Combined Trabectedin and anti-PD1 antibody produces a synergistic antitumor effect in a murine model of ovarian cancerReport as inadecuate




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Journal of Translational Medicine

, 13:247

Immunobiology andimmunotherapy

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.

AbbreviationsOCovarian carcinoma

mAbmonoclonal antibody

PD-1programmed cell death-1

PD-L1PD ligand 1

CTLA-4cytotoxic lymphocyte associated antigen 4

PLDHpegylated liposomal doxorubicin hydrochloride

FDAFood and Drug Administration

EMAEurope Medicine Agency

TAMtumor-associated macrophages

Tregregulatory T cells

MDSCmyeloid-derived suppressor cells

Th1T-helper 1

CTLcytotoxicity T lymphocytes

IFN-γinterferon-gamma

ILinterleukin

DMEMDulbecco’s minimum essential medium

RPMIRoswell Park Memorial Institute

NKnatural killer

DCdendritic cells

PBSphosphate-buffered saline

FBSfetal bovine serum

RT-PCRreverse transcription polymerase chain reaction

GAPDHglyceraldehyde phosphate dehydrogenase

SEMstandard error of mean

DMSOdimethylsulfoxide

Electronic supplementary materialThe online version of this article doi:10.1186-s12967-015-0613-y contains supplementary material, which is available to authorized users.

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Author: Zhiqiang Guo - Haolin Wang - Fandong Meng - Jie Li - Shulan Zhang

Source: https://link.springer.com/



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