Optimizing oncolytic virotherapy in cancer treatment

Harrington, Kevin J.; Freeman, Daniel J.; Kelly, Beth; Harper, J. A.; Soria, Jean‐Charles

doi:10.1038/s41573-019-0029-0

Cited by 397 publications

(304 citation statements)

References 201 publications

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“…Transgenes encoding toxic proteins can impact viral replication or affect viral DNA synthesis 8,21 . Moreover, if the transgene length is close to the viral encapsidation limit, the usage of exogenous promoters, required for early expression, will further increase the length of the construct, and further hinder viral assembly.…”

Section: Discussionmentioning

confidence: 99%

“…In the past 20 years, multiple preclinical and clinical trials have used these viruses as therapeutic agents in the treatment of different tumours [2][3][4][5][6][7] . Despite the encouraging results in terms of safety, the efficacy of adenoviral treatments still needs to be improved in order to increase the clinical usefulness of this strategy 8 .…”

Section: Introductionmentioning

confidence: 99%

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Transgene codon usage drives viral fitness and therapeutic efficacy in oncolytic adenoviruses

Núñez-Manchón

Farrera-Sal

Castellano

et al. 2020

Preprint

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Arming oncolytic adenoviruses with therapeutic transgenes is a well-established strategy for multimodal tumour attack. However, this strategy sometimes leads to unexpected attenuated viral replication and a loss of oncolytic effects, preventing these viruses from reaching the clinic. Previous work has shown that altering codon usage in viral genes can hamper viral fitness. Here, we have analysed how transgene codon usage impacts viral replication and oncolytic activity. We observe that, although transgenes with optimised codons show high expression levels at a first round of infection, they impair viral fitness and are therefore not expressed in a sustained manner. Conversely, transgenes encoded by suboptimal codons do not compromise viral replication and are thus stably expressed over time allowing a greater oncolytic activity both in vitro and in vivo. Altogether, our work shows that fine-tuning codon usage leads to a concerted optimisation of transgene expression and viral replication paving the way for the rational design of more efficacious oncolytic therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transgene codon usage drives viral fitness and therapeutic efficacy in oncolytic adenoviruses

Núñez-Manchón

Farrera-Sal

Castellano

et al. 2020

Preprint

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“…Conversely, 'cold' tumors contain increased suppressive immune-cell populations (e.g., myeloid-derived suppressive cells and T regulatory cells) and a low density of T-cell infiltrate and exhibit a low mutational burden and/ or antigen expression [6]. The multimodal mechanisms of OVs make them well suited to transform the tumor microenvironment (TME) of non-responding patients into 'hot' tumors; the liberation of tumor antigens via immunogenic cell lysis is expected to increase T-cell infiltration and, by way of their immunogenic properties, may also potentially reverse established suppressive elements [7]. Additionally, these same properties are expected to enhance responses in those patients who already benefited from IO therapy and, as such, provide rationale for MEDI5395 and IO combination approaches.…”

Section: Introductionmentioning

confidence: 99%

Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro

Burke

Shergold

Elder

et al. 2020

Cancer Immunol Immunother

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Oncolytic virus (OV) therapy is an emerging approach with the potential to redefine treatment options across a range of cancer indications and in patients who remain resistant to existing standards of care, including immuno-oncology (IO) drugs. MEDI5395, a recombinant Newcastle disease virus (NDV), engineered to express granulocyte-macrophage colonystimulating factor (GM-CSF), exhibits potent oncolytic activity. It was hypothesized that activation of immune cells by MEDI5395, coupled with its oncolytic activity, would enhance the priming of antitumor immunity. Using MEDI5395 and recombinant NDVs encoding fluorescent reporter genes, we demonstrated preferential virus uptake and non-productive infection in myeloid cells, including monocytes, macrophages, and dendritic cells (DCs). Infection resulted in immune-cell activation, with upregulation of cell surface activation markers (e.g., CD80, PD-L1, HLA-DR) and secretion of proinflammatory cytokines (IFN-α2a, IL-6, IL-8, TNF-α). Interestingly, in vitro M2-polarized macrophages were more permissive to virus infection than were M1-polarized macrophages. In a co-culture system, infected myeloid cells were effective virus vectors and mediated the transfer of infectious NDV particles to tumor cells, resulting in cell death. Furthermore, NDV-infected DCs stimulated greater proliferation of allogeneic T cells than uninfected DCs. Antigens released after NDV-induced tumor cell lysis were cross-presented by DCs and drove activation of tumor antigen-specific autologous T cells. MEDI5395 therefore exhibited potent immunostimulatory activity and an ability to enhance antigen-specific T-cell priming. This, coupled with its tumor-selective oncolytic capacity, underscores the promise of MEDI5395 as a multimodal therapeutic, with potential to both enhance current responding patient populations and elicit de novo responses in resistant patients.

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“…EVs can be utilized as vectors to deliver oncolytic viruses to tumor sites [107]. Oncolytic viruses are promising in the treatment of various cancers because they selectively infect cancer cells, synchronously stimulate the immune response and attract more immune cells to continue to kill residual cancer cells [108][109][110]. However, delivery of oncolytic viruses to tumor sites remains a major challenge.…”

Section: Oncolytic Virusesmentioning

confidence: 99%

Therapeutic Advances of Stem Cell-Derived Extracellular Vesicles in Regenerative Medicine

Yin

Liu

Shi

et al. 2020

Cells

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Extracellular vesicles (EVs), which are the main paracrine components of stem cells, mimic the regenerative capacity of these cells. Stem cell-derived EVs (SC-EVs) have been used for the treatment of various forms of tissue injury in preclinical trials through maintenance of their stemness, induction of regenerative phenotypes, apoptosis inhibition, and immune regulation. The efficiency of SC-EVs may be enhanced by selecting the appropriate EV-producing cells and cell phenotypes, optimizing cell culture conditions for the production of optimal EVs, and further engineering the EVs produced to transport therapeutic and targeting molecules. Cells 2020, 9, 707 2 of 28 storage, immune rejection, gene mutation, and tumorigenesis or tumor promotion in vivo limit its application. Stem cell derived-EVs (SC-EVs), as the main paracrine executor, overcome most limitations of stem cell applications. SC-EVs have allowed major advances in preclinical or clinical studies.In this review, the potential therapeutic applications of SC-EVs in regenerative medicine are discussed and the underlying molecular mechanisms are explored. Some of the possibilities for improving their secretion and altering their components to improve their efficacy toward diverse indications and diseases are summarized. Stem Cell-Derived EVs in the Treatment of Damaged TissueNumerous preclinical trials have reported that SC-EVs can carry active molecules, such as proteins, lipids, and nucleic acids, and good therapeutic effects against various diseases regarding different systems, including the nervous system, respiratory system, circulatory system, digestive system, urinary system, and others, have been observed. Neurological SystemBrain trauma is a common event that can cause nerve damage and disability. EXs derived from human adipose mesenchymal stem cells (AdMSC-EXs) can significantly increase the number of neurons, reduce inflammation, improve sensory and cognitive function, and produce better effects than AdMSCs alone in rats that have incurred traumatic brain injury (TBI) [6]. Kim et al. indicated that systemic administration of CD63+CD81+ EVs produced by human bone marrow-derived stem cells (BMSC-EVs) decreased neuroinflammation 12 h after a TBI in a mouse model of TBI induced by a controlled cortical impact device [7]. They also found that BMSC-EV infusion preserved the pattern separation and spatial learning abilities of mice, which were demonstrated respectively by an object-based behavioral test and a water maze test [7].Stroke is the sudden rupture or occlusion of cerebral blood vessels that interrupts the blood supply. It is the main cause of death and disability in Chinese adults. Preclinical studies have shown that SC-EVs seem to be a promising candidate for stroke treatment. Xin et al. showed that infusion of BMSC-EXs enhanced oligodendrogenesis and neurogenesis, remodeled synapses, reduced the incidence of stroke, and accelerated the recovery of neurological functions in a rat model of stroke induced by transient middle cerebral artery occl...

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Optimizing oncolytic virotherapy in cancer treatment

Cited by 397 publications

References 201 publications

Transgene codon usage drives viral fitness and therapeutic efficacy in oncolytic adenoviruses

Transgene codon usage drives viral fitness and therapeutic efficacy in oncolytic adenoviruses

Oncolytic Newcastle disease virus activation of the innate immune response and priming of antitumor adaptive responses in vitro

Therapeutic Advances of Stem Cell-Derived Extracellular Vesicles in Regenerative Medicine

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