Papers by Samuel Workenhe
Http Dx Doi Org 10 4161 Onci 27138, Dec 1, 2013
Oncolytic viruses are novel immunotherapeutic agents that appear to mediate potent antineoplastic... more Oncolytic viruses are novel immunotherapeutic agents that appear to mediate potent antineoplastic effects in both preclinical and clinical settings. Recent studies demonstrate that manipulating the mechanisms whereby cancer cells die in the course of oncolytic virotherapy has potential to boost anticancer immune responses.
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OncoImmunology, 2013
Oncolytic viruses are novel immunotherapeutic agents that appear to mediate potent antineoplastic... more Oncolytic viruses are novel immunotherapeutic agents that appear to mediate potent antineoplastic effects in both preclinical and clinical settings. Recent studies demonstrate that manipulating the mechanisms whereby cancer cells die in the course of oncolytic virotherapy has potential to boost anticancer immune responses.
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Molecular Therapy, 2014
Oncolytic viruses are novel immunotherapeutics with increasingly promising outcomes in cancer pat... more Oncolytic viruses are novel immunotherapeutics with increasingly promising outcomes in cancer patient clinical trials. Preclinical and clinical studies have uncovered the importance of virus-induced activation of antitumor immune responses for optimal therapeutic efficacy. Recently, several classes of chemotherapeutics have been shown to cause immunogenic cancer cell death characterized by the release of immunomodulatory molecules that activate antigen-presenting cells and thus trigger the induction of more potent anticancer adaptive immune responses. In preclinical models, several oncolytic viruses induce immunogenic cell death, which is associated with increased cross-priming of tumor-associated antigens. In this review, we discuss the recent advances in immunogenic cancer cell death as induced by chemotherapeutic treatments, including the roles of relevant danger-associated molecular patterns and signaling pathways, and highlighting the significance of the endoplasmic reticulum (ER) stress response. As virtually all viruses modulate both ER stress and cell death responses, we provide perspectives on future research directions that can be explored to optimize oncolytic viruses, alone or in combination with targeted drug therapies, as potent immunogenic cancer cell death-inducing agents. We propose that such optimized virus-drug synergistic strategies will improve the therapeutic outcomes for many currently intractable cancers.
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Developmental & Comparative Immunology, 2009
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Molecular Immunology, Aug 1, 2009
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Journal of Virological Methods, Oct 1, 2008
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Oncogene, 2015
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Molecular immunology, 2009
Infectious salmon anaemia virus (ISAV) is a marine orthomyxovirus of significant interest not onl... more Infectious salmon anaemia virus (ISAV) is a marine orthomyxovirus of significant interest not only as a cause of a fatal disease of farmed Atlantic salmon resulting in severe economic losses to the aquaculture industry, but also as the only poikilothermic orthomyxovirus. ISAV targets vascular endothelial cells and macrophages, and is known to influence the expression of both innate and adaptive immune response relevant genes. ISAV isolates from different geographic regions have been shown to vary considerably in their pathogenicity for Atlantic salmon. This study aimed to characterize the Atlantic salmon TO macrophage/dendritic-like cell responses to infection with a selection of ISAV isolates of different genotypes and pathogenicity phenotypes. The first TO infection trial used ISAV isolates NBISA01 and RPC/NB-04-085-1 of high and low pathogenicity, respectively, and global gene expression analyses were carried out using approximately 16,000 gene (16K) salmonid cDNA microarrays to ...
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Future oncology (London, England), 2015
Despite huge economic and intellectual investments, developing effective cancer treatments contin... more Despite huge economic and intellectual investments, developing effective cancer treatments continues to be an overarching challenge. Engineered oncolytic viruses (OVs) present self-amplifying immunotherapy platforms capable of preferential cytotoxicity to cancer cells and simultaneous activation of host anti-tumor immunity. In preclinical studies, OVs are showing potent therapeutic effects when used in combination with other immune therapy strategies. In the clinic, the immunotherapeutic effects of OVs are showing promising results. Here we review current strategies for engineering OVs, and present a perspective of future directions within a discussion of the current outcomes of combinatorial approaches with other cancer immunotherapy platforms.
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Although antitumor activity of herpes simplex virus 1 (HSV-1) ICP0 null oncolytic vectors has bee... more Although antitumor activity of herpes simplex virus 1 (HSV-1) ICP0 null oncolytic vectors has been validated in murine breast cancer models, oncolytic virus treatment alone is insufficient to break immune tolerance. Thus, we investigated enhancing efficacy through combination therapy with the immunogenic cell death–inducing chemotherapeutic drug, mitoxantrone. Despite a lack of enhanced cytotoxicity in vitro, HSV-1 ICP0 null oncolytic virus KM100 with 5 mmol/L mitoxantrone provided significant survival benefit to BALB/c mice bearing Her2/neu TUBO-derived tumors. This protection was mediated by increased intratumoral infiltration of neutrophils and tumor antigen-specific CD8 þ T cells. Depletion studies verified that CD8-, CD4-, and Ly6G-expressing cells are essential for enhanced efficacy of the combination therapy. Moreover, the addition of mitoxantrone to KM100 oncolytic virus treatment broke immune tolerance in BALB-neuT mice bearing TUBO-derived tumors. This study suggests that oncolytic viruses in combination with immunogenic cell death–inducing chemotherapeutics enhance the immunogenicity of the tumor-associated antigens, breaking immunologic tolerance established toward these antigens.
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Virology journal, Jan 25, 2007
Infectious salmon anaemia (ISA) virus (ISAV) is a fish orthomyxovirus that has recently been assi... more Infectious salmon anaemia (ISA) virus (ISAV) is a fish orthomyxovirus that has recently been assigned to the new genus Isavirus within the family Orthomyxoviridae. It possesses the major functional characteristics of the virus family including haemagglutinating, receptor destroying enzyme (RDE), and fusion activities associated with the virion surface proteins. It is generally accepted that ISAV agglutinates erythrocytes of several fish species and that the ISAV RDE activity dissolves this haemagglutination reaction except for Atlantic salmon (Salmo salar) erythrocytes. We used electron microscopy to examine the physical interaction between ISAV and erythrocytes from Atlantic salmon and rainbow trout (Oncorhynchus mykiss) during haemagglutination. We present evidence that ISAV enters into Atlantic salmon erythrocytes. Atlantic salmon erythrocytes incubated with ISAV for 4 hours showed endocytosis of the virus particles, which is consistent with virus infection. These observations su...
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OncoImmunology, 2014
Apoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune... more Apoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named "immunogenic cell…
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Virology Journal, 2008
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Molecular Immunology, 2010
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Journal of Virological Methods, 2008
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Cancer Gene Therapy, 2013
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Antiviral Research, 2012
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Within the oncolytic virus field, the extent of virus replication that is essential for immune st... more Within the oncolytic virus field, the extent of virus replication that is essential for immune stimulation to control tumor growth remains unresolved. Using infected cell protein 0 (ICP0)-defective oncolytic Herpes simplex virus type 1 (HSV-1) and HSV-2 viruses (dICP0 and dNLS) that show differences in their in vitro replication and cytotoxicity, we investigated the inherent features of oncolytic HSV viruses that are required for potent antitumor activity. In vitro, the HSV-2 vectors showed rapid cytotoxicity despite lower viral burst sizes compared to HSV-1 vectors. In vivo, although both of the dICP0 vectors initially replicated to a similar level, HSV-1 dICP0 was rapidly cleared from the tumors. In spite of this rapid clearance, HSV-1 dICP0 treatment conferred significant survival benefit. HSV-1 dICP0–treated tumors showed significantly higher levels of danger-associated molecular patterns that correlated with higher numbers of antigen-presenting cells within the tumor and increased antigen-specific CD8+ T-cell levels in the peripheral blood. This study suggests that, at least in the context of oncolytic HSV, the initial stages of immunogenic virus replication leading to activation of antitumor immunity are more important than persistence of a replicating virus within the tumor. This knowledge provides important insight for the design of therapeutically successful oncolytic viruses.
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Papers by Samuel Workenhe