Articles de revues : « Oncolytic viru »

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Shin, Dong Ho, Teresa Nguyen, Bulent Ozpolat, Frederick Lang, Marta Alonso, Candelaria Gomez-Manzano et Juan Fueyo. « Current strategies to circumvent the antiviral immunity to optimize cancer virotherapy ». Journal for ImmunoTherapy of Cancer 9, n^o 4 (avril 2021) : e002086. http://dx.doi.org/10.1136/jitc-2020-002086.

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Cancer virotherapy is a paradigm-shifting treatment modality based on virus-mediated oncolysis and subsequent antitumor immune responses. Clinical trials of currently available virotherapies showed that robust antitumor immunity characterizes the remarkable and long-term responses observed in a subset of patients. These data suggest that future therapies should incorporate strategies to maximize the immunotherapeutic potential of oncolytic viruses. In this review, we highlight the recent evidence that the antiviral immunity of the patients may limit the immunotherapeutic potential of oncolytic viruses and summarize the most relevant approaches to strategically redirect the immune response away from the viruses and toward tumors to heighten the clinical impact of viro-immunotherapy platforms.

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Raimondi, Giulia, Sabrina Gea-Sorlí, Marc Otero-Mateo et 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, n^o 13 (28 juin 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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Nguyen, Duong Hoang, Thomas Herrmann, Barbara Härtl, Dobrin Draganov, Ivelina Minev, Forrest Neuharth, Alberto Gomez et al. « Development of Allogeneic Stem Cell-Based Platform for Delivery and Potentiation of Oncolytic Virotherapy ». Cancers 14, n^o 24 (13 décembre 2022) : 6136. http://dx.doi.org/10.3390/cancers14246136.

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We describe the repurposing and optimization of the TK-positive (thymidine kinase) vaccinia virus strain ACAM1000/ACAM2000™ as an oncolytic virus. This virus strain has been widely used as a smallpox vaccine and was also used safely in our recent clinical trial in patients with advanced solid tumors and Acute Myeloid Leukemia (AML). The vaccinia virus was amplified in CV1 cells and named CAL1. CAL1 induced remarkable oncolysis in various human and mouse cancer cells and preferentially amplified in cancer cells, supporting the use of this strain as an oncolytic virus. However, the therapeutic potential of CAL1, as demonstrated with other oncolytic viruses, is severely restricted by the patients’ immune system. Thus, to develop a clinically relevant oncolytic virotherapy agent, we generated a new off-the-shelf therapeutic called Supernova1 (SNV1) by loading CAL1 virus into allogeneic adipose-derived mesenchymal stem cells (AD-MSC). Culturing the CAL1-infected stem cells allows the expression of virally encoded proteins and viral amplification prior to cryopreservation. We found that the CAL1 virus loaded into AD-MSC was resistant to humoral inactivation. Importantly, the virus-loaded stem cells (SNV1) released larger number of infectious viral particles and virally encoded proteins, leading to augmented therapeutic efficacy in vitro and in animal tumor models.

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Petrov, Ivan, Ivaylo Gentschev, Anna Vyalkova, Mohamed I. Elashry, Michele C. Klymiuk, Stefan Arnhold et Aladar A. Szalay. « Canine Adipose-Derived Mesenchymal Stem Cells (cAdMSCs) as a “Trojan Horse” in Vaccinia Virus Mediated Oncolytic Therapy against Canine Soft Tissue Sarcomas ». Viruses 12, n^o 7 (12 juillet 2020) : 750. http://dx.doi.org/10.3390/v12070750.

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Several oncolytic viruses (OVs) including various human and canine adenoviruses, canine distemper virus, herpes-simplex virus, reovirus, and members of the poxvirus family, such as vaccinia virus and myxoma virus, have been successfully tested for canine cancer therapy in preclinical and clinical settings. The success of the cancer virotherapy is dependent on the ability of oncolytic viruses to overcome the attacks of the host immune system, to preferentially infect and lyse cancer cells, and to initiate tumor-specific immunity. To date, several different strategies have been developed to overcome the antiviral host defense barriers. In our study, we used canine adipose-derived mesenchymal stem cells (cAdMSCs) as a “Trojan horse” for the delivery of oncolytic vaccinia virus Copenhagen strain to achieve maximum oncolysis against canine soft tissue sarcoma (CSTS) tumors. A single systemic administration of vaccinia virus-loaded cAdMSCs was found to be safe and led to the significant reduction and substantial inhibition of tumor growth in a CSTS xenograft mouse model. This is the first example that vaccinia virus-loaded cAdMSCs could serve as a therapeutic agent against CSTS tumors.

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Woo, Yanghee, Susanne G. Warner, Rula Geha, Marianne M. Stanford, Penelope Decarolis, Masmudur M. Rahman, Samuel Singer, Grant McFadden et Yuman Fong. « The Oncolytic Activity of Myxoma Virus against Soft Tissue Sarcoma Is Mediated by the Overexpression of Ribonucleotide Reductase ». Clinical Medicine Insights : Oncology 15 (janvier 2021) : 117955492199306. http://dx.doi.org/10.1177/1179554921993069.

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Background: Myxoma virus (MYXV) is an oncolytic poxvirus that lacks the gene for 1 of the subunits of ribonucleotide reductase (RR), a crucial DNA synthesis and repair enzyme. The overexpression of RR has been implicated in the invasiveness of several cancers, including soft tissue sarcomas (STS). The purpose of the study was to investigate the oncolytic efficacy of MYXV in STS with different levels of RR expression. Methods: The oncolytic effect of recombinant MYXV was evaluated in 4 human STS cell lines, LS141 (a dedifferentiated liposarcoma), DDLS8817 (a dedifferentiated liposarcoma), RDD2213 (recurrent dedifferentiated liposarcoma), and HSSYII (a synovial sarcoma) using infectivity and cytotoxicity assays. Following the overexpression of RRM2 by cDNA transfection and silencing of RRM2 by siRRM2 in these STS cell lines, the RRM2 expression levels were analyzed by Western blot. Results: We observed a direct correlation between viral oncolysis and RRM2 mRNA levels ( R = 0.96) in STS. Higher RRM2 expression was associated with a more robust cell kill. Silencing the RRM2 gene led to significantly greater cell survival (80%) compared with the control group ( P = .003), whereas overexpression of the RRM2 increased viral oncolysis by 33% ( P < .001). Conclusions: Our results show that the oncolytic effects of MYXV correlate directly with RR expression levels and are enhanced in STS cell lines with naturally occurring or artificially induced high expression levels of RR. Myxoma virus holds promise in the treatment of advanced soft tissue cancer, especially in tumors overexpressing RR.

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Martikainen, Miika, et Magnus Essand. « Virus-Based Immunotherapy of Glioblastoma ». Cancers 11, n^o 2 (5 février 2019) : 186. http://dx.doi.org/10.3390/cancers11020186.

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Glioblastoma (GBM) is the most common type of primary brain tumor in adults. Despite recent advances in cancer therapy, including the breakthrough of immunotherapy, the prognosis of GBM patients remains dismal. One of the new promising ways to therapeutically tackle the immunosuppressive GBM microenvironment is the use of engineered viruses that kill tumor cells via direct oncolysis and via stimulation of antitumor immune responses. In this review, we focus on recently published results of phase I/II clinical trials with different oncolytic viruses and the new interesting findings in preclinical models. From syngeneic preclinical GBM models, it seems evident that oncolytic virus-mediated destruction of GBM tissue coupled with strong adjuvant effect, provided by the robust stimulation of innate antiviral immune responses and adaptive anti-tumor T cell responses, can be harnessed as potent immunotherapy against GBM. Although clinical testing of oncolytic viruses against GBM is at an early stage, the promising results from these trials give hope for the effective treatment of GBM in the near future.

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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 et Rajeev Dhupar. « Fighting Fire With Fire : Oncolytic Virotherapy for Thoracic Malignancies ». Annals of Surgical Oncology 28, n^o 5 (11 février 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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Chavez, Valery A., Floritza Bustamante, Abner Murray, Ashok Saluja et Jaime Merchan. « Abstract 96 : A novel virus-drug combination to enhance oncolysis in colorectal cancer (crc) ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 96. http://dx.doi.org/10.1158/1538-7445.am2022-96.

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Abstract Background: While advances in immune and targeted therapies improve outcomes in selected cancers, only a minority of colorectal cancer (CRC) patients benefit from them. Oncolytic viruses (OVs) represent novel cancer biotherapies, and among them, the oncolytic measles virus (MV) has demonstrated safety and antitumor activity in early clinical studies. MV alone does is not associated with cancer cures. Triptolide, a diterpenoid epoxide extracted from the thunder god vine (Tripterygium wilfordii), has been reported to have potent antitumor effects via multiple mechanisms, including anti-proliferative, pro-apoptotic, antiangiogenic, and induction of ER stress. The effects of triptolide on viral colon cancer oncolysis have not been previously investigated. Objectives: To characterize the in vitro and in vivo mechanisms of novel stromal retargeted oncolytic MVs and improve efficacy by combining MVs with triptolide. Methods: The in vitro effects of triptolide alone, MV-GFP (Edmonston strain of Measles virus expressing eGFP, for human cancer cells), MV-m-uPA (MV retargeted against the murine uPA receptor, for murine cancer cells), or virus-triptolide combinations on tumor cell cytotoxicity were assessed by cell count (Vi cell counter) or xCelligence assays, on HT-29, HCT116, SW620, CT26, and MC38 cells. Molecular and mechanistic characterization of Triptolide’s effects alone and combination with MV in HT29 cells will be analyzed by the (Reverse Phase Protein Array (RPPA) and validated by western blot analysis (experiment undergoing). In vivo effects (tumor progression and survival) of minnelide (M) (water-soluble version of Triptolide) alone and in combination with Measles Virus were assessed in Balb/C mice bearing CT26. Results: While MV and T had dose-dependent cytotoxic activity as single agents, significant augmentation of MV oncolysis was induced by co-treatment with triptolide. In vivo experiments showed similar effects observed in vitro, with potent antitumor activity of triptolide and enhanced in vivo antitumor activity when minnelide was combined with MV vectors. Conclusions: our results strongly suggest that triptolide or minnelide enhances measles virus oncolysis in vitro and in vivo models of colorectal cancer. In vitro and in vivo mechanistic studies are underway to characterize the molecular mechanisms by which triptolide enhances MV oncolysis and will be presented at the meeting. Citation Format: Valery A. Chavez, Floritza Bustamante, Abner Murray, Ashok Saluja, Jaime Merchan. A novel virus-drug combination to enhance oncolysis in colorectal cancer (crc) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 96.

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Wang, Guan. « Immunodominant and cryptic tumor neoantigen-specific immune responses activated by an armed oncolytic virus expressing a PD-L1 inhibitor ». Journal of Immunology 202, n^o 1_Supplement (1 mai 2019) : 136.5. http://dx.doi.org/10.4049/jimmunol.202.supp.136.5.

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Abstract Tumor neoantigens are exclusively expressed in malignant cells representing an ideal target for tumor immunotherapy. Oncolytic virus selectively infects and lyses tumor cells releasing a full-array tumor antigens and danger factors. Combined with PD1 checkpoint blockade, oncolytic virus triggered tumor neoantigen-specific T cell immune responses through local treatments. The present study developed a novel therapeutic regimen that combines ddVV, GM-CSF, and a PD-L1 inhibitor into a single therapeutic agent by engineering ddVV to co-express GM-CSF and a PD-L1 inhibitor. The novel therapeutic regimen has triple functions: ddVV-mediated oncolysis, GM-CSF-mediated enhancement of dendritic cell recruitment and function, and PD-L1 inhibitor-mediated interruption of PD-1/PD-L1 interaction. As a result, the double-armed oncolytic virus eradicated primary tumor and prevented tumor recurrence more efficiently after local administration. Analyses of underlying mechanisms revealed that the double-armed ddVV possessed a superior capability of improving tumor environment and triggering systemic T cell immune responses against not only dominant but also cryptic tumor neo-antigens in tumor mouse models.

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Sherwood, Matthew, Robert Ewing, Carolini Kaid, Thiago Giove Mitsugi et Keith Okamoto. « MOMC-1. Employing the Zika Virus to kill paediatric nervous system tumour cells ». Neuro-Oncology Advances 3, Supplement_2 (1 juillet 2021) : ii3. http://dx.doi.org/10.1093/noajnl/vdab070.011.

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Abstract Malignant paediatric nervous system tumours, such as Medulloblastoma, Neuroblastoma and ATRT commonly harbour tumour cells with stem-like features which are highly tumorigenic and resistant to conventional cancer therapies. These tumours can exhibit high lethality and may result in severe sequelae, including cognitive and motor deficits that significantly affect patients’ quality of life. Oncolytic virotherapy is a novel therapy class that exploits viruses that preferentially infect and destroy tumour cells. These viruses present a unique advantage in targeting highly heterogeneous cancers, such as nervous system tumours, as they possess a secondary mechanism of action through which they induce a tumour-specific immune response. Clinical studies employing oncolytic virotherapy have in general reported low toxicity and minimal adverse effects, deeming oncolytic virotherapy as a potentially attractive and safer intervention against paediatric tumours. The Zika virus (ZIKV) is capable of infecting and destroying neural stem-like cancer cells from human embryonal Central Nervous System (CNS) tumours in vitro and in vivo. Infection of CNS tumour cells with ZIKV effectively inhibits tumour metastasis in mice and, in some cases, induces complete tumour remission. Neuroblastoma arises from immature nerve cells and multiple Neuroblastoma cell lines are susceptible to ZIKV infection and oncolysis. These initial findings have demonstrated the potential for a ZIKV-based virotherapy against paediatric nervous system tumours and warrants examination into the molecular mechanisms through which ZIKV executes its oncolytic ability. My research goal is to elucidate the mechanisms which are of paramount importance for ZIKV-induced oncolysis of brain tumour and Neuroblastoma cells. Utilising global expression omics profiling of ZIKV infection and mapping of viral protein-host protein interactions will identify these mechanisms both at the cellular pathway and molecular levels. These collectively will inform our understanding of how we can employ a future ZIKV-based virotherapy against paediatric nervous system tumours.

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Bryant, Jeffrey, Agnieszka Denslow, Jacqueline Hewett, Lingxin Cong, Ana De Almeida, Jennifer Lee, Judy Jacques et al. « Abstract 383 : ONCR-021 as a systemic intravenous synthetic RNA virus immunotherapy for the repeat treatment of cancer ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 383. http://dx.doi.org/10.1158/1538-7445.am2022-383.

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Abstract Oncolytic viruses (OV) have shown great potential to improve clinical outcomes when dosed intratumorally, however, their therapeutic efficacy when intravenously administered is likely limited by the rapid emergence of neutralizing antibodies. To overcome this limitation, we developed Synthetic RNA viruses consisting of a replication competent viral genomic RNA (vRNA) encapsulated within a lipid nanoparticle (LNP) for IV administration. Upon dosing and delivery of this infectious RNA payload, the vRNA initiates viral replication and virus production in neoplastic cells leading to oncolysis and tumor destruction. This formulation enables repeat intravenous dosing of a replication competent oncolytic virotherapy even in presence of circulating neutralizing antibody to the virus. Here we present ONCR-021, an LNP formulation of Coxsackievirus A21 (CVA21) vRNA. ONCR-021 vRNA encodes a novel ICAM1-dependent strain of CVA21 that results in greater in vitro and in vivo oncolysis compared to the previously described CVA21 Kuykendall strain. ONCR-021 is broadly oncolytic in cancer cell lines in vitro and is intended for clinical development in NSCLC, RCC, and HCC based upon the viral tropism. IV-administration of ONCR-021 vRNA results in rapid initiation of viral replication, oncolysis, and potent anti-tumor efficacy, even in the presence of circulating CVA21 neutralizing antibodies. This efficacy is principally driven by CVA21 amplification in situ after delivery to tumor cells and we demonstrate viral replication, virion production and spread within the tumor after dosing. We also observe only modest and transient production of CVA21 in healthy tissues of transgenic mice expressing the CVA21 entry receptor human ICAM1. Consistent with these findings, high doses levels of ONCR-021 were well-tolerated in this model. Altogether, these preclinical data support the development of ONCR-021, a novel synthetic oncolytic virus designed to overcome the challenges of repeat intravenous administration of viral immunotherapy for the treatment of disseminated cancers. Citation Format: Jeffrey Bryant, Agnieszka Denslow, Jacqueline Hewett, Lingxin Cong, Ana De Almeida, Jennifer Lee, Judy Jacques, Sonia Feau, Daniel. Wambua, Adrienne Yanez, Pam Shou-Ping Wang, Jessica Deterling, Matthew Scott, Jason Auer, Brian B. Haines, Christophe Quéva, Lorena Lerner, Edward M. Kennedy. ONCR-021 as a systemic intravenous synthetic RNA virus immunotherapy for the repeat treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 383.

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Tysome, James Russell, Ghassan Alusi, Nick Lemoine et Yaohe Wang. « Oncolytic Vaccinia Virus Gene Therapy for HNSCC ». Otolaryngology–Head and Neck Surgery 139, n^o 2_suppl (août 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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Bots, Selas T. F., et Rob C. Hoeben. « Non-Human Primate-Derived Adenoviruses for Future Use as Oncolytic Agents ? » International Journal of Molecular Sciences 21, n^o 14 (8 juillet 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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Schwertner, Barbara, Georg Lindner, Camila Toledo Toledo Stauner, Elisa Klapproth, Clara Magnus, Anette Rohrhofer, Stefanie Gross et al. « Nectin-1 Expression Correlates with the Susceptibility of Malignant Melanoma to Oncolytic Herpes Simplex Virus In Vitro and In Vivo ». Cancers 13, n^o 12 (19 juin 2021) : 3058. http://dx.doi.org/10.3390/cancers13123058.

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Talimogene laherparepvec (T-VEC), an oncolytic herpes simplex virus, is approved for intralesional injection of unresectable stage IIIB/IVM1a melanoma. However, it is still unclear which parameter(s) predict treatment response or failure. Our study aimed at characterizing surface receptors Nectin-1 and the herpes virus entry mediator (HVEM) in addition to intracellular molecules cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) as potential bio-markers for oncolytic virus treatment. In 20 melanoma cell lines, oncolytic activity of T-VEC was correlated with the expression of Nectin-1 but not HVEM, as evaluated via flow cytometry and immunohistochemistry. Knockout using CRISPR/Cas9 technology confirmed the superior role of Nectin-1 over HVEM for entry and oncolytic activity of T-VEC. Neither cGAS nor STING as evaluated by Western Blot and immunohistochemistry correlated with T-VEC induced oncolysis. The role of these biomarkers was retrospectively analyzed for the response of 35 cutaneous melanoma metastases of 21 patients to intralesional T-VEC injection, with 21 (60.0%) of these lesions responding with complete (n = 16) or partial regression (n = 5). Nectin-1 expression in pretreatment biopsies significantly predicted treatment outcome, while the expression of HVEM, cGAS, and STING was not prognostic. Altogether, Nectin-1 served as biomarker for T-VEC-induced melanoma regression in vitro and in vivo.

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Pathak, Upasana, Nagesh Malik et R. B. Pal. « NDV as an Oncolytic Agent - Study in Cancer Cell Lines ». Biosciences Biotechnology Research Asia 19, n^o 2 (30 juin 2022) : 413–21. http://dx.doi.org/10.13005/bbra/2996.

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Newcastle disease virus (NDV) exhibits oncolysis in its natural form. This oncolytic virus (OV) has the potential to specifically infect, propagate, and lyse cancer cells while sparing the normal cells. This study was aimed to screen for oncolytic NDV strain isolated from poultry. A total of ten velogenic NDV strains were propagated in 10 day old embryonated SPF chicken eggs and allantoic fluid of these infected eggs was collected for further study. The virus enumeration was carried out by hemagglutination assay (HA) and end point dilution method. The cytopathic effect of ten NDV strains on cancer cell lines like MDA-MB-231, MCF-7, PC3, and A549 along with normal control cell line HEK293 was determined by MTT assay 72 hours post infection. These cell lines were infected with three doses (1, 0.1, and 0.01 MOI). DNA laddering effect of the screened NDV isolate was studied after infecting all cancer and normal cells at MOI 1. Morphological changes in MDA-MB-231 on infection with the screened NDV isolate were analyzed using H&E hematoxylin and eosin staining. The screened NDV isolate showed the maximum cytopathic effect i.e. 61.55% on MDA-MB-231 at MOI 1 but had no potent cytotoxic effect on HEK293. DNA laddering effect was observed which confirmed the mode of death to be apoptosis. All the observed morphological changes in MDA-MB-231 were typical of the cytopathogenic effects of NDV on cancer cell lines. In conclusion, the screened oncolytic NDV shows effective oncolysis against MDA-MB-231 cell line. However, further study is required to determine the exact mode of action involved.

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Tumilasci, Vanessa Fonseca, Stephanie Olière, Thi Lien-Ahn Nguyên, April Shamy, John Bell et John Hiscott. « Targeting the Apoptotic Pathway with BCL-2 Inhibitors Sensitizes Primary Chronic Lymphocytic Leukemia Cells to Vesicular Stomatitis Virus-Induced Oncolysis ». Journal of Virology 82, n^o 17 (25 juin 2008) : 8487–99. http://dx.doi.org/10.1128/jvi.00851-08.

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ABSTRACT Chronic lymphocytic leukemia (CLL) is characterized by clonal accumulation of CD5+ CD19+ B lymphocytes that are arrested in the G0/G1 phase of the cell cycle and fail to undergo apoptosis because of overexpression of the antiapoptotic B-cell CLL/lymphoma 2 (BCL-2) protein. Oncolytic viruses, such as vesicular stomatitis virus (VSV), have emerged as potential anticancer agents that selectively target and kill malignant cells via the intrinsic mitochondrial pathway. Although primary CLL cells are largely resistant to VSV oncolysis, we postulated that targeting the apoptotic pathway via inhibition of BCL-2 may sensitize CLL cells to VSV oncolysis. In the present study, we examined the capacity of EM20-25—a small-molecule antagonist of the BCL-2 protein—to overcome CLL resistance to VSV oncolysis. We demonstrate a synergistic effect of the two agents in primary ex vivo CLL cells (combination index of 0.5; P < 0.0001). In a direct comparison of peripheral blood mononuclear cells from healthy volunteers with primary CLL, the two agents combined showed a therapeutic index of 19-fold; furthermore, the combination of VSV and EM20-25 increased apoptotic cell death in Karpas-422 and Granta-519 B-lymphoma cell lines (P < 0.005) via the intrinsic mitochondrial pathway. Mechanistically, EM20-25 blocked the ability of the BCL-2 protein to dimerize with proapoptotic BAX protein, thus sensitizing CLL to VSV oncolytic stress. Together, these data indicate that the use of BCL-2 inhibitors may improve VSV oncolysis in treatment-resistant hematological malignancies, such as CLL, with characterized defects in the apoptotic response.

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Yaacov, Barak, Itay Lazar, Shay Tayeb, Sivan Frank, Uzi Izhar, Michal Lotem, Riki Perlman, Dina Ben-Yehuda, Zichria Zakay-Rones et Amos Panet. « Extracellular matrix constituents interfere with Newcastle disease virus spread in solid tissue and diminish its potential oncolytic activity ». Journal of General Virology 93, n^o 8 (1 août 2012) : 1664–72. http://dx.doi.org/10.1099/vir.0.043281-0.

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Advanced melanoma cells, characterized by resistance to chemotherapy, have been shown to be highly sensitive to oncolysis by Newcastle disease virus (NDV). In the present study, we investigated the capacity of NDV to specifically infect and spread into solid tissues of human melanoma and lung carcinoma, in vivo and ex vivo. For this purpose a new model of SCID-beige mice implanted with human melanoma was developed. Surprisingly, the replication competent NDV-MTH and the attenuated, single-cycle replication NDV-HUJ strains, demonstrated a similar oncolytic activity in the melanoma-implanted mice. Further, ex vivo analysis, using organ cultures derived from the melanoma tissues indicated a limited spread of the two NDV strains in the tissue. Extracellular matrix (ECM) molecules, notably heparin sulfate and collagen, were found to limit viral spread in the tissue. This observation was validated with yet another solid tumour of human lung carcinoma. Taken together, the results indicate that the ECM acts as a barrier to virus spread within solid tumour tissues and that this restriction must be overcome to achieve effective oncolysis with NDV.

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Nair, Mitra, Maninder Khosla, Yoshihiro Otani, Margaret Yeh, Flora Park, Toshihiko Shimizu, Jin Muk Kang et al. « Enhancing Antitumor Efficacy of Heavily Vascularized Tumors by RAMBO Virus through Decreased Tumor Endothelial Cell Activation ». Cancers 12, n^o 4 (23 avril 2020) : 1040. http://dx.doi.org/10.3390/cancers12041040.

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Vascularization is a common pathology for many solid tumors, and therefore anti-angiogenic strategies are being investigated as a therapeutic target for treatment. Numerous studies are also being conducted regarding the effects of oncolytic viruses, including ImlygicTM, an FDA approved oncolytic herpes simplex virus-1 (oHSV) for the treatment of highly vascularized tumors such as Kaposi sarcoma (NCT04065152), and brain tumors. To our knowledge, the effects of combining oncolytic HSV with angiogenesis inhibition on endothelial cell activation has not been previously described. Here, we tested the effects of Rapid Antiangiogenesis Mediated By Oncolytic Virus (RAMBO), an oHSV which expresses a potent anti-angiogenic gene Vasculostatin on endothelial cell activation in heavily vascularized solid tumors. oHSV treatment induces endothelial cell activation, which inhibits virus propagation and oncolysis in adjacent tumor cells in vitro. Consistently, this was also observed in intravital imaging of intracranial tumor-bearing mice in vivo where infected tumor endothelial cells could efficiently clear the virus without cell lysis. Quantitative real-time PCR (Q-PCR), leukocyte adhesion assay, and fluorescent microscopy imaging data, however, revealed that RAMBO virus significantly decreased expression of endothelial cell activation markers and leukocyte adhesion, which in turn increased virus replication and cytotoxicity in endothelial cells. In vivo RAMBO treatment of subcutaneously implanted sarcoma tumors significantly reduced tumor growth in mice bearing sarcoma compared to rHSVQ. In addition, histological analysis of RAMBO-treated tumor tissues revealed large areas of necrosis and a statistically significant reduction in microvessel density (MVD). This study provides strong preclinical evidence of the therapeutic benefit for the use of RAMBO virus as a treatment option for highly vascularized tumors.

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Muharemagic, D., A. S. Zamay, S. M. Ghobadloo, J. C. Bell et M. V. Berezovski. « APTAMER-FACILITATED PROTECTION OF ONCOLYTIC VIRUS FROM NEUTRALIZING ANTIBODIES ». Siberian Medical Review, n^o 5 (2016) : 116. http://dx.doi.org/10.20333/25000136-2016-5-116-2.

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Nettelbeck, Dirk M., Mathias F. Leber, Jennifer Altomonte, Assia Angelova, Julia Beil, Susanne Berchtold, Maike Delic et al. « Virotherapy in Germany—Recent Activities in Virus Engineering, Preclinical Development, and Clinical Studies ». Viruses 13, n^o 8 (21 juillet 2021) : 1420. http://dx.doi.org/10.3390/v13081420.

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Virotherapy research involves the development, exploration, and application of oncolytic viruses that combine direct killing of cancer cells by viral infection, replication, and spread (oncolysis) with indirect killing by induction of anti-tumor immune responses. Oncolytic viruses can also be engineered to genetically deliver therapeutic proteins for direct or indirect cancer cell killing. In this review—as part of the special edition on “State-of-the-Art Viral Vector Gene Therapy in Germany”—the German community of virotherapists provides an overview of their recent research activities that cover endeavors from screening and engineering viruses as oncolytic cancer therapeutics to their clinical translation in investigator-initiated and sponsored multi-center trials. Preclinical research explores multiple viral platforms, including new isolates, serotypes, or fitness mutants, and pursues unique approaches to engineer them towards increased safety, shielded or targeted delivery, selective or enhanced replication, improved immune activation, delivery of therapeutic proteins or RNA, and redirecting antiviral immunity for cancer cell killing. Moreover, several oncolytic virus-based combination therapies are under investigation. Clinical trials in Germany explore the safety and potency of virotherapeutics based on parvo-, vaccinia, herpes, measles, reo-, adeno-, vesicular stomatitis, and coxsackie viruses, including viruses encoding therapeutic proteins or combinations with immune checkpoint inhibitors. These research advances represent exciting vantage points for future endeavors of the German virotherapy community collectively aimed at the implementation of effective virotherapeutics in clinical oncology.

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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, n^o 5 (1 septembre 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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Komorowski, Marcin, Joanna Tisonczyk, Agnieszka Kolakowska, Ryszard Drozdz et Danuta Kozbor. « Modulation of the Tumor Microenvironment by CXCR4 Antagonist-Armed Viral Oncotherapy Enhances the Antitumor Efficacy of Dendritic Cell Vaccines against Neuroblastoma in Syngeneic Mice ». Viruses 10, n^o 9 (26 août 2018) : 455. http://dx.doi.org/10.3390/v10090455.

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The induction of antitumor immune responses in tumor-bearing hosts depends on efficient uptake and processing of native or modified tumors/self-antigens by dendritic cells (DCs) to activate immune effector cells, as well as the extent of the immunosuppressive network in the tumor microenvironment (TME). Because the C-X-C motif chemokine receptor 4 (CXCR4) for the C-X-C motif chemokine 12 (CXCL12) is involved in signaling interactions between tumor cells and their TME, we used oncolytic virotherapy with a CXCR4 antagonist to investigate whether targeting of the CXCL12/CXCR4 signaling axis in murine neuroblastoma cells (NXS2)-bearing syngeneic mice affects the efficacy of bone marrow (BM)-derived DCs loaded with autologous tumor cells treated with doxorubicin for induction of immunogenic cell death. Here, we show that CXCR4 antagonist expression from an oncolytic vaccinia virus delivered intravenously to mice with neuroblastoma tumors augmented efficacy of the DC vaccines compared to treatments mediated by a soluble CXCR4 antagonist or oncolysis alone. This study is the first demonstration that modulating the tumor microenvironment by an armed oncolytic virus could have a significant impact on the efficacy of DC vaccines, leading to the generation of effective protection against neuroblastoma challenge.

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Westcott, Marlena M., Jingfang Liu, Karishma Rajani, Ralph D'Agostino, Douglas S. Lyles et Mercedes Porosnicu. « Interferon Beta and Interferon Alpha 2a Differentially Protect Head and Neck Cancer Cells from Vesicular Stomatitis Virus-Induced Oncolysis ». Journal of Virology 89, n^o 15 (20 mai 2015) : 7944–54. http://dx.doi.org/10.1128/jvi.00757-15.

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ABSTRACTOncolytic viruses (OV) preferentially kill cancer cells due in part to defects in their antiviral responses upon exposure to type I interferons (IFNs). However, IFN responsiveness of some tumor cells confers resistance to OV treatment. The human type I IFNs include one IFN-β and multiple IFN-α subtypes that share the same receptor but are capable of differentially inducing biological responses. The role of individual IFN subtypes in promoting tumor cell resistance to OV is addressed here. Two human IFNs which have been produced for clinical use, IFN-α2a and IFN-β, were compared for activity in protecting human head and neck squamous cell carcinoma (HNSCC) lines from oncolysis by vesicular stomatitis virus (VSV). Susceptibility of HNSCC lines to killing by VSV varied. VSV infection induced increased production of IFN-β in resistant HNSCC cells. When added exogenously, IFN-β was significantly more effective at protecting HNSCC cells from VSV oncolysis than was IFN-α2a. In contrast, normal keratinocytes and endothelial cells were protected equivalently by both IFN subtypes. Differential responsiveness of tumor cells to IFN-α and -β was further supported by the finding that autocrine IFN-β but not IFN-α promoted survival of HNSCC cells during persistent VSV infection. Therefore, IFN-α and -β differentially affect VSV oncolysis, justifying the evaluation and comparison of IFN subtypes for use in combination with VSV therapy. Pairing VSV with IFN-α2a may enhance selectivity of oncolytic VSV therapy for HNSCC by inhibiting VSV replication in normal cells without a corresponding inhibition in cancer cells.IMPORTANCEThere has been a great deal of progress in the development of oncolytic viruses. However, a major problem is that individual cancers vary in their sensitivity to oncolytic viruses. In many cases this is due to differences in their production and response to interferons (IFNs). The experiments described here compared the responses of head and neck squamous cell carcinoma cell lines to two IFN subtypes, IFN-α2a and IFN-β, in protection from oncolytic vesicular stomatitis virus. We found that IFN-α2a was significantly less protective for cancer cells than was IFN-β, whereas normal cells were equivalently protected by both IFNs. These results suggest that from a therapeutic standpoint, selectivity for cancer versus normal cells may be enhanced by pairing VSV with IFN-α2a.

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Peter, Malin, et Florian Kühnel. « Oncolytic Adenovirus in Cancer Immunotherapy ». Cancers 12, n^o 11 (13 novembre 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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Lazar, Itay, Barak Yaacov, Tamar Shiloach, Elad Eliahoo, Luna Kadouri, Michal Lotem, Riki Perlman, Zichria Zakay-Rones, Amos Panet et Dina Ben-Yehuda. « The Oncolytic Activity of Newcastle Disease Virus NDV-HUJ on Chemoresistant Primary Melanoma Cells Is Dependent on the Proapoptotic Activity of the Inhibitor of Apoptosis Protein Livin ». Journal of Virology 84, n^o 1 (28 octobre 2009) : 639–46. http://dx.doi.org/10.1128/jvi.00401-09.

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ABSTRACT Patients with advanced melanoma usually do not benefit from conventional chemotherapy treatment. There is therefore a true need for a new kind of therapy for melanoma. One factor responsible for the poor prognosis of melanoma is the inhibitor of apoptosis protein (IAP) family member Livin. In this study, we applied a novel approach for the treatment of melanoma, using a unique strain of the oncolytic Newcastle disease virus (NDV-HUJ). We found that, unlike chemotherapeutic drugs, NDV-HUJ, a one-cycle replicating virus, overcomes the resistance to apoptosis of melanoma primary cultures that over express the Livin protein. In contrast, melanoma tumor cells that do not express Livin are relatively resistant to NDV-HUJ treatment. Furthermore, we show that NDV-HUJ-induced oncolysis is attributed to the dual function of Livin: although Livin inhibits apoptosis through the inhibition of caspases, under the robust apoptotic stimulation of NDV-HUJ, caspases can cleave Livin to create a truncated protein with a paradoxical proapoptotic activity. Thus, NDV-HUJ is a potent inducer of apoptosis that can overcome the antiapoptotic effect of Livin and allow cleavage of Livin into the proapoptotic tLivin protein. Moreover, the results indicate that the interferon system, which is functional in melanoma, is not involved in NDV-induced oncolysis. Taken together, our data offer the possibility of a new viral oncolytic treatment for chemoresistant melanoma.

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Goenaga, Anne-Laure, I.-Ming Wang, Bryan S. Clay, Susanne Lang, Annabel Wang, Peter Weady, Smitha P. S. Pillai et al. « Abstract 5617 : A novel genetically modified oncolytic vaccinia virus selectively replicates in tumors to activate an inflammatory TME and induce tumor regression ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 5617. http://dx.doi.org/10.1158/1538-7445.am2022-5617.

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Abstract Oncolytic viruses (OVs) have been widely investigated as cancer immunotherapy platforms and are represented by a diverse group of DNA and RNA viruses. We are currently investigating a genetically modified oncolytic vaccinia virus as a best-in-class tumor-selective investigational product for the treatment of solid tumors. Specifically, the viral thymidine kinase (TK) has been deleted to enhance safety by greatly limiting replication in healthy tissues while taking advantage of relatively higher endogenous TK levels in tumors. In addition to tumor-selective replication, the oncolytic vaccinia virus encodes an IL-2 variant (IL-2v) protein, which diminishes preferential activation of immunosuppressive Treg cells while preserving activation of CD8+ and NK cells and avoiding toxicities associated with wild type IL-2. Using a murine surrogate of the oncolytic vaccinia virus, we assessed preclinical efficacy in multiple murine syngeneic tumor models demonstrating selective tumor localized replication resulting in tumor growth inhibition. Consistent with tumor selective virus replication, viral copy number and IL-2v transgene levels were increased and had prolonged expression in the tumors compared to the periphery. Intratumoral colocalization of the virus and IL-2v was confirmed by IHC and ISH, respectively. Tumor growth inhibition was associated with increases in tumor infiltrating CD8 and NK effector cells. Additionally, efficacy of the mouse surrogate virus was associated with systemic increases in circulating total CD8 and NK cells as well as pSTAT5+ CD8 and NK cells in the blood. In summary, we have demonstrated that arming a TK-deficient oncolytic vaccinia virus with an IL-2v transgene can effectively couple short-term destruction of tumor cells through oncolysis with the activation of anti-tumor immune response in the tumor microenvironment. These data support the study of this therapy in Phase 1 clinical trials. Citation Format: Anne-Laure Goenaga, I-Ming Wang, Bryan S. Clay, Susanne Lang, Annabel Wang, Peter Weady, Smitha P.S. Pillai, Sripad Ram, Leah Mitchell, Michael Eisenbraun, Joseph Binder, Liliana Maruri Avidal, David Kirn, Robert Hollingsworth, Clare Lees. A novel genetically modified oncolytic vaccinia virus selectively replicates in tumors to activate an inflammatory TME and induce tumor regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5617.

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Meng, Gang, Binghua Li, Anxian Chen, Meihong Zheng, Tiancheng Xu, Hailin Zhang, Jie Dong, Junhua Wu, Decai Yu et Jiwu Wei. « Targeting aerobic glycolysis by dichloroacetate improves Newcastle disease virus-mediated viro-immunotherapy in hepatocellular carcinoma ». British Journal of Cancer 122, n^o 1 (10 décembre 2019) : 111–20. http://dx.doi.org/10.1038/s41416-019-0639-7.

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Abstract Background Oncolytic viro-immunotherapy holds promise for cancer treatment. While immune activation can be robustly triggered by oncolytic viruses, negative feedback is often upregulated in the tumour microenvironment (TME). Lactate accumulation, signal transducer and activator of transcription 3 (STAT3) activation, indoleamine 2,3-dioxygenase 1 (IDO1) expression, and myeloid-derived suppressor cell (MDSC) infiltration coordinate to shape the immunosuppressive TME. Methods Representative hepatocellular carcinoma (HCC) cell lines and HCC-bearing mice were treated with oncolytic Newcastle disease virus (NDV), alone or in combination with dichloroacetate (DCA, a pyruvate dehydrogenase kinase (PDK) inhibitor). Results We found that infection with oncolytic NDV led to significant induction of the aforementioned suppressive factors. Interestingly, DCA significantly reduced lactate release, STAT3 activation, IDO1 upregulation, and MDSC infiltration in NDV-treated HCC. Consequently, DCA significantly enhanced the antitumour immune responses, leading to improved antitumour efficacy and prolonged survival in mouse models of ascitic and subcutaneous HCC. Furthermore, DCA increased NDV replication in a PDK-1-dependent manner in HCC. Conclusions Targeting aerobic glycolysis by DCA improves NDV-mediated viro-immunotherapy in HCC by mitigating immune negative feedback and promoting viral replication. These findings provide a rationale for targeting reprogrammed metabolism together with oncolytic virus-mediated viro-immunotherapy for HCC treatment.

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Schirrmacher, Volker. « Molecular Mechanisms of Anti-Neoplastic and Immune Stimulatory Properties of Oncolytic Newcastle Disease Virus ». Biomedicines 10, n^o 3 (28 février 2022) : 562. http://dx.doi.org/10.3390/biomedicines10030562.

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Oncolytic viruses represent interesting anti-cancer agents with high tumor selectivity and immune stimulatory potential. The present review provides an update of the molecular mechanisms of the anti-neoplastic and immune stimulatory properties of the avian paramyxovirus, Newcastle Disease Virus (NDV). The anti-neoplastic activities of NDV include (i) the endocytic targeting of the GTPase Rac1 in Ras-transformed human tumorigenic cells; (ii) the switch from cellular protein to viral protein synthesis and the induction of autophagy mediated by viral nucleoprotein NP; (iii) the virus replication mediated by viral RNA polymerase (large protein (L), associated with phosphoprotein (P)); (iv) the facilitation of NDV spread in tumors via the membrane budding of the virus progeny with the help of matrix protein (M) and fusion protein (F); and (v) the oncolysis via apoptosis, necroptosis, pyroptosis, or ferroptosis associated with immunogenic cell death. A special property of this oncolytic virus consists of its potential for breaking therapy resistance in human cancer cells. Eight examples of this important property are presented and explained. In healthy human cells, NDV infection activates the RIG-MAVs immune signaling pathway and establishes an anti-viral state based on a strong and uninhibited interferon α,ß response. The review also describes the molecular determinants and mechanisms of the NDV-mediated immune stimulatory effects, in which the viral hemagglutinin-neuraminidase (HN) protein plays a prominent role. The six viral proteins provide oncolytic NDV with a special profile in the treatment of cancer.

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Ho, Chun-Te, Mei-Hsuan Wu, Ming-Jen Chen, Shih-Pei Lin, Yu-Ting Yen et Shih-Chieh Hung. « Combination of Mesenchymal Stem Cell-Delivered Oncolytic Virus with Prodrug Activation Increases Efficacy and Safety of Colorectal Cancer Therapy ». Biomedicines 9, n^o 5 (13 mai 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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Koch, Jana, Julia Beil, Susanne Berchtold, Dina Mönch, Annika Maaß, Irina Smirnow, Andrea Schenk et al. « Establishing a New Platform to Investigate the Efficacy of Oncolytic Virotherapy in a Human Ex Vivo Peritoneal Carcinomatosis Model ». Viruses 15, n^o 2 (27 janvier 2023) : 363. http://dx.doi.org/10.3390/v15020363.

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Oncolytic virotherapy constitutes a promising treatment option for many solid cancers, including peritoneal carcinomatosis (PC), which still represents a terminal stage of many types of tumors. To date, the in vitro efficacy of oncolytic viruses is mostly tested in 2D-cultured tumor cell lines due to the lack of realistic 3D in vitro tumor models. We have investigated the feasibility of virotherapy as a treatment option for PC in a human ex vivo peritoneum co-culture model. Human HT-29 cancer cells stably expressing marker genes GFP and firefly luciferase (GFP/luc) were cultured on human peritoneum and infected with two prototypic oncolytic viruses (GLV-0b347 and MeV-DsRed). Both viral constructs were able to infect HT-29 cells in patient-derived peritoneum with high tumor specificity. Over time, both GFP signal and luciferase activity decreased substantially, thereby indicating successful virus-induced oncolysis. Furthermore, immunohistochemistry stainings showed specific virotherapeutic infections of HT-29 cells and effective tumor cell lysis in infected co-cultures. Thus, the PC model established here provides a clinically relevant screening platform to evaluate the therapeutic efficacy of virotherapeutic compounds and also to investigate, in an autologous setting, the immunostimulatory potential of oncolytic viruses for PC in a unique human model system superior to standard 2D in vitro models.

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Jing, Yuqi, F. Bustamante Guerrero et Jaime Merchan. « Abstract 3293 : In vitro cellular and molecular effects of oncolytic vaccinia virus in clear and non-clear cell renal cell carcinoma ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 3293. http://dx.doi.org/10.1158/1538-7445.am2022-3293.

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Abstract Oncolytic vaccinia virus has several advantages over other OV platforms, including an efficient life cycle, multiple mechanisms of viral spread, large genome, allowing acceptance of foreign therapeutic DNA inserts, and proven safety in humans, due to its use as smallpox vaccine. JX-594 (Pexavec, SillaJen) is an attenuated (TKdeactivated ) oncolytic vaccinia VV, engineered to express GM-CSF and to selectively target tumor over non-tumor tissues. It is currently being investigated as a novel therapeutic option in patients with advanced Renal Cell Carcinoma (RCC, NCT03294083). The present study was undertaken to investigate the effects of JX-954 in a panel of clear and non-clear cell RCC cell lines and characterize the potential mechanisms of JX-594 oncolysis in vitro. We evaluated the oncolytic potency of JX-594 in human clear cell RCCs (VHL mutant 786-0, A498, VHL wild type Caki-1), non-clear cell RCC (ACHN, papillary RCC, and UOK-262, an FH deficient papillary RCC cell) and murine renal cancer cells (RENCA). Potent and persistent cytotoxic effects were induced by JX-594 in all human RCC cells, regardless of the histological subtype, and by mJX-594 (a Western Reserve strain of vaccinia virus expressing murine GMCSF) in RENCA cells. Moreover, we observed efficient viral replication in human (786-0, ACHN) and murine (RENCA) cells, confirming RCC permissiveness to viral infection. Functional proteomics analysis of JX-594 treated 786-0 cells was performed by reverse phase protein array (RPPA) to gain knowledge on potential mechanisms of viral oncolysis. JX-594 treatment had significant effects on the expression levels of proteins related to inducing cell cycle, apoptosis, necrosis, Akt signaling, MAPK signaling, autophagy and stress induction. In particular, the proteins related to cell cycle (Wee1, Cdc25c, CHK1/2, and Cyclin B1) and Akt signaling (PI3K, mTOR, Rictor and FOXO), MAPK signaling (JAK2, PAK1, FAK and MEK1) were down regulated, while proteins involved in apoptosis and necrosis were upregulated. In summary, our studies show that human and murine renal cancer cells are permissive to infection and replication by JX-594 and mJX-594, which induce potent oncolytic effects in clear and non-clear cell RCC, effects associated with significant modulation of RCC pathways associated with cell cycle, proliferation, and survival and stress responses. Citation Format: Yuqi Jing, F Bustamante Guerrero, Jaime Merchan. In vitro cellular and molecular effects of oncolytic vaccinia virus in clear and non-clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3293.

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Morozov, Dmitriy A., Irina V. Kolyadina, Irina V. Poddubnaya, Petr M. Chumakov, Galina V. Ilinskaya, Vagan Yu Bokhian et Margarita I. Sopova. « The potential use of oncolytic viruses in breast cancer : historical aspects and future prospects (literature review) ». Journal of Modern Oncology 21, n^o 1 (15 mars 2019) : 31–35. http://dx.doi.org/10.26442/18151434.2019.1.190299.

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Viral oncolysis, an approach to cancer therapy that emerged in the XX century and based on the natural ability of viruses to kill (lyse) cells in which it multiplies, has been developed in recent years by identifying viruses or their engineering variants with selective tumor replication. Over the past decades, a number of specific interactions of oncolytic viruses (both RNA and IDNA-containing) with malignant tumor cells have been described, individual candidate viruses and the types of tumors that they lase have been detected. The therapeutic efficacy of oncolytic viruses is achieved through a combination of selective destruction of tumor cells through a direct cytotoxic effect and activation of antitumor immunity; In addition, oncolytic viruses can affect abberant signaling pathways followed by blockade of tumor cell apoptosis, which gives the virus more time to complete its life cycle. A number of oncolytic viruses have shown promising therapeutic efficacy in preclinical studies in breast cancer; thus, the herpes simplex virus has a high selectivity for replication in tumor cells, which contributes to the death and the formation of infiltration of CD8+ and CD4+ T cells around tumor islands. The ability of reoviruses to enhance the expression of PD-L1 protein in cells was found, and the measles virus armed with the BNiP3 proapoptosis gene is more active in the cell lines of triple negative breast cancer. Improved viruses, from the point of view of the effectiveness and selectivity of effects on the tumor, as well as optimized combinations with other "standard" types of systemic therapy, are very promising, especially in patients with developed drug resistance.

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Ho Shin, Dong, Teresa Nguyen, Hong Jiang, Sagar Sohoni, Sumit Gupta, Ashley Ossimetha, Marta M. Alonso, Candelaria Gomez-Manzano et Juan Fueyo. « EXTH-39. HEXON SWAPPING MITIGATES ANTI-VIRAL IMMUNE RESPONSE DURING BRAIN TUMOR VIROTHERAPY ». Neuro-Oncology 22, Supplement_2 (novembre 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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Clarkson, Matthew F., Aru Narendran et Randal N. Johnston. « Preclinical Evaluation of Oncolytic Reovirus in Targeted Therapeutics for High-Risk Pediatric Leukemia ». Blood 120, n^o 21 (16 novembre 2012) : 3571. http://dx.doi.org/10.1182/blood.v120.21.3571.3571.

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Abstract Abstract 3571 Purpose: Leukemia is the most common malignancy in children. Improved treatment strategies in recent decades have yielded substantially enhanced outcomes for children with leukemia, reaching survival rates >80%. However, there remain significant issues with current treatment. Certain subgroups of patients who are resistant to or relapse from current treatments have a dismal prognosis. Furthermore, there are significant late effects of intensive treatments, including secondary cancers, neurocognitive defects, cardiotoxicity, obesity and infertility. For these reasons, novel treatment strategies are urgently needed for high-risk leukemia in children. Reovirus type 3 Dearing is a wild-type double-stranded RNA virus that has shown great promise as a selective oncolytic agent by its ability to replicate in transformed cells but not in normal cells. Although a number of early phase clinical studies have been completed in patients with advanced, refractory solid tumors in adults, systematic evaluation of this agent in the treatment of refractory pediatric leukemia has not been reported. As an initial step towards developing an oncolytics based treatment approach, we report preclinical data with respect to the activity, target validation, target modulation and drug combinability of reovirus in childhood leukemia cells. Experimental Design: A panel of pediatric leukemia cell lines representing high-risk molecular features such as Bcr-Abl, MLL rearranged and mixed lineage was used (n =6). Expression of JAM-A, the cell surface receptor for reovirus, was assessed by flow cytometry. The Ras Activation Assay Kit (EMD Millipore) was used to assess activity of the RAS protein. Western Blots were used to assess the activation (phosphorylation) of the signaling partners downstream of RAS. Cells treated with reovirus, chemotherapy drugs, or both for distinct treatment schedules were assessed for cell viability by the CellTiter-Glo© Luminescent Cell Viability Assay (Promega), and cell death by apoptosis was confirmed by cleavage of PARP. Productive viral infection was assessed by measuring reoviral protein synthesis by Western Blots, and reoviral replication was assessed by virus plaque titration assay. Drug synergies were calculated according to the method of Chou and Talalay. Results: Target validation assays showed the expression of JAM-A, which facilitates effective viral entry into malignant cells, in five of six cell lines. These cell lines also demonstrated differential activation of RAS and downstream kinases, suggesting targeted susceptibility of these cells to reovirus oncolysis. To further test this, we infected cells with reovirus for 1–4 days and assessed cytopathic effects. Using phase contrast microscopy, we observed the virus treated cell lines to demonstrate morphological changes characteristic of cell death following infection. Cell viability assays were used to quantify this effect, and the mechanism of cell death was determined to be apoptotic as evidenced by caspase-dependent cleavage of PARP. Reovirus-induced cell death was correlated with viral protein production and replication. Next, we screened for the ability of reovirus to induce synergistic activity in a panel of conventional and novel targeted therapeutic agents. Our studies showed that, in contrast to the current antileukemic agents, the Bcl-2 inhibitor BH3 mimetic ABT-737 was able to significantly synergize with reovirus in all cell lines tested. Conclusions: In our in vitro studies, oncolytic reovirus as a single agent showed potent oncolytic activity against all pediatric leukemia cell lines tested that express the receptor for reovirus, regardless of the status of the RAS signaling pathway. Further, we found reovirus-induced oncolysis can be enhanced by combination with Bcl-2 inhibition but was unaltered or antagonized by the other drugs indicating a key relationship between the two pathways. As such, our data for the first time, show that pediatric leukemia cells carry the potential to be targeted by reovirus induced oncolysis and the identification of drug synergy and the biomarkers of target modulation provide the basis for further studies to develop this novel therapeutic approach for clinical studies in the near future. Disclosures: No relevant conflicts of interest to declare.

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Lee, Namhee, Yun-Hui Jeon, Jiyoon Yoo, Suk-kyung Shin, Songyi Lee, Mi-Ju Park, Byung-Jin Jung, Yun-Kyoung Hong, Dong-Sup Lee et Keunhee Oh. « Generation of novel oncolytic vaccinia virus with improved intravenous efficacy through protection against complement-mediated lysis and evasion of neutralization by vaccinia virus-specific antibodies ». Journal for ImmunoTherapy of Cancer 11, n^o 1 (janvier 2023) : e006024. http://dx.doi.org/10.1136/jitc-2022-006024.

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BackgroundOncolytic virus immunotherapy has revolutionized cancer immunotherapy by efficiently inducing both oncolysis and systemic immune activation. Locoregional administration has been used for oncolytic virus therapy, but its applications to deep-seated cancers have been limited. Although systemic delivery of the oncolytic virus would maximize viral immunotherapy’s potential, this remains a hurdle due to the rapid removal of the administered virus by the complement and innate immune system. Infected cells produce some vaccinia viruses as extracellular enveloped virions, which evade complement attack and achieve longer survival by expressing host complement regulatory proteins (CRPs) on the host-derived envelope. Here, we generated SJ-600 series oncolytic vaccinia viruses that can mimic complement-resistant extracellular enveloped virions by incorporating human CRP CD55 on the intracellular mature virion (IMV) membrane.MethodsThe N-terminus of the human CD55 protein was fused to the transmembrane domains of the six type I membrane proteins of the IMV; the resulting recombinant viruses were named SJ-600 series viruses. The SJ-600 series viruses also expressed human granulocyte-macrophage colony-stimulating factor (GM-CSF) to activate dendritic cells. The viral thymidine kinase (J2R) gene was replaced by genes encoding the CD55 fusion proteins and GM-CSF.ResultsSJ-600 series viruses expressing human CD55 on the IMV membrane showed resistance to serum virus neutralization. SJ-607 virus, which showed the highest CD55 expression and the highest resistance to serum complement-mediated lysis, exhibited superior anticancer activity in three human cancer xenograft models, compared with the control Pexa-Vec (JX-594) virus, after single-dose intravenous administration. The SJ-607 virus administration elicited neutralizing antibody formation in two immunocompetent mouse strains like the control JX-594 virus. Remarkably, we found that the SJ-607 virus evades neutralization by vaccinia virus-specific antibodies.ConclusionOur new oncolytic vaccinia virus platform, which expresses human CD55 protein on its membrane, prolonged viral survival by protecting against complement-mediated lysis and by evading neutralization by vaccinia virus-specific antibodies; this may provide a continuous antitumor efficacy until a complete remission has been achieved. Such a platform may expand the target cancer profile to include deep-seated cancers and widespread metastatic cancers.

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García-Romero, Noemi, Irina Palacín-Aliana, Susana Esteban-Rubio, Rodrigo Madurga, Sergio Rius-Rocabert, Josefa Carrión-Navarro, Jesús Presa et al. « Newcastle Disease Virus (NDV) Oncolytic Activity in Human Glioma Tumors Is Dependent on CDKN2A-Type I IFN Gene Cluster Codeletion ». Cells 9, n^o 6 (5 juin 2020) : 1405. http://dx.doi.org/10.3390/cells9061405.

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Glioblastoma (GBM) is the most aggressive and frequent primary brain tumor in adults with a median overall survival of 15 months. Tumor recurrence and poor prognosis are related to cancer stem cells (CSCs), which drive resistance to therapies. A common characteristic in GBM is CDKN2A gene loss, located close to the cluster of type I IFN genes at Ch9p21. Newcastle disease virus (NDV) is an avian paramyxovirus with oncolytic and immunostimulatory properties that has been proposed for the treatment of GBM. We have analyzed the CDKN2A-IFN I gene cluster in 1018 glioma tumors and evaluated the NDV oncolytic effect in six GBM CSCs ex vivo and in a mouse model. Our results indicate that more than 50% of GBM patients have some IFN deletion. Moreover, GBM susceptibility to NDV is dependent on the loss of the type I IFN. Infection of GBM with an NDV-expressing influenza virus NS1 protein can overcome the resistance to oncolysis by NDV of type I-competent cells. These results highlight the potential of using NDV vectors in antitumor therapies.

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Chumakov, P. M. « Could oncolytic viruses provide a breakthrough in oncology ? » Вестник Российской академии наук 89, n^o 5 (6 mai 2019) : 475–84. http://dx.doi.org/10.31857/s0869-5873895475-484.

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Despite the long-term and intensive studies of the nature of cancer and the development of numerous anti-cancer drugs, the incidence of cancer is growing, and the five-year survival of cancer patients diagnosed at the advanced stages of the disease remains unacceptably low. The author examines the causes of the failures in cancer therapy, which are rooted in the very nature of malignant cells, as these cells can adapt and acquire resistance to almost any systemic therapy. In this regard, considerable hopes are associated with oncolytic viruses, which represent a distinct type of remedies capable of complex influences on the disease. In addition to their ability to directly kill cancer cells, oncolytic viruses can stimulate the natural processes of immune surveillance and elimination of cancer cells. Furthermore, oncolytic viruses can kill tumor-initiating cancer stem cells, that are highly resistant to chemo- and radiotherapy, and overcome the immune suppression of the tumor micro-environment. These features make oncolytic viruses unique anti-cancer agents that fight cancer cells by multiple natural mechanisms. To implement virus-mediated cancer therapy into broad medical practice the following are required: intensified studies on viral oncolysis are required and which would include a development of new advanced therapeutic viral strains; development of tests for predicting which virus strains from therapeutic panels are suitable for the patient; and, improvement of technologies for local and systemic delivery of oncolytic viruses to the tumor and metastases. Major changes would be also required in the practices of testing therapeutic drugs that accelerate the introduction of new viral strains into medical practice. Achievements in this direction help to overcome many old problems in the therapy of metastatic forms of malignant diseases.

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Song, Xiaotong, Feng Yu, Stephen Gottschalk et David Bartlett. « Arming oncolytic vaccinia virus with T cell engager to improve virus therapy (P4413) ». Journal of Immunology 190, n^o 1_Supplement (1 mai 2013) : 205.16. http://dx.doi.org/10.4049/jimmunol.190.supp.205.16.

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Abstract Oncolytic vaccinia virus (VV) therapy has shown promise in preclinical models and in clinical studies. Complete responses, however, have rarely been observed. The limitations presented by VV therapy typically have been suboptimal virus spread through the tumor and the limited induction of antigen-specific T-cell responses. Here we describe a novel strategy to overcome these limitations. We have constructed T-cell Engager Armed Vaccinia Viruses (TEA-VVs) encoding secretory bi-specific T-cell engager (single chain variable fragment, scFv) that binds both to CD3 and a tumor cell surface antigen EphA2 (EphA2-TEA-VV). The expression of EphA2-TE was demonstrated in cell culture. Also, the replication and oncolysis efficiency of EphA2-TEA-VV in cell culture were similar to that of the parental virus. However, the EphA2-TEA-VV killed EphA2-positive tumor cells A549 more effectively in the presence of human PBMC as determined by target cell lysis, compared to unmodified VV. In addition, EphA2-TEA-VV induced bystander killing of tumor cells that are not infected with virus as determined by in vitro assay. Importantly, EphA2-TEA-VV resulted in a significant decrease in tumor growth in an established A549 lung cancer model. Thus, TEA-VV represents a unique and effective strategy to improve oncolytic virus therapy by engaging T cells for cancer therapy.

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Phillips, Lynette, Joy Gumin, Shoudong Li, Marc Daou, Daniel Ledbetter, Anwar Hossain, Brittany Parker Kerrigan, Candelaria Gomez-Manzano, Juan Fueyo et Frederick Lang. « TMOD-16. A NOVEL ADENOVIRAL-PERMISSIVE, IMMUNOCOMPETENT HAMSTER GLIOMA MODEL TO EVALUATE ONCOLYTIC ADENOVIRAL THERAPY ». Neuro-Oncology 22, Supplement_2 (novembre 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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Kolodkin-Gal, Dror, Gideon Zamir, Yair Edden, Eli Pikarsky, Alon Pikarsky, Hillel Haim, Yosef S. Haviv et Amos Panet. « Herpes Simplex Virus Type 1 Preferentially Targets Human Colon Carcinoma : Role of Extracellular Matrix ». Journal of Virology 82, n^o 2 (31 octobre 2007) : 999–1010. http://dx.doi.org/10.1128/jvi.01769-07.

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ABSTRACT Viral therapy of cancer (viral oncolysis) is dependent on selective destruction of the tumor tissue compared with healthy tissues. Several factors, including receptor expression, extracellular components, and intracellular mechanisms, may influence viral oncolysis. In the present work, we studied the potential oncolytic activity of herpes simplex virus type 1 (HSV-1), using an organ culture system derived from colon carcinoma and healthy colon tissues of mouse and human origin. HSV-1 infected normal colons ex vivo at a very low efficiency, in contrast to high-efficiency infection of colon carcinoma tissue. In contrast, adenoviral and lentiviral vectors infected both tissues equally well. To investigate the mechanisms underlying the preferential affinity of HSV-1 for the carcinoma tissue, intracellular and extracellular factors were investigated. Two extracellular components, collagen and mucin molecules, were found to restrict HSV-1 infectivity in the healthy colon. The mucin layer of the healthy colon binds to HSV-1 and thereby blocks viral interaction with the epithelial cells of the tissue. In contrast, colon carcinomas express small amounts of collagen and mucin molecules and are thus permissive to HSV-1 infection. In agreement with the ex vivo system, HSV-1 injected into a mouse colon carcinoma in vivo significantly reduced the volume of the tumor. In conclusion, we describe a novel mechanism of viral selectivity for malignant tissues that is based on variance of the extracellular matrix between tumor and healthy tissues. These insights may facilitate new approaches to the application of HSV-1 as an oncolytic virus.

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Mahasa, Khaphetsi Joseph, Rachid Ouifki, Amina Eladdadi et Lisette de Pillis. « A combination therapy of oncolytic viruses and chimeric antigen receptor T cells : a mathematical model proof-of-concept ». Mathematical Biosciences and Engineering 19, n^o 5 (2022) : 4429–57. http://dx.doi.org/10.3934/mbe.2022205.

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<abstract><p>Combining chimeric antigen receptor T (CAR-T) cells with oncolytic viruses (OVs) has recently emerged as a promising treatment approach in preclinical studies that aim to alleviate some of the barriers faced by CAR-T cell therapy. In this study, we address by means of mathematical modeling the main question of whether a single dose or multiple sequential doses of CAR-T cells during the OVs therapy can have a synergetic effect on tumor reduction. To that end, we propose an ordinary differential equations-based model with virus-induced synergism to investigate potential effects of different regimes that could result in efficacious combination therapy against tumor cell populations. Model simulations show that, while the treatment with a single dose of CAR-T cells is inadequate to eliminate all tumor cells, combining the same dose with a single dose of OVs can successfully eliminate the tumor in the absence of virus-induced synergism. However, in the presence of virus-induced synergism, the same combination therapy fails to eliminate the tumor. Furthermore, it is shown that if the intensity of virus-induced synergy and/or virus oncolytic potency is high, then the induced CAR-T cell response can inhibit virus oncolysis. Additionally, the simulations show a more robust synergistic effect on tumor cell reduction when OVs and CAR-T cells are administered simultaneously compared to the combination treatment where CAR-T cells are administered first or after OV injection. Our findings suggest that the combination therapy of CAR-T cells and OVs seems unlikely to be effective if the virus-induced synergistic effects are included when genetically engineering oncolytic viral vectors.</p></abstract>

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Wilson, Marnie Goodwin, Thi Lien-Anh Nguyen, Laura Shulak, Peyman Nakhaei et John Hiscott. « Epigenetic modifiers enhance vesicular Stomatitis virus-mediated oncolysis in the refractory PC3 cell line ». McGill Science Undergraduate Research Journal 5, n^o 1 (31 mars 2010) : 61–66. http://dx.doi.org/10.26443/msurj.v5i1.87.

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Introduction: Vesicular stomatitis Virus (VsV) is an oncolytic virus that preferentially replicates in and kills cancerous cells. however, many cancer cell lines are resistant to VsV treatment alone. previous work has shown that treating cancerous cells with histone deacetylase inhibitors makes them more susceptible to VsV infection and oncolysis. We hypothesize that treatment with a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (saha or Voronistat), and a methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5-aza or Decitabine), will result in an increase in VsV replication and virus-induced oncolysis in vitro. Methods: pC3 prostate cancer cells were treated with 1 μm saha, 1 μm 5-aza or both. of these samples, half were infected with oncolytic Vesicular stomatitis Virus expressing green fluorescent protein VsV aV1 – gFp at a multiplicity of infection of 1 × 10-2, 24 hours after treatment. Cells were then collected and subjected to either FaCs analysis or protein extraction at 12, 24, 48 and 72 hours post-infection. We confirmed increases in cell death by western blotting for cleavage of poly a Riboprotein, an important downstream effector of the Caspase pathway, as well as Caspases 8 and 9, hallmarks for the extrinsic and intrinsic apoptotic pathways respectively. results: Treatment with saha, 5-aza or a combination of both resulted in increases in VsV replication and cell death. These observations were consistent over four time points spanning 72 hours. discussion: Treatment with histone deacetylase inhibitor/methyltransferase inhibitor combination increases VsV replication and cell death in tumour cell lines resistant to VsV infection. In combination with previous work, this data suggests that modulation of the antiviral response and apoptotic pathways increases susceptibility to VsV.

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Boisgerault, Nicolas, Jean-Baptiste Guillerme, Daniel Pouliquen, Mariana Mesel-Lemoine, Carole Achard, Chantal Combredet, Jean-François Fonteneau, Frédéric Tangy et Marc Grégoire. « Natural Oncolytic Activity of Live-Attenuated Measles Virus against Human Lung and Colorectal Adenocarcinomas ». BioMed Research International 2013 (2013) : 1–11. http://dx.doi.org/10.1155/2013/387362.

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Lung and colorectal cancers are responsible for approximately 2 million deaths each year worldwide. Despite continual improvements, clinical management of these diseases remains challenging and development of novel therapies with increased efficacy is critical to address these major public health issues. Oncolytic viruses have shown promising results against cancers that are resistant to conventional anticancer therapies. Vaccine strains of measles virus (MV) exhibit such natural antitumor properties by preferentially targeting cancer cells. We tested the ability of live-attenuated Schwarz strain of MV to specifically infect tumor cells derived from human lung and colorectal adenocarcinomas and demonstrated that live-attenuated MV exhibits oncolytic properties against these two aggressive neoplasms. We also showed that Schwarz MV was able to prevent uncontrollable growth of large, established lung and colorectal adenocarcinoma xenografts in nude mice. Moreover, MV oncolysis is associated within vivoactivation of caspase-3 in colorectal cancer model, as shown by immunohistochemical staining. Our results provide new arguments for the use of MV as an antitumor therapy against aggressive human malignancies.

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Nikolaeva, E. Yu, Yu R. Shchetinina, I. E. Shokhin, V. V. Zverev, O. A. Svitich, O. Yu Susova, A. A. Mitrofanov et Yu I. Ammour. « Measles Virus as a Vector Platform for Glioblastoma Immunotherapy (Review) ». Drug development & ; registration 11, n^o 1 (23 février 2022) : 51–58. http://dx.doi.org/10.33380/2305-2066-2022-11-1-51-58.

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Introduction. Oncolytic virotherapy is one of the approaches in immunotherapy of solid brain tumors. Measles virus vaccine strains are prospective agents for the therapy of cancers such as neuroblastoma, mesothelioma, and glioblastoma multiforme. The hyperexpression of the CD46 and other receptors on the surface of malignant cells allows the measles virus to infect and lyse the tumor, thus inducing an immune response. However, widespread immunization of the population and the resistance of neoplasms to oncolysis present difficulties in clinical practice.Text. This review covers approaches to modifying the measles virus genome in order to increase specificity of virotherapy, overcome existing immunity, and enhance the oncolytic effect. It was shown that expression of proinflammatory cytokines on viral particles leads to tumor regression in mice and triggers a T-cell response. Several approaches have been used to overcome virus-neutralizing antibodies: shielding viral particles, using host cells, and altering the epitope of the protein that enables entry of the virus into the cell. Furthermore, the insertion of reporter genes allows the infection of target cells to be monitored in vivo. A combination with the latest immunotherapies, such as immune checkpoint inhibitors, demonstrates synergistic effects, which suggests the successful use of combined approaches in the therapy of refractory tumors.Conclusion. Measles virus attenuated strains appear to be an easy-to-modify and reliable platform for the therapy of solid brain tumors.

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Guo, Deyin, Fan Xing, Jingshu Xiao et Jiaming liang. « Abstract LB537 : CDK4/6 inhibition enhances oncolytic efficacy on refractory glioblastoma by potentiating tumor-selective cell killing and T cell activation ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : LB537. http://dx.doi.org/10.1158/1538-7445.am2022-lb537.

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Abstract Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor. Although oncolytic virus (OV) therapy has been proposed as a potential approach to treat GBM, the resistance is frequently observed because GBM cells are usually nonpermissive to OV. Here, we describe a dual-step drug screen for identifying chemical enhancers of oncolytic virus in GBM. An inhibitor of the cyclin-dependent kinases 4/6 (CDK4/6) was identified as the top enhancer from 1416 FDA-approved drugs, selectively increasing potency of the two OV strains, including VSVΔ51 and Zika virus. Mechanistically, CDK4/6 inhibition promoted the autophagic degradation of MAVS, resulting in impaired antiviral responses and enhanced tumor-selective replication of VSVΔ51 in vitro and in vivo. CDK4/6 inhibition cooperated with VSVΔ51 to induce severe DNA damage stress, leading to the amplification of oncolysis. In GBM xenograft models, combination treatment of CDK4/6 inhibitor and VSVΔ51 significantly inhibited the tumor growth and prolonged the survival time of tumor-bearing mice. Further investigation revealed that CDK4/6 inhibitor and VSVΔ51 synergistically induced the immunogenic cell death and boosted the anti-tumor immunity. Together, our study features a promising approach of treating aggressive GBM through the combination of CDK4/6 inhibitor with OV. Citation Format: Deyin Guo, Fan Xing, Jingshu Xiao, Jiaming liang. CDK4/6 inhibition enhances oncolytic efficacy on refractory glioblastoma by potentiating tumor-selective cell killing and T cell activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB537.

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Slavin, Shimon, Gila Kazimirsky, Amotz Ziv-Av et Chaya Brodie. « Role of mesenchymal stem cells in delivering Newcastle disease virus to glioma cells and glioma stem cells and enhancing the oncolytic effect of the virus by secreting TRAIL. » Journal of Clinical Oncology 31, n^o 15_suppl (20 mai 2013) : 3100. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3100.

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3100 Background: Newcastle disease virus (NDV), an avian paramyxovirus, is tumor selective and oncolytic by induction of apoptosis. Preclinical and clinical studies in patients with glioblastoma (GBM) using NDV demonstrated occasional clinical benefits with no major side effects. Limitations to the use of NDV as virotherapy of GBM is the inefficient delivery into cancer cells in the brain. Methods: Mesenchymal stromal cells (MSCs) can migrate towards cancer cells. We examined potential delivery of oncolytic effect of NDV (MTH-68/H) against glioma cell lines and glioma stem cells (GSCs) and the ability of MSCs to deliver NDV to glioma cells and GSCs in culture. Results: NDV induced a dose-dependent cell death in the glioma cells U87, A172 and U251 with maximal effects at 10 MOI. In contrast, we found only small level of apoptosis or changes in self-renewal in three GSCs infected with NDV. We found that MSCs derived from bone marrow, adipose tissue and cord were successfully infected by NDV and were able to deliver the virus to co-cultured glioma cells and GSCs. In addition, treatment of glioma cells and GSCs with culture supernatant of infected MSCs increase apoptosis of glioma cells as compared to the effect of direct infection of glioma cells. Moreover, the culture supernatants of the infected MSCs induced cell death in GSCs that were resistant to the oncolytic effect of NDV, suggesting that factor(s) secreted by the infected MSCs sensitized the glioma cells and GSCs to the cytotoxic effects of NDV. Using antibody array and ELISA we identified TRAIL as the factor secreted from infected MSCs. Indeed, treatment of infected glioma cells with TRAIL increased the cytotoxic effect of NDV and sensitized GSCs to the oncolytic effects of NDV. Conclusions: MSCs can be employed to deliver NDV to GBM. In addition, MSCs can also sensitize glioma cells and GSCs to oncolysis by NDV. Considering the resistance of GSCs to chemotherapy and radiation therapy, treatment of GBM with MSC-mediated targeted oncolytic NDV may provide a new clinical tool for treatment of GBM and eradication of GSCs.

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Stavrakaki, Eftychia, Anne Kleijn, Wouter B. van den Bossche, Rutger K. Balvers, Lisette B. Vogelezang, Jie Ju, Andrew Stubbs et al. « Abstract 3560 : Towards personalized oncolytic virotherapy : Differential response of four oncolytic viruses in primary glioblastoma cultures ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 3560. http://dx.doi.org/10.1158/1538-7445.am2022-3560.

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Abstract Background: The brain tumor glioblastoma (GBM) is one of the most aggressive forms of cancer. The dismal prognosis of these patients, with a median survival of less than 15 months despite maximal therapy makes the need for new therapeutic approaches urgent. Clinical trials employing oncolytic viruses (OVs) have shown encouraging results, however, it appears that for each OV only a small group of patients responds to treatment. As inter- and intra-tumoral heterogeneity is a hallmark of GBM, we hypothesized that fresh patient-derived GBM cell cultures will reflect this inter-tumoral variability in response and allow identification of potential biomarkers of susceptibility to specific OVs. Furthermore, we established a co-culture system of primary GBM cultures with autologous peripheral blood mononuclear cells (PBMCs) to capture the degree of OV-induced oncolysis in conjunction with subsequent immune activation. Using these model systems, we attempt to develop tools which may guide future personalized trials of OV treatment for GBM. Methods: We tested the oncolytic potency of four OVs derived from different viral families (DNX2401, rQnestin34.5 V1, wild type Reovirus, lentogenic NDV-f0-GFP) on a panel of 19 molecularly characterized GBM cultures and calculated the half maximal effective concentration (EC50) for each virus on each cell culture. Quantitative PCR was performed to assess cytokine expression in tumor cells after infection with the 4 different OVs. OV-induced changes in the gene and protein expression of immune associated genes were assessed in co-cultures of GBM cells with PBMCs using Nanostring nCounter System and Elisa. Results: Screening of the 4 OVs on the panel of patient-derived GBM cell cultures revealed great inter-tumoral variability in oncolysis and cytokine response to the 4 different OVs with some degree of OV specific cytokine response profiles. Correlation analysis of transcriptome data with susceptibility to the four OVs shows that genes involved in distinct pathways are related to specific OV-sensitivity. In particular, cell cycle and immune related biological processes discriminate responders and non-responders. The co-culture of OV-infected glioma cells with PBMCs suggests that infection with different OVs leads to expression of distinct sets of genes and proteins in PBMCs; indicating that each OV mounts a specific immune response. Conclusion: Heterogeneity in OV sensitivity is demonstrated in primary GBM cultures, in terms of oncolysis, cytokine induction and in virus-specific changes in gene and protein expression in OV-infected tumor cells/PBMCs co-cultures. These results support the hypothesis that improving the response rates in oncolytic virotherapy for GBM may require a personalized approach. Citation Format: Eftychia Stavrakaki, Anne Kleijn, Wouter B. van den Bossche, Rutger K. Balvers, Lisette B. Vogelezang, Jie Ju, Andrew Stubbs, Yunlei Li, Dana Mustafa, Federica Fabro, Bernadette van den Hoogen, Rob Hoeben, William F. Goins, Hiroshi Nakashima, E. Antonio Chiocca, Clemens M. Dirven, Martine L. Lamfers. Towards personalized oncolytic virotherapy: Differential response of four oncolytic viruses in primary glioblastoma cultures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3560.

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Marchica, Valentina, Federica Costa, Gaetano Donofrio et Nicola Giuliani. « Oncolytic Virotherapy and Microenvironment in Multiple Myeloma ». International Journal of Molecular Sciences 22, n^o 5 (24 février 2021) : 2259. http://dx.doi.org/10.3390/ijms22052259.

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Multiple myeloma (MM) is a hematologic malignancy characterized by the accumulation of bone marrow (BM) clonal plasma cells, which are strictly dependent on the microenvironment. Despite the improvement of MM survival with the use of new drugs, MM patients still relapse and become always refractory to the treatment. The development of new therapeutic strategies targeting both tumor and microenvironment cells are necessary. Oncolytic virotherapy represent a promising approach in cancer treatment due to tumor-specific oncolysis and activation of the immune system. Different types of human viruses were checked in preclinical MM models, and the use of several viruses are currently investigated in clinical trials in MM patients. More recently, the use of alternative non-human viruses has been also highlighted in preclinical studies. This strategy could avoid the antiviral immune response of the patients against human viruses due to vaccination or natural infections, which could invalid the efficiency of virotherapy approach. In this review, we explored the effects of the main oncolytic viruses, which act through both direct and indirect mechanisms targeting myeloma and microenvironment cells inducing an anti-MM response. The efficacy of the oncolytic virus-therapy in combination with other anti-MM drugs targeting the microenvironment has been also discussed.

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Scheubeck, Gabriel, Susanne Berchtold, Irina Smirnow, Andrea Schenk, Julia Beil et Ulrich M. Lauer. « Starvation-Induced Differential Virotherapy Using an Oncolytic Measles Vaccine Virus ». Viruses 11, n^o 7 (5 juillet 2019) : 614. http://dx.doi.org/10.3390/v11070614.

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Starvation sensitizes tumor cells to chemotherapy while protecting normal cells at the same time, a phenomenon defined as differential stress resistance. In this study, we analyzed if starvation would also increase the oncolytic potential of an oncolytic measles vaccine virus (MeV-GFP) while protecting normal cells against off-target lysis. Human colorectal carcinoma (CRC) cell lines as well as human normal colon cell lines were subjected to various starvation regimes and infected with MeV-GFP. The applied fasting regimes were either short-term (24 h pre-infection) or long-term (24 h pre- plus 96 h post-infection). Cell-killing features of (i) virotherapy, (ii) starvation, as well as (iii) the combination of both were analyzed by cell viability assays and virus growth curves. Remarkably, while long-term low-serum, standard glucose starvation potentiated the efficacy of MeV-mediated cell killing in CRC cells, it was found to be decreased in normal colon cells. Interestingly, viral replication of MeV-GFP in CRC cells was decreased in long-term-starved cells and increased after short-term low-glucose, low-serum starvation. In conclusion, starvation-based virotherapy has the potential to differentially enhance MeV-mediated oncolysis in the context of CRC cancer patients while protecting normal colon cells from unwanted off-target effects.

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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 (novembre 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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