Combined Trabectedin and anti-PD1 antibody produces a synergistic antitumor effect in a murine model of ovarian cancer.

Zhiqiang Guo,Jie Li,Fandong Meng,Shulan Zhang,Haolin Wang

doi:10.1186/s12967-015-0613-y

Abstract

BackgroundMonoclonal antibodies (mAb) that block programmed death (PD)-1 signaling pathway hold great potential as a novel cancer immunotherapy. Recent evidence suggests that combining with conventional, targeted or other immunotherapies, these mAb can induce synergistic antitumor responses. In this study, we investigated whether Trabectedin (ET-743), a novel anticancer agent currently used for treating relapsed ovarian cancer, can synergize with anti (α)-PD-1 mAb to increase antitumor activity in the murine ID8 ovarian cancer model.MethodsMice with established peritoneal ID8 tumor were treated with either single or combined Trabectedin and α-PD-1 mAb, their overall survival was recorded; tumor-associated immune cells and immune gene expression in tumors from treated mice were analyzed by flow cytometry and quantitative RT-PCR, respectively, and antigen-specific immunity of effector CD8+ T cells was evaluated by ELISA and cytotoxicity assay. In addition, the effect of Trabectedin on tumoral PD-L1 expression was analyzed by both flow cytometry and immunofluorescence staining.ResultsThough single treatment showed a modest antitumor effect in mice bearing 10-day-established ID8 tumor, combined Trabectedin and α-PD-1 mAb treatment induced a strong antitumor immune response, leading to a significant tumor regression with half of mice tumor-free 90 days after tumor inoculation. Mechanistic investigation revealed that combination treatment induces a systemic tumor-specific immunity with an indispensable role of both CD4+ and CD8+ T cells, and effector CD8+ T cells exhibited the antigen-specific cytokine secretion and cytotoxicity upon tumor antigen stimulation; additionally, combination treatment increased the IFN-γ-producing effector T cells and decreased the immunosuppressive cells in peritoneal cavity; accordingly, it enhanced the expression of Th1-associated immune-stimulating genes while reducing the transcription of regulatory/suppressive immune genes, reshaping tumor microenvironment from a immunosuppressive to a stimulatory state. Finally, in vivo Trabectedin treatment has been shown to induce IFN-γ-dependent PD-L1 expression within tumor, possibly constituting a mechanistic basis for its synergistic antitumor effect with α-PD-1 mAb therapy.ConclusionThis study provides the evidence that α-PD-1 mAb can produce a synergistic antitumor efficacy when combined with Trabectedin, a clinically available anticancer agent, supporting a direct translation of this combination strategy in clinic for the treatment of ovarian cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0613-y) contains supplementary material, which is available to authorized users.

Highlights

Monoclonal antibodies that block programmed death (PD)-1 signaling pathway hold great potential as a novel cancer immunotherapy
Combined Trabectedin and α‐PD‐1 Monoclonal antibodies (mAb) treatment synergistically induces a durable antitumor effect depending on both CD4+ and CD8+ T cells As Trabectedin induces a profound growth inhibition and cell apoptosis in human ovarian cancer cell lines and our previous data showed that ID8 murine ovarian cancer cells do not express programmed death 1 (PD-1) and its ligand PD ligand 1 (PD-L1) on their surface [25], we first evaluated the direct effect of Trabectedin and/or α-PD-1 mAb on the survival of ID8 cells in vitro
Treatment with Trabectedin alone show a modest tumor-suppressing activity, resulting in a slight increase in overall survival (Fig. 1b); when tumor-bearing mice received the treatment of combined Trabectedin and α-PD-1 mAb, their overall survival were significantly prolonged with 50% (3 out of 6 mice) of mice surviving at the end of experiment (90 days after tumor injection), these long-term surviving mice were tumor free in peritoneal cavity when they were examined at postmortem; though remaining half of mice succumbed to tumor growth, their median survival time was markedly longer than mice receiving control or single treatment (Fig. 1c; median survival 33, 34, 37 and 89 days for control, α-PD-1, Trabectedin and Trabectedin/α-PD-1)

Summary

Introduction

Monoclonal antibodies (mAb) that block programmed death (PD)-1 signaling pathway hold great potential as a novel cancer immunotherapy. Recent evidence suggests that combining with conventional, targeted or other immunotherapies, these mAb can induce synergistic antitumor responses. We investigated whether Trabectedin (ET-743), a novel anticancer agent currently used for treating relapsed ovarian cancer, can synergize with anti (α)-PD-1 mAb to increase antitumor activity in the murine ID8 ovarian cancer model. OC cells express many tumorassociated antigens against which specific immune responses have been detected [6,7,8,9,10]; endogenous anti-tumor immunity has been thought to impose a major impact on the outcomes of patients with OC as evidenced by the close correlation between patient survival and tumoral T cell infiltration in large annotated clinical samples [11]. Despite the abundant evidence supporting OC immunotherapy, clinical success with immune-based therapies for OC has generally been modest [13]

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Conclusion