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

  • Br J Cancer. 2024 Sep;131(5):783-796. doi: 10.1038/s41416-024-02704-9.
Abdoulaye Karaboué  1  2 ,  Pasquale F Innominato  3  4 ,  Nicholas I Wreglesworth  3  5 ,  Boris Duchemann  1  6 ,  René Adam  1  7 ,  Francis A Lévi  8  9  10
Affiliations
  • 1. UPR "Chronotherapy, Cancer and Transplantation", Medical School, Paris-Saclay University, 94800, Villejuif, France.
  • 2. Medical Oncology Unit, GHT Paris Grand Nord-Est, Le Raincy-Montfermeil, 93770, Montfermeil, France.
  • 3. North Wales Cancer Centre, Ysbyty Gwynedd, Betsi Cadwaladr University Health Board, Bangor, LL57 2PW, UK.
  • 4. Cancer Chronotherapy Team, Division of Biomedical Sciences, Medical School, Warwick University, Coventry, CV4 7AL, UK.
  • 5. School of Medical Sciences, Bangor University, Bangor, LL57 2PW, UK.
  • 6. Thoracic and Medical Oncology Unit, Avicenne Hospital, Assistance Publique-Hôpitaux de Paris, 93000, Bobigny, France.
  • 7. Hepato-Biliary Center, Paul Brousse Hospital, Assistance Publique-Hopitaux de Paris, 94800, Villejuif, France.
  • 8. UPR "Chronotherapy, Cancer and Transplantation", Medical School, Paris-Saclay University, 94800, Villejuif, France. [email protected].
  • 9. Gastro-intestinal and Medical Oncology Service, Paul Brousse Hospital, 94800, Villejuif, France. [email protected].
  • 10. Department of Statistics, University of Warwick, Coventry, UK. [email protected].
PMID: 38834742 DOI: 10.1038/s41416-024-02704-9
Abstract

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.