Circadian Timing of Immune Checkpoint Inhibitors: Beyond Good Times and Bad Times

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After almost a century of limited efficacy of cancer immunotherapy,1 the breakthrough happened in 2012 with the discovery of immune checkpoint inhibitors,2,3 leading to the 2018 Nobel Prize in Physiology or Medicine for James P. Allison and Tasuku Honjo. Yet about 40% of patients on immune checkpoint inhibitors do not currently benefit from these drugs due to toxicity and/or poor efficacy. Moreover, several cancer types, such as microsatellite-stable colorectal and pancreatic, seem to be refractory to the current immune checkpoint inhibitors.4,5

Strikingly, immunotherapy progress roadmaps have not considered the possible relevance of drug timing along the 24-hour timescale,6 despite pervasive well-known large amplitude circadian rhythms in the immune system, such as the near doubling of circulating CD4 T and CD8 T cells between early morning and early night.7-10 These rhythms determine striking differences of vaccine effects, with morning administration being able to elicit stronger immunity compared with other times of the day.11,12

Francis Lévi, MD, PhD

Francis Lévi, MD, PhD

A Matter of Time

As summarized in this issue of The ASCO Post and in the November issue of The Lancet Oncology, Qian et al13 have boldly awakened the field of clinical cancer chronoimmunotherapy. In 299 patients with stage IV malignant melanoma, more frequent morning or early afternoon dosing of immune checkpoint inhibitors nearly doubled overall survival as compared with more frequent late afternoon or evening dosing.

In a propensity score–matched analysis of 146 patients, the risks of earlier disease progression or death were nearly twice as low in the patients receiving less than 20% of nivolumab, pembrolizumab, and/or ipilimumab infusions after 4:30 PM, as compared with those receiving 20% or more infusions after 4:30 PM, thus highlighting reduced efficacy of immune checkpoint inhibitors following evening dosing.

In their study, the timing of immunotherapy was an independent prognostic factor for overall survival in multivariate analysis and remained unaltered using different types of immune checkpoint inhibitors or prior corticosteroids or brain radiotherapy. More than 10 immune checkpoint inhibitors infusions were given to 55% of the patients treated at “good times” as compared with 37% of those treated at “bad times” in the propensity score–matched populations. This imbalance in the number of immune checkpoint inhibitor courses reflected early disease progression in patients receiving more evening courses. It is possible that the increased exposure duration of those patients receiving fewer infusions after 4:30 PM might account for a fourfold increase in immune checkpoint inhibitor–limiting colitis in the “good times” group (16% vs 4%), calling for mapping of timing-dependent efficacy/toxicity dynamics for these agents.

A Closer Look at Early Findings in Chronotherapy

These striking results can be explained by the occurrence of endogenous 24-hour rhythms in cellular metabolism, proliferation, and trafficking, which are generated within each of our cells by a genetic circadian clock involving 15 clock genes.14 The discovery of the transcription/post-transcription molecular dynamics that make circadian clocks tick and rhythmically control cellular processes by Jeffrey Hall, Michael Rosbash, and Michael Young was recognized by their receipt of the 2017 Nobel Prize in Physiology or Medicine—precisely 1 year before that awarded to Drs. Allison and Honjo!15

The molecular clocks in our cells are coordinated by the suprachiasmatic nuclei in the hypothalamus. This circadian pacemaker also helps reset the molecular clocks timing based on environmental day/night and other cycle signaling.14 Lymphocytes and macrophages are also endowed with autonomous circadian clocks.8-10,16 An important challenge ahead obviously consists in the integration of the new knowledge on biologic clocks for advancing precision cancer medicine.

The relevance of treatment timing for tolerability and efficacy has been largely demonstrated for 50 anticancer agents in experimental models, whereas the clinical testing of the chronotherapy hypothesis has generated significant yet overlooked progress.14,17 Thus, in the mid-to-late 1990s, the delivery of anticancer treatments according to circadian rhythms, so-called chronotherapy, proved to be critical for the discovery of both oxaliplatin efficacy and safety in patients with colon cancer18 and the efficacy of neoadjuvant chemotherapy with curative intent for liver metastases from colorectal cancer.19 These chronotherapy-driven advances in the oncologic management of patients with colorectal cancer further pioneered and established the current worldwide strategy for effective management of liver metastases from colorectal cancer.20

Subsequently, similar strategies were applied to patients with liver metastases from other cancer types, such as breast, or with other tumor sites.21 However, no large trial has tested the chronotherapy hypothesis since 2006, when the EORTC 05963 trial showed that FOLFOX (leucovorin, fluorouracil, oxaliplatin) achieved similar overall survival in the overall population of patients with metastatic colorectal cancer receiving conventional or fixed-time chronomodulated delivery.22 The trial, however, revealed for the first time the need for sex-specific chronotherapy schedules, with a large and significant 3-month improvement in median survival for men on chronotherapy but not for women. This finding was confirmed in a meta-analysis of three international, randomized comparisons of conventional administration of FOLFOX vs fixed-time chronotherapy in a total of 842 patients with colorectal cancer.23

Emerging Questions on Chronoimmunotherapy

The thought-provoking clinical investigation by Qian et al raises important questions for broadly expanding cancer chronoimmunotherapy. Mechanisms of the circadian cycles in the susceptibility or resistance to immune checkpoint inhibitors likely differ from those that regulate the effects of chemotherapy and radiotherapy.14,17 For instance, the efficacy of immune checkpoint inhibitors appears quite unrelated to their blood pharmacokinetics,24 whereas immune checkpoint inhibitor pharmacodynamics in tumors and their draining lymph nodes might critically impact efficacy.25,26 The relevance of rhythms there might be critical, since it has been found that intratumoral immune rhythm disruption or robustness respectively sped up or halted the experimental progression of melanoma.27,28

The Qian et al study limitations are inherent to its retrospective and exploratory nature. The threshold of 4:30 PM that differentiates “good times” (before) from “bad times” (after) corresponds to a midpoint extrapolated from immune response patterns in several vaccination studies involving healthy people.11,12 In contrast, the patients in the analysis had stage IV malignant melanoma, with unknown circadian rhythms in CD8 T cells or other immune functions or circadian biomarkers such as rest/activity, temperature, or cortisol rhythms.

The 4:30 PM timing threshold might even be appropriate for women, but not for men, because timing effects appeared most robust in women. Thus, sex could indeed moderate optimal circadian timing and amplitude of the effects of immune checkpoint inhibitors, as has been shown for irinotecan both in mice and in patients with colorectal cancer29,30 and for FOLFOX in patients with colorectal cancer as well.23,31 Moreover, striking sex-related differences in tolerability and efficacy are increasingly being reported for time-unspecified treatment administrations, including immune checkpoint inhibitors,32,33 chemotherapy,34 and targeted biologic therapies.35 We do not know yet whether the reported differences in treatment effects in male or female patients with cancer reflect sex-specific circadian rhythms in drug effects.

The broad clinical significance of Qian et al’s findings for time-dependent efficacy of immune checkpoint inhibitors is further supported by the results of a pilot retrospective study.36 In this study, 95 consecutive patients with stage IV non–small cell lung cancer received the majority of nivolumab infusions before or after 12:54 PM, the median time of the total of 1,818 infusions. The administration of the majority of nivolumab infusions in the morning, rather than in the afternoon, reduced the risk of early disease progression by fourfold and the risk of earlier death; the timing of nivolumab administration was reported to be an independent prognostic factor for progression-free and overall survival in multivariate analyses.

Further progress could result from the personalization of the optimal timing of immunotherapy, according to continuously telemonitored circadian biomarkers ( identifier NCT04263948),37 and/or the estimation of molecular clock functionality and timing, based on the application of novel artificial intelligence algorithms to single tumor genomics data.38 

Closing Thoughts

The analysis of the timing effects of immune checkpoint inhibitors by Qian et al13 represents challenging, clinically driven research that could be practice-changing at no cost. Prospective randomized trials should identify the optimal timing of such treatment tailored to individual patients’ circadian biomarkers, including sex-specific timing. The further development of circadian clock–based immunochemotherapy would indeed shift cancer medicine into true precision oncology.

Dr. Lévi works at Paris-Saclay University, Paul-Brousse Hospital, Assistance Publique-Hôpitaux de Paris, Villejuif, and with the Cancer Chronotherapy Team, Warwick Medical School, Coventry, UK.

DISCLOSURE: Dr Lévi reported no conflicts of interest.


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