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

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.

Fig. 1. Bar graph of efficacy endpoints of immune checkpoint inhibitors in compared timing groups from 18 studies involving a total of 3250 patients with different cancer types.

a Median progression-free survival data. b Median overall survival data. Violet bars correspond to late time-of-day ICI dosing. Blue bars correspond to early time-of-day of ICI administration. The main characteristics of these studies are summarized in Table S1. Note: Qian et al. study results not shown despite statistically significant differences in overall survival in favor of the early time-of-day group, because median values were not reached Reported p values from timing groups comparisons of PFS or survival curves: *P > 0.20; ** 0.05 < p ≤ 0.20; *** 0.01 < p ≤ 0.05; ****0.001 < p ≤ 0.01.

Fig. 2. Interactions between the circadian timing and the immune systems.

Ʃ and paraƩ = sympathetic and parasympathetic systems.

Fig. 3. Schematic polar representation of the distribution of peak times of selected rhythmic immune functions involved in antitumor immunity in rodent models over 24 h.

Peak time data are shown in three key compartments, i.e. bloodstream [red], lymph nodes [green], and tumor immune microenvironment [purple]). The circle in the center depicts the light-dark synchronization schedule of nocturnally active mice or rats. HALO Hours After Light Onset.

Fig. 4. Spectrum in peak times of selected human circulating immunological factors with a proven 24-h rhythm relevant to cancer immunotherapy.

a Healthy (male) subjects. CD8 cytotoxic Central memory [red], effector [blue], plasma cortisol [green]. b Salivary cortisol in four individual patients with advanced cancer. c Distribution of daily timings of ICI administration in two studies: Karaboué et al. Cancers [11] [green] and Qian et al. Lancet Oncol. [12] [purple].