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

Abstract

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.

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

“…The most important thing should be to determine the roles and the relative importance of each key components of immune system in antitumor efficacy of oncolytic virotherapy. To more fully explore the roles of T cells in oncolytic Ad therapy in the hamster model, we developed a mAb against Syrian hamster CD3 (mAB4F11) that can efficiently delete T cells in vivo (16). Here, we show that deletion of T cells remarkably impairs the antitumor efficacy of oncolytic Ad, especially the long-term control of tumor recurrence.…”

“…Numerous strategies have been developed to circumvent this hurdle (31). For example, two or more antigenically distinct viruses were applied so that the specific immunity that arises subsequently to the first virus does not inhibit the therapeutic effects of the second therapeutic virus (16). Alternatively, the therapeutic viruses were masked from antibody neutralization with chemical conjugates (32,33).…”

“…The mouse mAb against Syrian hamster CD3e (clone 4F11, IgG1 isotype) and anti-KLH mAb were prepared as described previously (16).…”

“…Viral DNA levels were evaluated as described previously (16). Results were expressed as genome copy number/gram based on the weight of tumor tissues.…”

“…Anti-Ad5 antibodies were detected as described previously (16). The relative levels of total antibodies in all samples were shown as the value of OD 450nm .…”