Harnessing Oncolytic Virus-mediated Antitumor Immunity in an Infected Cell Vaccine

Lemay, Chantal G.; Rintoul, Julia L.; Kuś, Agnieszka; Paterson, Jennifer M; Garcia, Vanessa; Falls, Theresa; Ferreira, Lisa; Bridle, Byram W.; Conrad, David P.; Tang, Vera A.; Diallo, Jean-Simon; Arulanandam, Rozanne; Bœuf, Fabrice Le; Garson, Kenneth; Vanderhyden, Barbara C.; Stojdl, David F.; Lichty, Brian D.; Atkins, Harold L.; Parato, Kelley A.; Bell, John C.; Auer, Rebecca C.

doi:10.1038/mt.2012.128

Cited by 74 publications

(71 citation statements)

References 44 publications

(48 reference statements)

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“…The Indiana serotype of VSV (VSVD51 or wild type) was used throughout this study and was propagated in Vero cells. VSVD51-expressing GFP, firefly luciferase or murine GM-CSF are recombinant derivatives of VSVD51 described previously 7,42 . Maraba MG-1 as described in ref.…”

Section: Methodsmentioning

confidence: 99%

Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

et al. 2015

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In this study, we show that several microtubule-destabilizing agents used for decades for treatment of cancer and other diseases also sensitize cancer cells to oncolytic rhabdoviruses and improve therapeutic outcomes in resistant murine cancer models. Drug-induced microtubule destabilization leads to superior viral spread in cancer cells by disrupting type I IFN mRNA translation, leading to decreased IFN protein expression and secretion. Furthermore, microtubule-destabilizing agents specifically promote cancer cell death following stimulation by a subset of infection-induced cytokines, thereby increasing viral bystander effects. This study reveals a previously unappreciated role for microtubule structures in the regulation of the innate cellular antiviral response and demonstrates that unexpected combinations of approved chemotherapeutics and biological agents can lead to improved therapeutic outcomes.

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Section: Methodsmentioning

confidence: 99%

Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

et al. 2015

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“…Furthermore, the immunogenicity of whole tumor-cell vaccines can be increased by modulating tumor cells with an inflammatory cytokine, such as GM-CSF or a replicating virus, which facilitates DC maturation and antigen presentation (26). However, it is still unclear in what form tumor antigens are transferred to DCs following exposure to tumor cells or their extracts.…”

Section: Cd8mentioning

confidence: 99%

Cell-free Tumor Microparticle Vaccines Stimulate Dendritic Cells via cGAS/STING Signaling

Zhang

Tang

Zhang

et al. 2015

Cancer Immunology Research

121

149

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Tumor antigens and innate signals are vital considerations in developing new therapeutic or prophylactic antitumor vaccines. The role or requirement of intact tumor cells in the development of an effective tumor vaccine remains incompletely understood. This study reveals the mechanism by which tumor cell-derived microparticles (T-MP) can act as a cell-free tumor vaccine. Vaccinations with T-MPs give rise to prophylactic effects against the challenge of various tumor cell types, while T-MP-loaded dendritic cells (DC) also exhibit therapeutic effects in various tumor models. Such antitumor effects of T-MPs are perhaps attributable to their ability to generate immune signaling and to represent tumor antigens. Mechanically, T-MPs effectively transfer DNA fragments to DCs, leading to type I IFN production through the cGAS/STING-mediated DNA-sensing pathway. In turn, type I IFN promotes DC maturation and presentation of tumor antigens to T cells for antitumor immunity. These findings highlight a novel tumor cell-free vaccine strategy with potential clinical applications.

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“…We previously demonstrated that infecting autologous tumor cells ex vivo with oncolytic viruses can elicit a robust immune response against established, nonpermissive, tumors in vivo (18). To determine whether MG1 and MG1-IL12 could similarly induce an immune response when used as an ICV, we i.v.…”

Section: Mg1-il12-icv Enhanced Nk Cell-mediated Tumor Rejectionmentioning

confidence: 99%

“…Our laboratory and others have endeavored to improve upon this vaccination paradigm by infecting autologous tumor cells with oncolytic viruses engineered to express immune modulating cytokines (16)(17)(18). We have previously provided evidence for this approach by demonstrating that an oncolytic rhabdovirus, VSVDM51 expressing GM-CSF could significantly enhance immune activation and prevent tumor outgrowth (18). GM-CSF exerts its antitumor activity through enhancing DCs activation and antigen presentation.…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, the majority of patients do not mount such a response, either because the cell vaccine is not immunogenic enough or because the host immune system is suppressed in response to the cancer. Our laboratory and others have endeavored to improve upon this vaccination paradigm by infecting autologous tumor cells with oncolytic viruses engineered to express immune modulating cytokines (16)(17)(18). We have previously provided evidence for this approach by demonstrating that an oncolytic rhabdovirus, VSVDM51 expressing GM-CSF could significantly enhance immune activation and prevent tumor outgrowth (18).…”

Section: Introductionmentioning

confidence: 99%

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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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Harnessing Oncolytic Virus-mediated Antitumor Immunity in an Infected Cell Vaccine

Cited by 74 publications

References 44 publications

Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

Cell-free Tumor Microparticle Vaccines Stimulate Dendritic Cells via cGAS/STING Signaling

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

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