Effect of Preexisting Immunity on Oncolytic Adenovirus Vector INGN 007 Antitumor Efficacy in Immunocompetent and Immunosuppressed Syrian Hamsters

Dhar, Debanjan; Spencer, Jacqueline F.; Tóth, Károly; Wold, William S.M.

doi:10.1128/jvi.02127-08

Cited by 60 publications

(76 citation statements)

References 40 publications

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“…These results suggest that the enhanced antitumor efficacy induced by sequential combination of adenovirus and vaccinia virus was not a result of reduction of humoral immunity to each virus. Of note, the neutralizing antibody against adenovirus is much lower in our experiments as compared with the previous study (30). This is likely due to the lower doses of adenovirus that we used.…”

Section: Resultscontrasting

confidence: 51%

A Novel Therapeutic Regimen to Eradicate Established Solid Tumors with an Effective Induction of Tumor-Specific Immunity

Tysome

Wang

et al. 2012

Clinical Cancer Research

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Purpose: The efficacy of oncolytic viruses depends on multiple actions including direct tumor lysis, modulation of tumor perfusion, and stimulation of tumor-directed immune responses. In this study, we investigated whether a sequential combination of immunologically distinct viruses might enhance antitumor efficacy through the induction of tumor-specific immunity and circumvention or mitigation of antiviral immune responses.Experimental Design: The Syrian hamster as an immune-competent model that supports replication of both adenovirus and vaccinia virus was evaluated in vitro and in vivo. The antitumor efficacy of either virus alone or sequential combination of the two viruses was examined in pancreatic and kidney cancer models. The functional mechanism of the regimen developed here was investigated by histopathology, immunohistochemistry staining, CTL assay, and T-cell depletion.Results: The Syrian hamster is a suitable model for assessment of oncolytic adenovirus and vaccinia virus. Three low doses of adenovirus followed by three low doses of vaccinia virus resulted in a superior antitumor efficacy to the reverse combination, or six doses of either virus alone, against pancreatic and kidney tumors in Syrian hamsters. A total of 62.5% of animals bearing either tumor type treated with the sequential combination became tumor-free, accompanied by the induction of effective tumor-specific immunity. This enhanced efficacy was ablated by CD3þ T-cell depletion but was not associated with humoral immunity against the viruses.Conclusion: These findings show that sequential treatment of tumors with oncolytic adenovirus and vaccinia virus is a promising approach for cancer therapy and that T-cell responses play a critical role.

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Section: Resultscontrasting

confidence: 51%

A Novel Therapeutic Regimen to Eradicate Established Solid Tumors with an Effective Induction of Tumor-Specific Immunity

Tysome

Wang

et al. 2012

Clinical Cancer Research

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“…Meanwhile, it further supports that Ad genome is cleared by innate rather than adaptive immunity. Consistent with the previous study (8), the preexisting antiAd immunity did not affect the antitumor efficacy of oncolytic Ad. However, T-cell deletion also abrogated the antitumor effect of oncolytic Ad in preimmunized animals (Fig.…”

Section: Preexisting Anti-ad Immunity Promotes Viral Clearance Of Tumsupporting

confidence: 80%

“…However, the preimmunization, which induced a persistent high-level of neutralizing anti-Ad antibody and disabled the detection of the infectious virus injected in tumors, had no effect on the antitumor efficacy of oncolytic Ad in immunocompetent animals. In the preimmunized tumor-bearing animals, cyclophosphamide treatment had no effect on tumor growth, although the titer of neutralizing anti-Ad antibody stayed steady at all time points, and tumors had moderate amount of virus (8). These results suggest that curative viral oncolysis on its own probably only occurs in the instance when tumors are completely devoid of any virus defense system.…”

Section: Introductionmentioning

confidence: 63%

The Efficacy of Oncolytic Adenovirus Is Mediated by T-cell Responses against Virus and Tumor in Syrian Hamster Model

Wang

et al. 2017

Clinical Cancer Research

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Purpose: Oncolytic adenoviruses (Ad) represent an innovative approach to cancer therapy. Its efficacy depends on multiple actions, including direct tumor lysis and stimulation of antiviral and antitumor immune responses. In this study, we investigated the roles of T-cell responses in oncolytic adenoviral therapy.Experimental Design: An immunocompetent and viral replication-permissive Syrian hamster tumor model was used. The therapeutic mechanisms of oncolytic Ad were investigated by Tcell deletion, immunohistochemical staining, and CTL assay.Results: Deletion of T cells with an anti-CD3 antibody completely demolished the antitumor efficacy of oncolytic Ad. Intratumoral injection of Ad induced strong virus-and tumorspecific T-cell responses, as well as antiviral antibody response.Both antiviral and antitumor T-cell responses contributed to the efficacy of oncolytic Ad. Deletion of T cells increased viral replication and extended the persistence of infectious virus within tumors but almost abrogated the antitumor efficacy. Preexisting antiviral immunity promoted the clearance of injected oncolytic Ad from tumors but had no effect on antitumor efficacy. Strikingly, the repeated treatment with oncolytic Ad has strong therapeutic effect on relapsed tumors or tumors insensitive to the primary viral therapy.Conclusions: These results demonstrate that T cell-mediated immune responses outweigh the direct oncolysis in mediating antitumor efficacy of oncolytic Ad. Our data have a high impact on redesigning the regimen of oncolytic Ad for cancer treatment.

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“…34 In our study, patient N21, who had a 71.1% reduction in tumor size and complete clearance of bone marrow disease, had relatively low induction of NAb titer (1:1024) but the titer remained constant for 4.5 months after treatment. In contrast, O24 had a response 80 days after treatment but had rapid induction of a high NAb titer (1:16 384) and the titer remained high at least for 5 weeks.…”

Section: Discussionmentioning

confidence: 98%

Prolonged systemic circulation of chimeric oncolytic adenovirus Ad5/3-Cox2L-D24 in patients with metastatic and refractory solid tumors

et al. 2010

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Effect of Preexisting Immunity on Oncolytic Adenovirus Vector INGN 007 Antitumor Efficacy in Immunocompetent and Immunosuppressed Syrian Hamsters

Cited by 60 publications

References 40 publications

A Novel Therapeutic Regimen to Eradicate Established Solid Tumors with an Effective Induction of Tumor-Specific Immunity

A Novel Therapeutic Regimen to Eradicate Established Solid Tumors with an Effective Induction of Tumor-Specific Immunity

The Efficacy of Oncolytic Adenovirus Is Mediated by T-cell Responses against Virus and Tumor in Syrian Hamster Model

Prolonged systemic circulation of chimeric oncolytic adenovirus Ad5/3-Cox2L-D24 in patients with metastatic and refractory solid tumors

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