Characterization of the adaptive and innate immune response to intravenous oncolytic reovirus (Dearing type 3) during a phase I clinical trial

White, C. L.; Twigger, Katie; Vidal, Laura; Bono, Johann S. de; Coffey, Matt; Heinemann, Lucy; Morgan, Rhian; Merrick, Alison; Errington, Fiona; Vile, Richard G.; Melcher, Alan; Pandha, Hardev; Harrington, Kevin

doi:10.1038/gt.2008.21

Cited by 134 publications

(136 citation statements)

References 17 publications

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“…The production of neutralizing Abs has been identified as a potential obstacle to the systemic delivery of reovirus to tumors (47), although recent data using a combination therapy with cyclophosphamide in murine models has shown promise in reducing the generation of neutralizing Abs and promoting viral delivery (48). However, the importance of the cellular innate immune response to reovirus therapy remains uncertain.…”

Section: Discussionmentioning

confidence: 99%

Reciprocal Human Dendritic Cell–Natural Killer Cell Interactions Induce Antitumor Activity Following Tumor Cell Infection by Oncolytic Reovirus

Prestwich

Errington

Steele

et al. 2009

The Journal of Immunology

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Oncolytic virotherapy may mediate antitumor effects via direct oncolysis or immune-mediated tumor regression. Although the ability of oncolytic viruses to generate adaptive antitumor immunity has been characterized, their interactions with the innate immune system are relatively unclear. Using a human in vitro system, this study investigates the innate immunological consequences of reovirus therapy and its potential to activate NK cell-mediated antitumor activity. Dendritic cells (DC) loaded with reovirus-infected human melanoma Mel888 cells (DC-MelReo), but not reovirus-infected tumor cells alone, induced IFN-γ production within the NK cell population upon coculture with PBMC, in a cell-to-cell contact-dependent manner. DC-MelReo secreted the chemokines CCL2, 3, 4, 5, 7, 8, 11, and CXCL10; these culture supernatants induced NK cell chemotaxis. Coculture of DC-MelReo with purified NK cells induced reciprocal contact-dependent phenotypic DC maturation, while DC-MelReo elicited up-regulation of the activation marker CD69 on NK cells, in a partially contact and partially IL-12 dependent manner. Significantly, DC-MelReo induced NK cell cytotoxicity toward tumor cells by a type I IFN dependent mechanism. These data demonstrate that tumor infection by reovirus can act via DC to induce NK cell recruitment, activation, and cytotoxicity, along with reciprocal DC maturation. These findings suggest that reciprocal DC-NK cell interactions, following reovirus therapy, may play an important role in altering the immune milieu of the tumor microenvironment and mediating tumor regression.

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Section: Discussionmentioning

confidence: 99%

Reciprocal Human Dendritic Cell–Natural Killer Cell Interactions Induce Antitumor Activity Following Tumor Cell Infection by Oncolytic Reovirus

Prestwich

Errington

Steele

et al. 2009

The Journal of Immunology

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“…Additionally, the lack of preexisting neutralizing antibodies in human populations, a major hurdle that is associated with many other oncolytic viruses, warrants further development for clinical applications (20,(38)(39)(40)(41). Our multimodal approach that utilizes the engineered oncolytic MG1-IL12 virus in the form of ICV has a combined effect on tumors by (i) infecting and directly lysing the tumor tissues as an initial tumor debulking process, (ii) recruiting the innate (NK cell) immune system to the tumor microenvironment by overexpressing IL12, (iii) activating and maturing DCs through expression of viral proteins and IFNg secreted by activated NK cells, and (iv) the activated DC, in turn secrete IP-10, which further recruits NK cells to the vaccination site ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

NK-Cell Recruitment Is Necessary for Eradication of Peritoneal Carcinomatosis with an IL12-Expressing Maraba Virus Cellular Vaccine

Alkayyal

Tai

Kennedy

et al. 2017

Cancer Immunology Research

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Despite improvements in chemotherapy and radical surgical debulking, peritoneal carcinomatosis (PC) remains among the most common causes of death from abdominal cancers. Immunotherapies have been effective for selected solid malignancies, but their potential in PC has been little explored. Here, we report that intraperitoneal injection of an infected cell vaccine (ICV), consisting of autologous tumor cells infected ex vivo with an oncolytic Maraba MG1 virus expressing IL12, promotes the migration of activated natural killer (NK) cells to the peritoneal cavity in response to the secretion of IFNγ-induced protein-10 (IP-10) from dendritic cells. The recruitment of cytotoxic, IFNγ-secreting NK cells was associated with reduced tumor burden and improved survival in a colon cancer model of PC. Even in mice with bulky PC (tumors > 8 mm), a complete radiologic response was demonstrated within 8 to14 weeks, associated with 100% long-term survival. The impact of MG1-IL12-ICV upon NK-cell recruitment and function observed in the murine system was recapitulated in human lymphocytes exposed to human tumor cell lines infected with MG1-IL12. These findings suggest that an MG1-IL12-ICV is a promising therapy that could provide benefit to the thousands of patients diagnosed with PC each year. Cancer Immunol Res; 5(3); 211–21. ©2017 AACR.

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“…[61,63,69] In contrast, other studies showed no evidence of hematological toxicities at all. [62,70] Taken together, toxicity results indicate that reovirus is well tolerated by patients, with generally only mild manageable adverse events.…”

Section: Evolution Of Reovirus In Cancer Therapymentioning

confidence: 97%

Evolution of Reovirus in Cancer Therapy

Jayaprakash¹,

Veeraiyan²,

Gunaseelan³

et al. 2017

IOSRJPBS

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Characterization of the adaptive and innate immune response to intravenous oncolytic reovirus (Dearing type 3) during a phase I clinical trial

Cited by 134 publications

References 17 publications

Reciprocal Human Dendritic Cell–Natural Killer Cell Interactions Induce Antitumor Activity Following Tumor Cell Infection by Oncolytic Reovirus

Reciprocal Human Dendritic Cell–Natural Killer Cell Interactions Induce Antitumor Activity Following Tumor Cell Infection by Oncolytic Reovirus

NK-Cell Recruitment Is Necessary for Eradication of Peritoneal Carcinomatosis with an IL12-Expressing Maraba Virus Cellular Vaccine

Evolution of Reovirus in Cancer Therapy

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