Transition of the PD‑1 occupancy of nivolumab on T cells after discontinuation and response of nivolumab re‑challenge

Nose, Taku; Funakoshi, Yohei; Suto, Hirotaka; Nagatani, Yoshiaki; Imamura, Yoshiaki; Toyoda, Masanori; Kiyota, Naomi; Minami, Hironobu

doi:10.3892/mco.2022.2537

Cited by 7 publications

(5 citation statements)

References 24 publications

(32 reference statements)

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“…The elimination half-life of PD-1 antibody is 12-20 days, whereas PD-1 occupancy of peripheral T cells with PD-1 antibody is sustained at 57%-70% for ∼60 days and PD-1 occupancy declines gradually over time. 29 , 30 In the KEYNOTE-048 trial, PFS until progression under subsequent chemotherapy was longer for patients receiving pembrolizumab-containing treatment. 31 Furthermore, combination of PD-1 antibody and cetuximab showed promising activity for platinum-refractory R/M-HNSCC.…”

Section: Discussionmentioning

confidence: 99%

A phase II trial of paclitaxel plus biweekly cetuximab for patients with recurrent or metastatic head and neck cancer previously treated with both platinum-based chemotherapy and anti-PD-1 antibody

Koyama,

Kiyota,

Boku

et al. 2024

ESMO Open

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Section: Discussionmentioning

confidence: 99%

A phase II trial of paclitaxel plus biweekly cetuximab for patients with recurrent or metastatic head and neck cancer previously treated with both platinum-based chemotherapy and anti-PD-1 antibody

Koyama,

Kiyota,

Boku

et al. 2024

ESMO Open

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“…Thus the circulating steady state is usually reached after 2-4 months [112]. About 8 months are needed to decrease T-cell PD-1 occupancy by 50% after ICIs [113]. The proportion of late ToD courses associated with worse survival also needs to be specified, as it currently ranges from >20 to 67%.…”

Section: Discussionmentioning

confidence: 99%

“…As a result, the steady state is usually reached after 2-4 months [112]. Additionally, it takes 32.4 weeks to reduce T-cell PD-1 occupancy by 50%, after nivolumab discontinuation [113]. These data reveal that ICIs timing might only moderate their pharmacokinetics over the initial 2-4 months of treatment, i.e.…”

Section: Chronopharmacokineticsmentioning

confidence: 95%

Why does circadian timing of administration matter for immune checkpoint inhibitors’ efficacy?

Karaboué,

Innominato,

Wreglesworth

et al. 2024

Br J Cancer

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Background Tolerability and antitumour efficacy of chemotherapy and radiation therapy can vary largely according to their time of administration along the 24-h time scale, due to the moderation of their molecular and cellular mechanisms by circadian rhythms. Recent clinical data have highlighted a striking role of dosing time for cancer immunotherapy, thus calling for a critical evaluation. Methods Here, we review the clinical data and we analyse the mechanisms through which circadian rhythms can influence outcomes on ICI therapies. We examine how circadian rhythm disorders can affect tumour immune microenvironment, as a main mechanism linking the circadian clock to the 24-h cycles in ICIs antitumour efficacy. Results Real-life data from 18 retrospective studies have revealed that early time-of-day (ToD) infusion of immune checkpoint inhibitors (ICIs) could enhance progression-free and/or overall survival up to fourfold compared to late ToD dosing. The studies involved a total of 3250 patients with metastatic melanoma, lung, kidney, bladder, oesophageal, stomach or liver cancer from 9 countries. Such large and consistent differences in ToD effects on outcomes could only result from a previously ignored robust chronobiological mechanism. The circadian timing system coordinates cellular, tissue and whole-body physiology along the 24-h timescale. Circadian rhythms are generated at the cellular level by a molecular clock system that involves 15 specific clock genes. The disruption of circadian rhythms can trigger or accelerate carcinogenesis, and contribute to cancer treatment failure, possibly through tumour immune evasion resulting from immunosuppressive tumour microenvironment. Conclusions and perspective Such emerging understanding of circadian rhythms regulation of antitumour immunity now calls for randomised clinical trials of ICIs timing to establish recommendations for personalised chrono-immunotherapies with current and forthcoming drugs.

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“…It is not simply a one-way differentiation; this process is regulated by epigenetic and transcriptomic factors and could be disorganized when lymphocytes encounter other antigens, e.g. viruses (we are talking about real-life, not sterile laboratory conditions) [12]. It means that the formation and maintenance of immunological memory is a very dynamic and variable process.…”

Section: Theoretical Background For the Rechallenge Of Immune Checkpo...mentioning

confidence: 99%

Rechallenge of immunotherapy in non-small cell lung cancer patients — navigating indications and evolving perspectives

Knetki-Wróblewska,

Chmielewska,

Wojas-Krawczyk

et al. 2024

Oncol Clin Pract

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Indications for immunotherapy in patients with non-small-cell lung cancer (NSCLC) are expanding, with an increasing number of patients receiving immunotherapy in the perioperative setting or as consolidation of radiochemotherapy. Immune checkpoint inhibitor (ICI)-based regimens are also being used more and more often in the first-line systemic setting. However, in many cases, the efficacy of immunotherapy is limited, and it is necessary to determine the optimal sequence of systemic treatment. There is some theoretical rationale for repeated use of immune checkpoint inhibitors, but it is debatable which subgroups of patients are likely to benefit clinically from such treatment. Currently, data on the efficacy of immunotherapy retreatment are derived mainly from retrospective analyses and reviews of small subgroups of patients treated in clinical trials, making it difficult to draw reliable conclusions. There is a need for research identifying factors that will guide clinical decision-making, such as the time from the completion of immunotherapy, the initial response achieved, the expression of PD-L1, and others. It appears that patients who discontinued immunotherapy due to disease progression should not be requalified for treatment with currently available ICIs. Treatment in controlled clinical trials is the optimal strategy in such cases.

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Transition of the PD‑1 occupancy of nivolumab on T cells after discontinuation and response of nivolumab re‑challenge

Cited by 7 publications

References 24 publications

A phase II trial of paclitaxel plus biweekly cetuximab for patients with recurrent or metastatic head and neck cancer previously treated with both platinum-based chemotherapy and anti-PD-1 antibody

A phase II trial of paclitaxel plus biweekly cetuximab for patients with recurrent or metastatic head and neck cancer previously treated with both platinum-based chemotherapy and anti-PD-1 antibody

Why does circadian timing of administration matter for immune checkpoint inhibitors’ efficacy?

Rechallenge of immunotherapy in non-small cell lung cancer patients — navigating indications and evolving perspectives

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