The therapeutic efficacy of the oncolytic virus Delta24-RGD in a murine glioma model depends primarily on antitumor immunity

Kleijn, Anne; Kloezeman, Jenneke J.; Treffers-Westerlaken, Elike; Fulci, Giulia; Leenstra, Sieger; Dirven, Clemens; Debets, Reno; Lamfers, Martine L.M.

doi:10.4161/21624011.2014.955697

Cited by 14 publications

(11 citation statements)

References 8 publications

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“…Our results expand on previous work demonstrating the importance of the immune system for the therapeutic efficacy of oncolytic virotherapy in murine gliomas 21, 25, 26. Our findings indicate that even the replication-incompetent adenovirus has some cytotoxicity in murine glioma cells in vitro, and accompanying this cytotoxicity was an increase in tumor-infiltrating CD8+ T cells and tumor antigen-specific CD8+ T cells in vivo; albeit, this influx of lymphocytes was not associated with a corresponding increase in survival for animals treated with this virus.…”

Section: Discussionsupporting

confidence: 87%

A Comparative Study of Replication-Incompetent and -Competent Adenoviral Therapy-Mediated Immune Response in a Murine Glioma Model

Kim

Miska

Young

et al. 2017

Molecular Therapy - Oncolytics

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Oncolytic virotherapy is a treatment approach with increasing clinical relevance, as indicated by the marked survival benefit seen in animal models and its current exploration in human patients with cancer. The use of an adenovirus vector for this therapeutic modality is common, has significant clinical benefit in animals, and its efficacy has recently been linked to an anti-tumor immune response that occurs following tumor antigen presentation. Here, we analyzed the adaptive immune system’s response following viral infection by comparing replication-incompetent and replication-competent adenoviral vectors. Our findings suggest that cell death caused by replication-competent adenoviral vectors is required to induce a significant anti-tumor immune response and survival benefits in immunocompetent mice bearing intracranial glioma. We observed significant changes in the repertoire of immune cells in the brain and draining lymph nodes and significant recruitment of CD103+ dendritic cells (DCs) in response to oncolytic adenoviral therapy, suggesting the active role of the immune system in anti-tumor response. Our data suggest that the response to oncolytic virotherapy is accompanied by local and systemic immune responses and should be taken in consideration in the future design of the clinical studies evaluating oncolytic virotherapy in patients with glioblastoma multiforme (GBM).

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Section: Discussionsupporting

confidence: 87%

A Comparative Study of Replication-Incompetent and -Competent Adenoviral Therapy-Mediated Immune Response in a Murine Glioma Model

Kim

Miska

Young

et al. 2017

Molecular Therapy - Oncolytics

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“…Therapeutic administration of oncolytic viruses (OV) into tumors promotes strong antiviral immune response accompanied by the production of cytokines such as type-1 interferons and chemokines. 17 , 26-28 Type-1 interferons promote the expression of PD-L1 on the surface of cancer cells, while chemokines like CCL3 and CCL4 attract immune cells which often express PD-1 or CTLA-4. 29-32 Thus, antiviral immunological events inflame the tumor and make it ‘hot’.…”

mentioning

confidence: 99%

Heating it up: Oncolytic viruses make tumors ‘hot’ and suitable for checkpoint blockade immunotherapies

2018

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Immune checkpoint blockade is less efficient in patients bearing immunologically ‘cold’ tumors. Oncolytic viruses, which were originally discovered for their ability to preferentially kill malignant cells, can recondition the tumor microenvironment. Supporting this hypothesis, two new studies published in Science Translational Medicine show that adjuvant-like activities of oncolytic viruses make brain and breast tumors ‘hot’ and sensitize them for subsequent immune checkpoint blockade.

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“…Despite current therapies, the survival benefits are measured in months (36). Based on previous reports, oncolytic virotherapy possesses the potential to repress glioblastoma (37)(38)(39). Here we found that the oncolytic virus M1 kills a diverse range of glioblastoma cell lines and exhibits therapeutic potential in vivo.…”

Section: Discussionmentioning

confidence: 65%

Deficiency of the IRE1α-Autophagy Axis Enhances the Antitumor Effects of the Oncolytic Virus M1

Xing

et al. 2018

J Virol

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Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancer cells. M1 is a naturally occurring alphavirus () which shows potent oncolytic activities against many cancers. Accumulation of unfolded proteins during virus replication leads to a transcriptional/translational response known as the unfolded protein response (UPR), which might counteract the antitumor effect of the oncolytic virus. In this report, we show that either pharmacological or biological inhibition of IRE1α or PERK, but not ATF6, substantially increases the oncolytic effects of the M1 virus. Moreover, inhibition of IRE1α blocks M1 virus-induced autophagy, which restricts the antitumor effects of the M1 virus through degradation of viral protein, in glioma cells. In addition, IRE1α suppression significantly increases the oncolytic effect of M1 virus in an orthotopic glioma model. From a molecular pathology study, we found that IRE1α is expressed at lower levels in higher-grade gliomas, suggesting greater antitumor efficacy of the oncolytic virus M1. Taken together, these findings illustrate a defensive mechanism of glioma cells against the oncolytic virus M1 and identify possible approaches to enhance the oncolytic viral protein accumulation and the subsequent lysis of tumor cells. Although oncolytic virotherapy is showing great promise in clinical applications, not all patients are benefiting. Identifying inhibitory signals in refractory cancer cells for each oncolytic virus would provide a good chance to increase the therapeutic effect. Here we describe that infection with the oncolytic virus M1 triggers the unfolded protein response (UPR) and subsequent autophagy, while blocking the UPR-autophagy axis significantly potentiates the antitumor efficacy of M1 and A survey of cancer tissue banks revealed that IRE1α, a key element in the UPR pathway, is commonly downregulated in higher-grade human gliomas, suggesting favorable prospects for the application of M1. Our work provides a potential predictor and target for enhancement of the therapeutic effectiveness of the M1 virus. We predict that the mechanism-based combination therapy will promote cancer virotherapy in the future.

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The therapeutic efficacy of the oncolytic virus Delta24-RGD in a murine glioma model depends primarily on antitumor immunity

Cited by 14 publications

References 8 publications

A Comparative Study of Replication-Incompetent and -Competent Adenoviral Therapy-Mediated Immune Response in a Murine Glioma Model

A Comparative Study of Replication-Incompetent and -Competent Adenoviral Therapy-Mediated Immune Response in a Murine Glioma Model

Heating it up: Oncolytic viruses make tumors ‘hot’ and suitable for checkpoint blockade immunotherapies

Deficiency of the IRE1α-Autophagy Axis Enhances the Antitumor Effects of the Oncolytic Virus M1

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