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

Abstract

BACKGROUND:

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. 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.

METHODS:

Mice 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.

RESULTS:

Though 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.

CONCLUSION:

This 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.

• Authors: Zhiqiang Guo, Haolin Wang, Fandong Meng, Jie Li, Shulan Zhang
• Journal: Journal of translational medicine (J Transl Med) Vol. 13 Pg. 247 (Jul 29 2015) ISSN: 1479-5876 [Electronic] England
• PMID: 26219551 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neoplasm
• Antigens, Neoplasm
• Dioxoles
• Programmed Cell Death 1 Receptor
• Tetrahydroisoquinolines
• Interferon-gamma
• Trabectedin

Topics

• Animals
• Antibodies, Neoplasm (pharmacology, therapeutic use)
• Antigens, Neoplasm (immunology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• CD4-Positive T-Lymphocytes (drug effects, immunology)
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Cell Line, Tumor
• Cytotoxicity, Immunologic (drug effects)
• Dioxoles (pharmacology, therapeutic use)
• Disease Models, Animal
• Drug Synergism
• Female
• Immunization
• Immunosuppression Therapy
• Interferon-gamma (biosynthesis)
• Mice, Inbred C57BL
• Ovarian Neoplasms (drug therapy, immunology)
• Peritoneal Lavage
• Programmed Cell Death 1 Receptor (immunology)
• Tetrahydroisoquinolines (pharmacology, therapeutic use)
• Trabectedin
• Tumor Microenvironment (drug effects)