 22 (September 17, 2008): 11009–15. http://dx.doi.org/10.1128/jvi.01608-08.
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ABSTRACT MicroRNAs have emerged as important players in tissue-specific mammalian gene regulation and have also been exploited in experimental targeting of gene expression. We have constructed a recombinant adenovirus that contains sequences complementary to the liver-specific microRNA 122 (miR122) in the 3′ untranslated region of the E1A gene. In Huh7 cells, which resemble normal hepatocytes in expressing high levels of miR122, this feature resulted in strongly reduced levels of E1A mRNA and protein. This property allowed us to generate a novel recombinant adenovirus that was severely attenuated in cells of hepatic origin but replicated normally in other cells. This strategy may be useful in circumventing liver toxicity associated with the systemic delivery of oncolytic adenoviruses. These data provide the first example of exploiting differential microRNA expression patterns to alter the natural tropism of a DNA virus. In addition, these results suggest that other microRNAs expressed in a tissue- or transformation-specific manner may also be used for the targeting of adenoviral replication and that the same principle may be applied to other viruses that have shown promise as oncolytic or gene delivery platforms.
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Schröer, Katrin, Fatima Arakrak, Annika Bremke, Anja Ehrhardt, and Wenli Zhang. "HEHR: Homing Endonuclease-Mediated Homologous Recombination for Efficient Adenovirus Genome Engineering." Genes 13, no. 11 (November 16, 2022): 2129. http://dx.doi.org/10.3390/genes13112129.
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Adenoviruses are non-enveloped linear double-stranded DNA viruses with over 100 types in humans. Adenovirus vectors have gained tremendous attention as gene delivery vehicles, as vaccine vectors and as oncolytic viruses. Although various methods have been used to generate adenoviral vectors, the vector-producing process remains technically challenging regarding efficacious genome modification. Based on our previously reported adenoviral genome modification streamline via linear–circular homologous recombination, we further develop an HEHR (combining Homing Endonucleases and Homologous Recombination) method to engineer adenoviral genomes more efficiently. I-PpoI, a rare endonuclease encoded by a group I intron, was introduced into the previously described ccdB counter-selection marker. We found that the I-PpoI pre-treatment of counter-selection containing parental plasmid increased the homologous recombination efficiency up to 100%. The flanking of the counter-selection marker with either single or double I-PpoI sites showed enhanced efficacy. In addition, we constructed a third counter-selection marker flanked by an alternative restriction enzyme: AbsI, which could be applied in case the I-PpoI site already existed in the transgene cassette that was previously inserted in the adenovirus genome. Together, HEHR can be applied for seamless sequence replacements, deletions and insertions. The advantages of HEHR in seamless mutagenesis will facilitate rational design of adenoviral vectors for diverse purposes.
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Santos, Joao, Camilla Heiniö, Dafne Quixabeira, Sadia Zafar, James Clubb, Santeri Pakola, Victor Cervera-Carrascon, Riikka Havunen, Anna Kanerva, and Akseli Hemminki. "Systemic Delivery of Oncolytic Adenovirus to Tumors Using Tumor-Infiltrating Lymphocytes as Carriers." Cells 10, no. 5 (April 22, 2021): 978. http://dx.doi.org/10.3390/cells10050978.
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Immunotherapy with tumor-infiltrating lymphocytes (TIL) or oncolytic adenoviruses, have shown promising results in cancer treatment, when used as separate therapies. When used in combination, the antitumor effect is synergistically potentiated due oncolytic adenovirus infection and its immune stimulating effects on T cells. Indeed, studies in hamsters have shown a 100% complete response rate when animals were treated with oncolytic adenovirus coding for TNFa and IL-2 (Ad5/3-E2F-D24-hTNFa-IRES-hIL2; TILT-123) and TIL therapy. In humans, one caveat with oncolytic virus therapy is that intratumoral injection has been traditionally preferred over systemic administration, for achieving sufficient virus concentrations in tumors, especially when neutralizing antibodies emerge. We have previously shown that 5/3 chimeric oncolytic adenovirus can bind to human lymphocytes for avoidance of neutralization. In this study, we hypothesized that incubation of oncolytic adenovirus (TILT-123) with TILs prior to systemic injection would allow delivery of virus to tumors. This approach would deliver both components in one self-amplifying product. TILs would help deliver TILT-123, whose replication will recruit more TILs and increase their cytotoxicity. In vitro, TILT-123 was seen binding efficiently to lymphocytes, supporting the idea of dual administration. We show in vivo in different models that virus could be delivered to tumors with TILs as carriers.
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Hao, Jiali, Wenjie Xie, Hui Li, and Runsheng Li. "Prostate Cancer-Specific of DD3-driven oncolytic virus-harboring mK5 gene." Open Medicine 14, no. 1 (December 24, 2018): 1–9. http://dx.doi.org/10.1515/med-2019-0001.
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AbstractProstate cancer (PCa) is the second most diagnosed cancer in Western male population. In this study, we insert mK5 (the mutational kringle5 of human plasminogen) into a DD3-promoted (differential display code 3) oncolytic adenovirus to construct OncoAd.mK5.DD3. E1A.dE1B, briefly, OAd.DD3.mK5. DD3 is one of the most prostate cancer specific promoters which can transcriptionally control adenoviral replication. mK5 has been proved to be able to inhibit the tumor angiogenesis and inhibit cell proliferation. Our results suggested that targeting PCa with OAd.DD3.mK5 elicited strong antitumor effect.
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Yano, Shuya, Hiroshi Tazawa, Hiroyuki Kishimoto, Shunsuke Kagawa, Toshiyoshi Fujiwara, and Robert M. Hoffman. "Real-Time Fluorescence Image-Guided Oncolytic Virotherapy for Precise Cancer Treatment." International Journal of Molecular Sciences 22, no. 2 (January 17, 2021): 879. http://dx.doi.org/10.3390/ijms22020879.
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Oncolytic virotherapy is one of the most promising, emerging cancer therapeutics. We generated three types of telomerase-specific replication-competent oncolytic adenovirus: OBP-301; a green fluorescent protein (GFP)-expressing adenovirus, OBP-401; and Killer-Red-armed OBP-301. These oncolytic adenoviruses are driven by the human telomerase reverse transcriptase (hTERT) promoter; therefore, they conditionally replicate preferentially in cancer cells. Fluorescence imaging enables visualization of invasion and metastasis in vivo at the subcellular level; including molecular dynamics of cancer cells, resulting in greater precision therapy. In the present review, we focused on fluorescence imaging applications to develop precision targeting for oncolytic virotherapy. Cell-cycle imaging with the fluorescence ubiquitination cell cycle indicator (FUCCI) demonstrated that combination therapy of an oncolytic adenovirus and a cytotoxic agent could precisely target quiescent, chemoresistant cancer stem cells (CSCs) based on decoying the cancer cells to cycle to S-phase by viral treatment, thereby rendering them chemosensitive. Non-invasive fluorescence imaging demonstrated that complete tumor resection with a precise margin, preservation of function, and prevention of distant metastasis, was achieved with fluorescence-guided surgery (FGS) with a GFP-reporter adenovirus. A combination of fluorescence imaging and laser ablation using a KillerRed-protein reporter adenovirus resulted in effective photodynamic cancer therapy (PDT). Thus, imaging technology and the designer oncolytic adenoviruses may have clinical potential for precise cancer targeting by indicating the optimal time for administering therapeutic agents; accurate surgical guidance for complete resection of tumors; and precise targeted cancer-specific photosensitization.
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Garza-Morales, Rodolfo, Kavitha Yaddanapudi, Rigoberto Perez-Hernandez, Eric Riedinger, Kelly M. McMasters, Haval Shirwan, Esma Yolcu, Roberto Montes de Oca-Luna, and Jorge G. Gomez-Gutierrez. "Temozolomide renders murine cancer cells susceptible to oncolytic adenovirus replication and oncolysis." Cancer Biology & Therapy 19, no. 3 (January 22, 2018): 188–97. http://dx.doi.org/10.1080/15384047.2017.1416274.
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Tazawa, Hiroshi, Joe Hasei, Shuya Yano, Shunsuke Kagawa, Toshifumi Ozaki, and Toshiyoshi Fujiwara. "Bone and Soft-Tissue Sarcoma: A New Target for Telomerase-Specific Oncolytic Virotherapy." Cancers 12, no. 2 (February 18, 2020): 478. http://dx.doi.org/10.3390/cancers12020478.
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Adenovirus serotype 5 (Ad5) is widely and frequently used as a virus vector in cancer gene therapy and oncolytic virotherapy. Oncolytic virotherapy is a novel antitumor treatment for inducing lytic cell death in tumor cells without affecting normal cells. Based on the Ad5 genome, we have generated three types of telomerase-specific replication-competent oncolytic adenoviruses: OBP-301 (Telomelysin), green fluorescent protein (GFP)-expressing OBP-401 (TelomeScan), and tumor suppressor p53-armed OBP-702. These viruses drive the expression of the adenoviral E1A and E1B genes under the control of the hTERT (human telomerase reverse transcriptase-encoding gene) promoter, providing tumor-specific virus replication. This review focuses on the therapeutic potential of three hTERT promoter-driven oncolytic adenoviruses against bone and soft-tissue sarcoma cells with telomerase activity. OBP-301 induces the antitumor effect in monotherapy or combination therapy with chemotherapeutic drugs via induction of autophagy and apoptosis. OBP-401 enables visualization of sarcoma cells within normal tissues by serving as a tumor-specific labeling reagent for fluorescence-guided surgery via induction of GFP expression. OBP-702 exhibits a profound antitumor effect in OBP-301-resistant sarcoma cells via activation of the p53 signaling pathway. Taken together, telomerase-specific oncolytic adenoviruses are promising antitumor reagents that are expected to provide novel therapeutic options for the treatment of bone and soft-tissue sarcomas.
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Ho Shin, Dong, Teresa Nguyen, Hong Jiang, Sagar Sohoni, Sumit Gupta, Ashley Ossimetha, Marta M. Alonso, Candelaria Gomez-Manzano, and Juan Fueyo. "EXTH-39. HEXON SWAPPING MITIGATES ANTI-VIRAL IMMUNE RESPONSE DURING BRAIN TUMOR VIROTHERAPY." Neuro-Oncology 22, Supplement_2 (November 2020): ii95. http://dx.doi.org/10.1093/neuonc/noaa215.393.
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Abstract Cancer virotherapy is a paradigm-shifting treatment modality based on the capabilities of virus-mediated oncolysis to elicit an anti-tumor immune response. Phase 1 and 2 clinical trials have demonstrated the safety and efficacy of our oncolytic adenovirus DNX-2401 (Delta-24-RGD) for patients with recurrent malignant gliomas. While a subset of the patients showed significant benefits, our goal is to improve the response rate. Clearance of the therapeutic virus by dominant anti-viral immune responses may contribute to the observed limits of the virotherapy. Adenovirus serotype 5 that provides the backbone of most oncolytic adenoviruses is highly prevalent in the human population and neutralizing antibodies against the capsid protein hexon may inhibit viral infection and replication. In this study, we showed using immunofluorescence that in mice bearing orthotopic syngeneic glioblastoma GSC005 treated with Delta-24-RGD, IgG antibodies crossed the disrupted blood-brain barrier and infiltrated the brain tumor parenchyma to colocalize with the viral hexon, suggesting that the systemic immune response may eradicate the virus within the infected tumor. To overcome this obstacle, we generated a chimeric virus called Delta-24-RGD-H43m with hexon hypervariable regions replaced with those from a lesser prevalent serotype 43 to avoid recognition by antibodies generated against serotype 5. The molecular swapping of the hexon did not significantly interfere with virion assembly nor attenuate its anti-glioma effect. Thus, the two viruses showed comparable efficacy in vitro (P= 0.568) and in vivo for animals without prior virus exposures (P= 0.228). Importantly, Delta-24-RGD-H43m evaded neutralizing antibodies generated against Delta-24-RGD and maintained its oncolytic ability (P< 0.0001). We conclude that hexon swapping strategies may improve virotherapy by alleviating the dominant immune response against the virus. Despite limited understanding of the interaction between oncolytic viruses and the host immune system, further research on strategies to circumvent virus-specific immune responses should aid the development of enhanced, glioma-targeted virotherapies.
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Sallard, Erwan, Wenli Zhang, Malik Aydin, Katrin Schröer, and Anja Ehrhardt. "The Adenovirus Vector Platform: Novel Insights into Rational Vector Design and Lessons Learned from the COVID-19 Vaccine." Viruses 15, no. 1 (January 11, 2023): 204. http://dx.doi.org/10.3390/v15010204.
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The adenovirus vector platform remains one of the most efficient toolboxes for generation of transfer vehicles used in gene therapy and virotherapy to treat tumors, as well as vaccines to protect from infectious diseases. The adenovirus genome and capsids can be modified using highly efficient techniques, and vectors can be produced at high titers, which facilitates their rapid adaptation to current needs and disease applications. Over recent years, the adenovirus vector platform has been in the center of attention for vaccine development against the ongoing coronavirus SARS-CoV-2/COVID-19 pandemic. The worldwide deployment of these vaccines has greatly deepened the knowledge on virus-host interactions and highlighted the need to further improve the effectiveness and safety not only of adenovirus-based vaccines but also of gene therapy and oncolytic virotherapy vectors. Based on the current evidence, we discuss here how adenoviral vectors can be further improved by intelligent molecular design. This review covers the full spectrum of state-of-the-art strategies to avoid vector-induced side effects ranging from the vectorization of non-canonical adenovirus types to novel genome engineering techniques.
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Baker, Alexander, Carmen Aguirre-Hernández, Gunnel Halldén, and Alan Parker. "Designer Oncolytic Adenovirus: Coming of Age." Cancers 10, no. 6 (June 14, 2018): 201. http://dx.doi.org/10.3390/cancers10060201.
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The licensing of talimogene laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with immune-checkpoint inhibitors, the quest continues for a virus capable of specific tumour cell killing via systemic administration. One candidate is oncolytic adenovirus (Ad); it’s double stranded DNA genome is easily manipulated and a wide range of strategies and technologies have been employed to empower the vector with improved pharmacokinetics and tumour targeting ability. As well characterised clinical and experimental agents, we have detailed knowledge of adenoviruses’ mechanisms of pathogenicity, supported by detailed virological studies and in vivo interactions. In this review we highlight the strides made in the engineering of bespoke adenoviral vectors to specifically infect, replicate within, and destroy tumour cells. We discuss how mutations in genes regulating adenoviral replication after cell entry can be used to restrict replication to the tumour, and summarise how detailed knowledge of viral capsid interactions enable rational modification to eliminate native tropisms, and simultaneously promote active uptake by cancerous tissues. We argue that these designer-viruses, exploiting the viruses natural mechanisms and regulated at every level of replication, represent the ideal platforms for local overexpression of therapeutic transgenes such as immunomodulatory agents. Where T-Vec has paved the way, Ad-based vectors now follow. The era of designer oncolytic virotherapies looks decidedly as though it will soon become a reality.
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Sato-Dahlman, Mizuho, Christopher J. LaRocca, Chikako Yanagiba, and Masato Yamamoto. "Adenovirus and Immunotherapy: Advancing Cancer Treatment by Combination." Cancers 12, no. 5 (May 21, 2020): 1295. http://dx.doi.org/10.3390/cancers12051295.
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Gene therapy with viral vectors has significantly advanced in the past few decades, with adenovirus being one of the most commonly employed vectors for cancer gene therapy. Adenovirus vectors can be divided into 2 groups: (1) replication-deficient viruses; and (2) replication-competent, oncolytic (OVs) viruses. Replication-deficient adenoviruses have been explored as vaccine carriers and gene therapy vectors. Oncolytic adenoviruses are designed to selectively target, replicate, and directly destroy cancer cells. Additionally, virus-mediated cell lysis releases tumor antigens and induces local inflammation (e.g., immunogenic cell death), which contributes significantly to the reversal of local immune suppression and development of antitumor immune responses (“cold” tumor into “hot” tumor). There is a growing body of evidence suggesting that the host immune response may provide a critical boost for the efficacy of oncolytic virotherapy. Additionally, genetic engineering of oncolytic viruses allows local expression of immune therapeutics, thereby reducing related toxicities. Therefore, the combination of oncolytic virus and immunotherapy is an attractive therapeutic strategy for cancer treatment. In this review, we focus on adenovirus-based vectors and discuss recent progress in combination therapy of adenoviruses with immunotherapy in preclinical and clinical studies.
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Stewart, Georgia Rose, Simon Tazzyman, Darren Lath, Jenny Down, John A. Snowden, Michelle Lawson, Munitta Muthana, and Andrew D. Chantry. "Myeloma-Specific Oncolytic Adenovirus Induces Significant Tumour Oncolysis In Vitro and In Vivo and Prevents Cell Line Regrowth." Blood 132, Supplement 1 (November 29, 2018): 3213. http://dx.doi.org/10.1182/blood-2018-99-118056.
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Abstract Multiple myeloma is a largely incurable disease and despite current therapies achieving good initial responses, patients frequently relapse. Therefore, new approaches are required that not only reduce the tumour load, but also prevent the growth of residual disease. One such approach is the use of oncolytic viruses. We developed an oncolytic adenovirus that utilizes transcriptional control of E1A under the myeloma-specific promoter CS1 (ADCE1A). We hypothesised that ADCE1A would be myeloma-specific, inducing tumour oncolysis and preventing tumour regrowth. A panel of myeloma cell lines (JJN3, L-363, OPM-2, U-266, RMPI-8226, NCI-H929, KMS-11, KMS-12-BM) were assessed for expression of CS1 by flow cytometry (FC). The same panel were treated with ADCE1A and cell death was monitored after 72 hours using FC and propidium iodide staining. Apoptosis was assessed following ADCE1A infection using annexin V staining and analysed by FC at 6 and 24 hours post treatment. CD138+ plasma cells from bone marrow aspirates were obtained from myeloma and plasma cell leukaemia patients and from the peripheral blood from healthy donors. The CD138+ and CD138- populations from these samples were treated with ADCE1A and cell death was monitored after 4 days using FC and propidium iodide staining. Myeloma cell regrowth was assessed after bortezomib (0.56-2.81nM) or bortezomib in combination with ADCE1A treatment using cell counts. Viral efficacy was tested in a xenograft model of myeloma, where 5 weeks after tumour cell injection (106 U266 cells intravenously), mice were treated with ADCE1A (1x107 pfu, 2x/wk) or control (PBS) for 3 weeks. Tumour burden was measured ex vivo in bone marrow flushes of the long bones by FC. CS1 was expressed in all myeloma cell lines, except KMS-12-BM. ADCE1A infected, replicated and caused oncolysis in JJN-3, L-363, OPM-2, U-266, RPMI-8226, NCI-H929, and KMS-11 myeloma cell lines. However, KMS-12-BM had the lowest sensitivity to ADCE1A. This correlated with CS1 expression, as CS1 was not expressed at the protein level in this cell line. Apoptosis, as detected by annexin V staining, was found to be a cell death mechanism involved in ADCE1A oncolysis. Importantly, ADCE1A induced oncolysis in primary patient malignant CD138+ plasma cells, but not in the non-malignant CD138- bone marrow mononuclear population from these patients. Additionally, ADCE1A had no effect on cell death in non-malignant CD138+ plasma cells and non-malignant CD138- peripheral blood mononuclear population from healthy donors. ADCE1A prevented regrowth of myeloma cell lines following treatment with bortezomib in vitro. In the U266 xenograft model, tumour load was significantly reduced (p<0.05) compared to control treated mice. In summary, ADCE1A has potential clinical efficacy as shown by preclinical models and patient tumour samples. Additionally, ADCE1A was able to stop tumour cell regrowth after chemotherapy in vitro, therefore, the use of oncolytic adenoviruses to target minimal residual disease may be a novel yet promising approach for the treatment of myeloma. Disclosures Snowden: Jannssen/J&J: Other: Speaker fees; Jazz & Sanofi: Other: Speaker fees at ASH.
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Nakashima, H., and E. A. Chiocca. "Switching a Replication-Defective Adenoviral Vector into a Replication-Competent, Oncolytic Adenovirus." Journal of Virology 88, no. 1 (October 23, 2013): 345–53. http://dx.doi.org/10.1128/jvi.02668-13.
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Laevskaya, Anastasia, Anton Borovjagin, Peter S. Timashev, Maciej S. Lesniak, and Ilya Ulasov. "Metabolome-Driven Regulation of Adenovirus-Induced Cell Death." International Journal of Molecular Sciences 22, no. 1 (January 5, 2021): 464. http://dx.doi.org/10.3390/ijms22010464.
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A viral infection that involves virus invasion, protein synthesis, and virion assembly is typically accompanied by sharp fluctuations in the intracellular levels of metabolites. Under certain conditions, dramatic metabolic shifts can result in various types of cell death. Here, we review different types of adenovirus-induced cell death associated with changes in metabolic profiles of the infected cells. As evidenced by experimental data, in most cases changes in the metabolome precede cell death rather than represent its consequence. In our previous study, the induction of autophagic cell death was observed following adenovirus-mediated lactate production, acetyl-CoA accumulation, and ATP release, while apoptosis was demonstrated to be modulated by alterations in acetate and asparagine metabolism. On the other hand, adenovirus-induced ROS production and ATP depletion were demonstrated to play a significant role in the process of necrotic cell death. Interestingly, the accumulation of ceramide compounds was found to contribute to the induction of all the three types of cell death mentioned above. Eventually, the characterization of metabolite analysis could help in uncovering the molecular mechanism of adenovirus-mediated cell death induction and contribute to the development of efficacious oncolytic adenoviral vectors.
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Ene, Chibawanye I., Juan Fueyo, and Frederick F. Lang. "Delta-24 adenoviral therapy for glioblastoma: evolution from the bench to bedside and future considerations." Neurosurgical Focus 50, no. 2 (February 2021): E6. http://dx.doi.org/10.3171/2020.11.focus20853.
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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.
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Su, Yinghan, Jiang Li, Weidan Ji, Gang Wang, Lin Fang, Qin Zhang, Lin Ang, et al. "Triple-serotype chimeric oncolytic adenovirus exerts multiple synergistic mechanisms against solid tumors." Journal for ImmunoTherapy of Cancer 10, no. 5 (May 2022): e004691. http://dx.doi.org/10.1136/jitc-2022-004691.
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BackgroundOncolytic virotherapy has become an important branch of cancer immunotherapy. This study investigated the efficacy of an oncolytic adenovirus (OAV), OncoViron, with synergistic mechanisms in the treatment of multiple solid tumors.MethodsAn OAV, OncoViron, was constructed and investigated by cytological experiments and implanted tumor models of multiple solid tumor cell lines to certify its anticancer efficacy, the synergistic effects of viral oncolysis and transgene anticancer activity of OncoViron, as well as oncolytic virotherapy combined with immunotherapy, were also verified.ResultsThe selective replication of OncoViron mediated high expression of anticancer factors, specifically targeted a variety of solid tumors and significantly inhibited cancer cell proliferation. On a variety of implanted solid tumor models in immunodeficient mice, immunocompetent mice, and humanized mice, OncoViron showed great anticancer effects on its own and in combination with programmed death 1 (PD-1) antibody and chimeric antigen receptor (CAR) T cells. Pathological examination, single-cell sequencing, and spatial transcriptome analysis of animal implanted tumor specimens confirmed that OncoViron significantly altered the gene expression profile of infected cancer cells, not only recruiting a large number of lymphocytes, natural killer cells, and mononuclear macrophages into tumor microenvironment (TME) and activated immune cells, especially T cells but also inducing M1 polarization of macrophages and promoting the release of more immune cytokines, thereby remodeling the TME for coordinating PD-1 antibody or CAR T therapy.ConclusionsThe chimeric OncoViron is a novel broad-spectrum anticancer product with multiple mechanisms of synergistic and potentiated immunotherapy, creating a good opportunity for combined immunotherapy against solid tumors.
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Ulasov, I. V., N. V. Kaverina, and A. Yu Baryshnikov. "SUPPRESSION OF CELLULAR P53 PROMOTES CYTOTOXICITY OF ONCOLYTIC VECTOR AT THE MODELS OF HUMAN GLIOBLASTOMA." Russian Journal of Biotherapy 14, no. 1 (March 30, 2015): 25–28. http://dx.doi.org/10.17650/1726-9784-2015-14-1-25-28.
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Glioblastoma multiforme resistance requires a new approach for glioma therapy. Protein p53 is one of the main cellular oncogene, overexpressed in 50% of brain tumor cases. Impact of p53 attenuation was evaluated in the presence of oncolytic adenovirus and temodar, which exhibit anti-glioma effect using in vitro glioma models. Using U87 human glioma cells we observed an additive effect between alkilated chemotherapeutic agent temodar and oncolytic adenovirus which results into p53 inhibition. It occurs that attenuation of p53 using PFTa inhibitor, significantly prolongs cell death type II - autophagy and, therefore improves effect mediated by autophagy induced agents. In conclusion, combination of PFTa and temodar might represent a powerful therapeutic combination which sensibilises glioma cells to the infection with oncolytic vector.
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Bots, Selas T. F., Sanne L. Landman, Martijn J. W. E. Rabelink, Diana J. M. van den Wollenberg, and Rob C. Hoeben. "Immunostimulatory Profile of Cancer Cell Death by the AdV-Lumc007-Derived Oncolytic Virus ‘GoraVir’ in Cultured Pancreatic Cancer Cells." Viruses 15, no. 2 (January 19, 2023): 283. http://dx.doi.org/10.3390/v15020283.
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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy which shows unparalleled therapeutic resistance. Oncolytic viruses have emerged as a new treatment approach and convey their antitumor activity through lysis of cancer cells. The therapeutic efficacy of oncolytic viruses is largely dependent on the induction of immunogenic cell death (ICD) and the subsequent antitumor immune responses. However, the concurrent generation of antiviral immune responses may also limit the a virus’ therapeutic window. GoraVir is a new oncolytic adenovirus derived from the Human Adenovirus B (HAdV-B) isolate AdV-lumc007 which was isolated from a gorilla and has demonstrated excellent lytic activity in both in vitro and in vivo models of PDAC. In this study, we characterized the immunostimulatory profile of cancer cell death induced by GoraVir and the concerted cellular antiviral responses in three conventional pancreatic cancer cell lines. While GoraVir was shown to induce late apoptotic/necrotic cell death at earlier time points post infection than the human adenovirus type 5 (HAdV-C5), similar levels of ICD markers were expressed. Moreover, GoraVir was shown to induce ICD not dependent on STING expression and regardless of subsequent antiviral responses. Together, these data demonstrate that GoraVir is an excellent candidate for use in oncolytic virotherapy.
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Sendra, Luis, Antonio Miguel, M. Carmen Navarro-Plaza, María José Herrero, José de la Higuera, Consuelo Cháfer-Pericás, Elena Aznar, et al. "Gold Nanoparticle-Assisted Virus Formation by Means of the Delivery of an Oncolytic Adenovirus Genome." Nanomaterials 10, no. 6 (June 17, 2020): 1183. http://dx.doi.org/10.3390/nano10061183.
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Oncolytic adenoviruses are a therapeutic alternative to treat cancer based on their ability to replicate selectively in tumor cells. However, their use is limited mainly by the neutralizing antibody (Nab) immune response that prevents repeated dosing. An alternative to facilitate the DNA access to the tumor even in the presence of anti-viral Nabs could be gold nanoparticles able to transfer DNA molecules. However, the ability of these nanoparticles to carry large DNA molecules, such as an oncolytic adenovirus genome, has not been studied. In this work, gold nanoparticles were functionalized with different amounts of polyethylenimine to transfer in a safe and efficient manner a large oncolytic virus genome. Their transfer efficacy and final effect of the oncolytic virus in cancer cells are studied. For each synthesized nanoparticle, (a) DNA loading capacity, (b) complex size, (c) DNA protection ability, (d) transfection efficacy and (e) cytotoxic effect were studied. We observed that small gold nanoparticles (70–80 nm in diameter) protected DNA against nucleases and were able to transfect the ICOVIR-15 oncolytic virus genome encoded in pLR1 plasmid. In the present work, efficient transgene RNA expression, luciferase activity and viral cytopathic effect on cancer cells are reported. These results suggest gold nanoparticles to be an efficient and safe vector for oncolytic adenovirus genome transfer.