Safety and Antitumor Activity of Anti–PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer

Hamanishi, Junzo; Mandai, Masaki; Ikeda, Takafumi; Minami, Manabu; Kawaguchi, Atsushı; Murayama, Toshinori; Kanai, Masashi; Mori, Yoshio; Matsumoto, Shigemi; Chikuma, Shunsuke; Matsumura, Noriomi; Abiko, Kaoru; Baba, Tsukasa; Yamaguchi, Ken; Ueda, Akihiko; Hosoe, Yuko; Morita, Satoshi; Yokode, Masayuki; Shimizu, Akira; Honjo, Tasuku; Konishi, Ikuo

doi:10.1200/jco.2015.62.3397

Cited by 988 publications

(799 citation statements)

References 33 publications

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“…Remarkably, in a recent study, the clinical efficacy of an anti-PD-1 mAb has been reported in patients with ovarian carcinoma. 66 It is possible that the beneficial effects documented in this study might reflect not only a blockade of PD-1/PD-L on tumor-infiltrating lymphocytes but also on PD-1 1 NK cells.…”

Section: Discussionmentioning

confidence: 96%

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

Pesce

Greppi

Tabellini

et al. 2017

Journal of Allergy and Clinical Immunology

382

386

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Background: Programmed death 1 (PD-1) is an immunologic checkpoint that limits immune responses by delivering potent inhibitory signals to T cells on interaction with specific ligands expressed on tumor/virus-infected cells, thus contributing to immune escape mechanisms. Therapeutic PD-1 blockade has been shown to mediate tumor eradication with impressive clinical results. Little is known about the expression/function of PD-1 on human natural killer (NK) cells. Objective: We sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features. Methods: We performed multiparametric cytofluorimetric analysis of PD-1 1 NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays. Results: We provide unequivocal evidence that PD-1 is highly expressed (PD-1 bright ) on an NK cell subset detectable in the peripheral blood of approximately one fourth of healthy subjects. These donors are always serologically positive for human cytomegalovirus. PD-1 is expressed by CD56 dim but not CD56 bright NK cells and is confined to fully mature NK cells characterized by the NKG2A 2 KIR 1 CD57 1 phenotype. Proportions of PD-1 bright NK cells were higher in the ascites of a cohort of patients with ovarian carcinoma, suggesting their

show abstract

Section: Discussionmentioning

confidence: 96%

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

Pesce

Greppi

Tabellini

et al. 2017

Journal of Allergy and Clinical Immunology

382

386

View full text Add to dashboard Cite

show abstract

“…Immunotherapy using antibodies targeting checkpoint proteins has become of increasing interest and a number of clinical trials using these antibodies for several different cancer types have shown clinical responses 22, 23, 24, 25, 26, 27, 28. However, studies with animal models and cancer patients have also shown that combining antibody blockade of the PD‐1/PD‐L1 axis with other forms of immunotherapy can lead to more meaningful clinical responses 32, 33, 34, 35.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, pembrolizumab treatment of patients with PD‐L1‐positive advanced non‐small‐cell lung cancer prolonged their overall survival 25. Using a different PD‐1 blockade antibody, nivolumab, clinical efficacy was shown for patients with metastatic renal cell carcinoma and for patients with ovarian cancer 26, 27. Nivolumab also increased survival of patients with non‐squamous non‐small‐cell lung cancer that resisted prior chemotherapy 28.…”

Section: Introductionmentioning

confidence: 99%

Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

Levingston

Young

2017

Intl Journal of Cancer

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A carcinogen‐induced premalignant oral lesion model that progresses to oral cancer was used to examine the impact of blocking PD‐1 on cytokine expression and on progression of lesions to cancer. The results of this study show increased production of IL‐2 and the inflammatory cytokines IL‐6, IL‐17 and TNF‐α by spleen cells of lesion‐bearing mice that were treated with PD‐1 antibody for 1 week compared to cytokine production by spleen cells of lesion‐bearing mice treated with control antibody. Production of IFN‐γ increased at 3 weeks of PD‐1 antibody treatment, although production of the other Th1 and inflammatory mediators declined. By 5 weeks, levels of these cytokines declined for both control and PD‐1 antibody‐treated mice. Flow cytometric analysis for IFN‐γ‐expressing cells showed shifts in CD4+ cells expressing IFN‐γ consistent with the changes in cytokine secretion. Whether or not treatment generated reactivity to lesions or HNSCC was determined. Spleen cells from PD‐1 antibody‐treated mice were stimulated by lysates of premalignant lesion and HNSCC tongue tissues to produce increased levels of Th1 and select inflammatory cytokines early in the course of PD‐1 antibody treatment. However, with continued treatment, reactivity to lesion and HNSCC lysates declined. Analysis of clinical response to treatment suggested an early delay in lesion progression but, with continued treatment, lesions in PD‐1 antibody‐treated mice progressed to the same degree as in control antibody‐treated mice. Overall, these results show an early beneficial response to PD‐1 antibody treatment, which then fails with continued treatment and lesion progression.

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“…Some phase Ib-II trials have investigated the activity and safety of anti-PD1 or anti-PD-L1 mAbs in platinum-resistant EOC, with objective response (OR) (complete response (CR)+ partial response (PR)) rates ranging from 5.9% to 15% (22,(39)(40)(41) and with grade (G)≥3 AE rates ranging from 3.8% to 40% (Table I). Nivolumab obtained an OR and a disease control (CR+PR+stable disease (SD)) in 15% and 45% of 20 patients who had received at least two prior chemotherapy lines (39) ( Table I).…”

Section: Epithelial Ovarian Cancermentioning

confidence: 99%

Immune Checkpoint Inhibitors in Gynecological Cancers: Update of Literature and Perspectives of Clinical Research

2017

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Safety and Antitumor Activity of Anti–PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer

Cited by 988 publications

References 33 publications

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

Immune Checkpoint Inhibitors in Gynecological Cancers: Update of Literature and Perspectives of Clinical Research

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