Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

Léveillé, Simon; Samuel, Sara; Ml, Goulet; Hiscott, John

doi:10.1038/cgt.2011.14

Cited by 43 publications

(35 citation statements)

References 33 publications

(60 reference statements)

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“…1f). VSV is present at the tumor for only a few days (18,23), which correlated with detectable levels of Flt3L in the sera of treated animals for less than 6 days (data not shown). Given that rFlt3L has been shown to augment circulating DC in humans and mice after 8 to 10 days of continuous treatment (26), VSV-Flt3L expression may be not sustained for a sufficient time to reproduce the survival advantage observed with rFlt3L.…”

Section: Resultsmentioning

confidence: 84%

“…To optimize the presentation of tumor antigens, rFlt3L injections were over- VOL. 85, 2011 VSV ONCOLYSIS ABROGATES TUMOR ANTIGEN PRESENTATION 12161 lapped with VSV infections so that the peak number of tumor DC coincided with maximal tumor cell lysis and antigen release, which occur at 24 to 48 h following the initial injection of VSV (18,23) (Fig. 1b).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Vesicular Stomatitis Virus Oncolytic Treatment Interferes with Tumor-Associated Dendritic Cell Functions and Abrogates Tumor Antigen Presentation

Léveillé

Goulet

Lichty

et al. 2011

J Virol

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Oncolytic virotherapy is a promising biological approach to cancer treatment that contributes to tumor eradication via immune-and non-immune-mediated mechanisms. One of the remaining challenges for these experimental therapies is the necessity to develop a durable adaptive immune response against the tumor. Vesicular stomatitis virus (VSV) is a prototypical oncolytic virus (OV) that exemplifies the multiple mechanisms of oncolysis, including direct cell lysis, cellular hypoxia resulting from the shutdown of tumor vasculature, and inflammatory cytokine release. Despite these properties, the generation of sustained antitumor immunity is observed only when VSV is engineered to express a tumor antigen directly. In the present study, we sought to increase the number of tumor-associated dendritic cells (DC) in vivo and tumor antigen presentation by combining VSV treatment with recombinant Fms-like tyrosine kinase 3 ligand (rFlt3L), a growth factor promoting the differentiation and proliferation of DC. The combination of VSV oncolysis and rFLt3L improved animal survival in two different tumor models, i.e., VSV-resistant B16 melanoma and VSV-sensitive E.G7 T lymphoma; however, increased survival was independent of the adaptive CD8 T cell response. Tumorassociated DC were actively infected by VSV in vivo, which reduced their viability and prevented their migration to the draining lymph nodes to prime a tumor-specific CD8 T cell response. These results demonstrate that VSV interferes with tumor DC functions and blocks tumor antigen presentation.Cancer therapy using oncolytic viruses (OV) has achieved remarkable therapeutic effects in numerous preclinical tumor models and clinical trials (4, 30). Of the different OV currently evaluated for efficacy, vesicular stomatitis virus (VSV) has emerged as a prototypical OV based on properties such as cancer cell tropism, cell lysis efficacy, and sensitivity to host antiviral responses (3,24,33). Tumor regression induced by VSV oncolysis is a complex event that is not limited to direct cell killing by virus infection; cellular hypoxia resulting from the shutdown of tumor vasculature also cooperates to reduce tumor burden (7,8). Moreover, the innate immune response and accompanying inflammatory cytokine release contribute to the therapeutic effect observed in various murine models (18,28,36).VSV oncolytic therapy has also been proposed to induce a tumor-specific adaptive immune response because infection and concomitant cell lysis expose tumor antigens within a proinflammatory milieu. Early studies demonstrated the presence of tumor-specific CD8 T cells following VSV treatment and a reduction of the therapeutic effect after CD8 T cell depletion (15). However, subsequent studies indicated that tumor-specific CD8 T cells either were not detected in the tumor, spleen, or draining lymph nodes following VSV treatment (35) or were detected at low levels that were not statistically significant (9,10,17,37). It was also suggested that tumor regression in CD8 T cell depletion experiments was ...

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Section: Resultsmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Vesicular Stomatitis Virus Oncolytic Treatment Interferes with Tumor-Associated Dendritic Cell Functions and Abrogates Tumor Antigen Presentation

Léveillé

Goulet

Lichty

et al. 2011

J Virol

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“…Several approaches could be employed to address such limitations. For example, using VSV encoding suicide genes like herpesvirus thymidine kinase (41) or cytosine deaminase (65,66) enhanced the bystander effect and increased tumor regression compared to parental virus treatment. Penetration and spread within the tumor mass also were shown to be improved by incorporation of fusogenic proteins from Newcastle disease virus (67,68) or simian parainfluenza virus (69) and resulted in enhanced tumor killing and prolonged survival compared to parental virus.…”

Section: Discussionmentioning

confidence: 99%

Oncolytic Vesicular Stomatitis Virus in an Immunocompetent Model of MUC1-Positive or MUC1-Null Pancreatic Ductal Adenocarcinoma

Hastie

Besmer

Shah

et al. 2013

J Virol

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Vesicular stomatitis virus (VSV) is a promising oncolytic agent against various malignancies. Here, for the first time, we tested VSV in vitro and in vivo in a clinically relevant, immunocompetent mouse model of pancreatic ductal adenocarcinoma (PDA). Our system allows the study of virotherapy against PDA in the context of overexpression (80% of PDA patients) or no expression of human mucin 1 (MUC1), a major marker for poor prognosis in patients. In vitro, we tested three VSV recombinants, wildtype VSV, VSV-green fluorescent protein (VSV-GFP), and a safe oncolytic VSV-⌬M51-GFP, against five mouse PDA cell lines that either expressed human MUC1 or were MUC1 null. All viruses demonstrated significant oncolytic abilities independent of MUC1 expression, although VSV-⌬M51-GFP was somewhat less effective in two PDA cell lines. In vivo administration of VSV-⌬M51-GFP resulted in significant reduction of tumor growth for tested mouse PDA xenografts (؉MUC1 or MUC1 null), and antitumor efficacy was further improved when the virus was combined with the chemotherapeutic drug gemcitabine. The antitumor effect was transient in all tested groups. The developed system can be used to study therapies involving various oncolytic viruses and chemotherapeutics, with the goal of inducing tumor-specific immunity while preventing premature virus clearance.

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“…[14][15][16][17][18][19] Conversely, antiviral immunity (be it innate or adaptive) often constitutes an obstacle against the efficacious implementation of oncolytic virotherapy in cancer patients, mostly because it sequesters or neutralizes viral particles before they reach malignant lesions. [20][21][22][23][24][25][26][27][28][29][30] Thus, considerable efforts have recently been dedicated at the development of oncolytic viral particles with improved features, including: (1) a refined oncotropism, based on the targeting of tumor-associated antigens (TAAs) exposed on the surface of malignant cells; [31][32][33][34][35] (2) an optimized selectivity of replication, based on various systems that allow for the expression of essential viral proteins only in cells of a predetermined tissue, 36-45 transformed cells, 46-57 cells exhibiting specific molecular defects, 58-65 or cells exposed to precise microenvironmental conditions (naturally or artificially); [66][67][68] (3) an exacerbated cytotoxicity, based on the expression of potentially lethal enzymes [69][70][71][72][73][74][75][76] or other tumor-targeting molecules; 13,46,[77][78][79][80][81][82][83][84] …”

Section: Introductionmentioning

confidence: 99%

Trial Watch—Oncolytic viruses and cancer therapy

et al. 2015

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Oncolytic virotherapy relies on the administration of non-pathogenic viral strains that selectively infect and kill malignant cells while favoring the elicitation of a therapeutically relevant tumor-targeting immune response. During the past few years, great efforts have been dedicated to the development of oncolytic viruses with improved specificity and potency. Such an intense wave of investigation has culminated this year in the regulatory approval by the US Food and Drug Administration (FDA) of a genetically engineered oncolytic viral strain for use in melanoma patients. Here, we summarize recent preclinical and clinical advances in oncolytic virotherapy.

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Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

Cited by 43 publications

References 33 publications

Vesicular Stomatitis Virus Oncolytic Treatment Interferes with Tumor-Associated Dendritic Cell Functions and Abrogates Tumor Antigen Presentation

Vesicular Stomatitis Virus Oncolytic Treatment Interferes with Tumor-Associated Dendritic Cell Functions and Abrogates Tumor Antigen Presentation

Oncolytic Vesicular Stomatitis Virus in an Immunocompetent Model of MUC1-Positive or MUC1-Null Pancreatic Ductal Adenocarcinoma

Trial Watch—Oncolytic viruses and cancer therapy

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