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
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 (ClinicalTrials.gov 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.
REFERENCES
1. Kirkwood JM, Butterfield LH, Tarhini AA, et al: Immunotherapy of cancer in 2012. CA Cancer J Clin 62:309-335, 2012.
2. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-2454, 2012.
3. Brahmer JR, Tykodi SS, Chow LQM, et al: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455-2465, 2012.
4. Marmorino F, Boccaccino A, Germani MM, et al: Immune checkpoint inhibitors in pMMR metastatic colorectal cancer: A tough challenge. Cancers (Basel) 12:2317, 2020.
5. Schizas D, Charalampakis N, Kole C, et al: Immunotherapy for pancreatic cancer: A 2020 update. Cancer Treat Rev 86:102016, 2020.
6. Kraehenbuehl L, Weng CH, Eghbali S, et al: Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways. Nat Rev Clin Oncol 19:37-50, 2022.
7. Lévi FA, Canon C, Touitou Y, et al: Seasonal modulation of the circadian time structure of circulating T and natural killer lymphocyte subsets from healthy subjects. J Clin Invest 81:407-413, 1988.
8. Druzd D, Matveeva O, Ince L, et al: Lymphocyte circadian clocks control lymph node trafficking and adaptive immune responses. Immunity 46:120-132, 2017.
9. Scheiermann C, Gibbs J, Ince L, et al: Clocking in to immunity. Nat Rev Immunol 18:423-437, 2018.
10. Downton P, Early JO, Gibbs JE: Circadian rhythms in adaptive immunity. Immunology 161:268-277, 2020.
11. Nobis CC, Dubeau Laramée G, Kervezee L, et al: The circadian clock of CD8 T cells modulates their early response to vaccination and the rhythmicity of related signaling pathways. Proc Natl Acad Sci U S A 116: 20077-20086, 2019.
12. de Bree LCJ, Mourits VP, Koeken VA, et al: Circadian rhythm influences induction of trained immunity by BCG vaccination. J Clin Invest 130:5603-5617, 2020.
13. Qian DC, Kleber T, Brammer B, et al: Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): A propensity score-matched analysis of a single-centre, longitudinal study. Lancet Oncol 22:1777-1786, 2021.
14. Lévi F, Okyar A, Dulong S, et al: Circadian timing in cancer treatments. Annu Rev Pharmacol Toxicol 50:377-421, 2010.
15. Dolgin E: News in Brief: Cancer “clock” opens new therapeutic avenues. Cancer Discovery 7:1358, 2017.
16. Keller M, Mazuch J, Abraham U, et al: A circadian clock in macrophages controls inflammatory immune responses. Proc Natl Acad Sci U S A 106:21407-21412, 2009.
17. Dallmann R, Okyar A, Lévi F: Dosing-time makes the poison: Circadian regulation and pharmacotherapy. Trends Mol Med 22:430-445, 2016.
18. Lévi F, Zidani R, Misset JL: Randomized multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet 350:681-686, 1997.
19. Giacchetti S, Itzhaki M, Gruia G, et al: Long-term survival of patients with unresectable colorectal liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 10:663-669, 1999.
20. Adam R, Wicherts DA, de Haas RJ, et al: Patients with initially unresectable colorectal liver metastases: Is there a possibility of cure? J Clin Oncol 27:1829-1835, 2009.
21. Golse N, Adam R: Liver metastases from breast cancer: What role for surgery? Indications and results. Clin Breast Cancer 17:256-265, 2017.
22. Giacchetti S, Bjarnason G, Garufi C, et al: Phase III trial of 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first line chemotherapy of metastatic colorectal cancer: The EORTC Chronotherapy Group. J Clin Oncol 24:3562-3569, 2006.
23. Giacchetti S, Dugué PA, Innominato PF, et al: Sex moderates circadian chemotherapy effects on survival of patients with metastatic colorectal cancer: A meta-analysis. Ann Oncol 23:3110-3116, 2012.
24. Bellesoeur A, Ollier E, Allard M, et al: Is there an exposure-response relationship for nivolumab in real-world NSCLC patients? Cancers (Basel)11:1784, 2019.
25. Fransen MF, van Hall T, Ossendorp F: Immune checkpoint therapy: Tumor draining lymph nodes in the spotlights. Int J Mol Sci 22:9401, 2021.
26. Francis DM, Manspeaker MP, Schudel A, et al: Blockade of immune checkpoints in lymph nodes through locoregional delivery augments cancer immunotherapy. Sci Transl Med 12:eaay3575, 2020.
27. Kiessling S, Beaulieu-Laroche L, Blum ID, et al: Enhancing circadian clock function in cancer cells inhibits tumor growth. BMC Biol 15:13, 2017.
28. Aiello I, Mul Fedele ML, Román F, et al: Circadian disruption promotes tumor-immune microenvironment remodeling favoring tumor cell proliferation. Sci Adv 6:eaaz4530, 2020.
29. Li XM, Mohammad-Djafari A, Dumitru M, et al: A circadian clock transcription model for the personalization of cancer chronotherapy. Cancer Res 73:7176-7188, 2013.
30. Innominato PF, Ballesta A, Huang Q, et al: Sex-dependent least toxic timing of irinotecan combined with chronomodulated chemotherapy for metastatic colorectal cancer: Randomized multicenter EORTC 05011 trial. Cancer Med 9:4148-4159, 2020.
31. Lévi F, Focan C, Karaboué A, et al: Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Adv Drug Deliv Rev 59:1015-1035, 2007.
32. Conforti F, Pala L, Bagnardi V, et al: Cancer immunotherapy efficacy and patients’ sex: A systematic review and meta-analysis. Lancet Oncol 19:737-746, 2018.
33. Ye Y, Jing Y, Li L, et al: Sex-associated molecular differences for cancer immunotherapy. Nat Commun 11:1779, 2020.
34. Wagner AD, Grothey A, Andre T, et al: Sex and adverse events of adjuvant chemotherapy in colon cancer: An analysis of 34,640 patients in the ACCENT database. J Natl Cancer Inst 113:400-407, 2021.
35. Vandeputte C, Bregni G, Gkolfakis P, et al: Sex and regorafenib toxicity in refractory colorectal cancer: Safety analysis of the RegARd-C trial. Clin Colorectal Cancer 20:326-333, 2021.
36. Karaboué A, Collon T, Pavese I, et al: Time-dependent efficacy of checkpoint inhibitor nivolumab in metastatic lung cancer patients. 2021 ASCO Annual Meeting. Abstract 9096. Presented June 4, 2021.
37. Lévi F, Komarzynski S, Huang Q, et al: Tele-monitoring of cancer patients’ rhythms during daily life identifies actionable determinants of circadian and sleep disruption. Cancers (Basel) 12:1938, 2020.
38. Vlachou D, Bjarnason GA, Giacchetti S, et al: TimeTeller: A new tool for precision circadian medicine and cancer prognosis. bioRxiv. Available at https://www.biorxiv.org/content/10.1101/622050v1. Accessed on January 6, 2022.
