Selectivity of Oncolytic Viral Replication Prevents Antiviral Immune Response and Toxicity, but Does Not Improve Antitumoral Immunity

Gürlevik, Engin; Woller, Norman; Strüver, N.; Schache, Peter; Kloos, Arnold; Manns, Michael P.; Zender, Lars; Kühnel, Florian; Kubicka, Stefan

doi:10.1038/mt.2010.163

Cited by 22 publications

(20 citation statements)

References 41 publications

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“…In contrast to rdAd, the unselective Ad5-WT and the tumor-selective hTert-Ad induced similar lysis in all investigated tumor cells in vitro and in vivo (data not shown). Interestingly, we observed no significant difference between hTert-Ad and Ad5-WT in ODC (Figure 6), in agreement with our previously described findings that the degree of tumor selectivity of Ad DNA replication only marginally influences antitumoral immune responses, but strongly determines anti-vector immunity and systemic toxicity in mice (27). However, whereas replication of viral DNA was an essential precondition for the efficacy of ODC, as shown in our previous experiments, we observed no differences in the antitumoral immune responses in all tumor models (Figure 6), which indicates that de novo gen- Figure 7A), confirming the absence of substantial viral infection and DNA replication in lung colonies.…”

Section: Vaccination On Day 3 (supporting

confidence: 81%

Virus-induced tumor inflammation facilitates effective DC cancer immunotherapy in a Treg-dependent manner in mice

Woller

Knocke²,

Mundt³

et al. 2011

J. Clin. Invest.

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Section: Vaccination On Day 3 (supporting

confidence: 81%

Virus-induced tumor inflammation facilitates effective DC cancer immunotherapy in a Treg-dependent manner in mice

Woller

Knocke²,

Mundt³

et al. 2011

J. Clin. Invest.

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“…Interestingly, injection with Ad‐p53T viruses showed significantly decreased antiviral CD8‐specific immune responses and also the decreased antiviral cytotoxicity in liver. In contrast, no significant difference was identified for the antitumoral immune responses 22. Their study demonstrated the first piece of critical information for the immune responses induced by the tumor selective oncolytic adenoviruses.…”

Section: Discussionmentioning

confidence: 93%

“…For clinical use, multiple consecutive injections of oncolytic virus are recommended to achieve a more prominent effect 19, 20. However, its feasibility has not been investigated in the immunocompoent animal models established previously 21–24. Therefore, we proposed to address both issues using an immunocompetent HCC model of HBx transgenic mice.…”

mentioning

confidence: 99%

“…19,20 However, its feasibility has not been investigated in the immunocompoent animal models established previously. [21][22][23][24] Therefore, we proposed to address both issues using an immunocompetent HCC model of HBx transgenic mice. In this model, the HBx protein, the major viral protein contributing to HBVrelated HCC, is specifically expressed in hepatocytes (driven by albumin promoter).…”

mentioning

confidence: 99%

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Telomerase‐specific oncolytic adenoviral therapy for orthotopic hepatocellular carcinoma in HBx transgenic mice

Lin

Yeh

Yang

et al. 2012

Intl Journal of Cancer

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The telomerase-specific replication-competent oncolytic adenovirus, Telomelysin, was developed for virus-mediated preferential lysis of tumor cells. Its selectivity is derived from a human telomerase reverse transcriptase (hTERT) promoterdriven active viral replication, which occurs in cancer cells with high telomerase activity but not in normal cells lacking such activity. Because the TERT activity is elevated in most cases of hepatocellular carcinoma (HCC), the current study aims to investigate whether Telomelysin can be used for treatment of HCC. The oncolytic effect of Telomelysin has been investigated both in vitro using cell culture and in vivo using an immunocompetent in situ orthotopic HCC model. In this model, HCC developed spontaneously in the liver of HBx transgenic mice, which is pathologically and genetically similar to human HCC. In cell culture assay, Telomelysin lyses HCC cell lines at a low multiplicity of infection (MOI), ranging 0. 77-6.35 (MOI [PFU/cell]).In the orthotopic HCC model, Telomelysin showed a potent oncolytic effect on HCC but spared normal liver tissue. Dose escalation analysis identified a safety dose of 1.25 3 10 8 PFU for this model. The effect of multiple injections of Telomelysin was also evaluated in this immunocompetent HCC model. We found that the virus replicates in HCC after a second intratumoral injection despite an immune response induced by the previous injection. This preclinical study shows that Telomelysin can be used for treatment of human HCC at an appropriate dosage and that its tumor-killing activity persists after multiple injections.

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“…Quantitation of adenoviral infection by hexon quantitative PCR (qPCR) has been described elsewhere (31).…”

Section: Determination Of Viral Infection In Vivomentioning

confidence: 99%

PolySia-Specific Retargeting of Oncolytic Viruses Triggers Tumor-Specific Immune Responses and Facilitates Therapy of Disseminated Lung Cancer

Kloos

Woller

Gürlevik

et al. 2015

Cancer Immunology Research

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Polysialic acid (polySia) is expressed on several malignant tumors of neuroendocrine origin, including small cell lung cancer. In this study, we investigated the therapeutic efficacy of tumor-directed T-cell responses, elicited by polySia-retargeted oncolytic adenovirus infection, in an orthotopic murine model of disseminated polySia-positive lung cancer. In several cell lines, we demonstrated highly polySia-selective retargeting of adenoviral infection using a bispecific adapter comprising the ectodomain of the coxsackievirus/adenovirus receptor and a polySia-recognizing single-chain antibody domain. PolySiadependent systemic infection in vivo facilitated effective uptake of viruses in subcutaneous polySia-expressing human tumors, whereas hepatic viral load and hepatotoxicity were significantly reduced. The impact and nature of antitumoral immune responses triggered by systemic delivery of polySia-retargeted oncolytic adenoviruses were investigated in an orthotopic model of disseminated lung cancer. Interestingly, improved transduction by polySia-retargeted oncolytic adenoviruses led to CD45-positive cell infiltrates in close association with large lytic areas. Consistently, enhanced tumor regression and prolonged survival was only observed in immunocompetent mice, but not in T-celldeficient mice. To investigate whether improved systemic infection by polySia retargeting would elicit a tumor-specific T-cell response, we screened the used lung cancer cells for mutated oncogenes by complete exon sequencing. In agreement with our other results, only retargeted oncolysis was able to induce a significant response specific for the tumor-associated neoepitope Gsta2-Y9H. In conclusion, we demonstrated that effective retargeting of oncolytic adenovirus against polySia-expressing tumors elicits an effective tumor-directed T-cell response after systemic virus delivery and facilitates therapy of disseminated lung cancer.

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Selectivity of Oncolytic Viral Replication Prevents Antiviral Immune Response and Toxicity, but Does Not Improve Antitumoral Immunity

Cited by 22 publications

References 41 publications

Virus-induced tumor inflammation facilitates effective DC cancer immunotherapy in a Treg-dependent manner in mice

Virus-induced tumor inflammation facilitates effective DC cancer immunotherapy in a Treg-dependent manner in mice

Telomerase‐specific oncolytic adenoviral therapy for orthotopic hepatocellular carcinoma in HBx transgenic mice

PolySia-Specific Retargeting of Oncolytic Viruses Triggers Tumor-Specific Immune Responses and Facilitates Therapy of Disseminated Lung Cancer

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