Chemotherapy injections are more effective in the morning, while new vaccines work better when administered late in the afternoon. That is because cells closely tied to cancer or immune responses move in step with the 24-hour circadian rhythm. Phenomena known from treating patients have been confirmed in clinical trials with causal links. If the research advances, simply adjusting the time of drug administration is expected to further boost treatment efficacy.
A team led by Professor Zhang Yongchang (Yongchang Zhang) of Central South University Medical School in China said in Nature Medicine on Feb. 3 that "in a phase 3 clinical trial, patients with Non-small cell lung cancer (NSCLC) who received immunotherapy before 3 p.m. had more delayed disease progression than those treated later." The study was conducted jointly by researchers in China, Hong Kong and France.
◇ Extended survival for cancer patients by nearly 70%
Lung cancer is divided into small cell carcinoma and larger non-small cell carcinoma by cancer cell size, and non-small cell carcinoma accounts for about 80% of all lung cancers. The researchers randomly divided 210 patients with advanced non-small cell lung cancer into two groups: one received the immunotherapies Keytruda (generic name pembrolizumab) or Tyvyt (sintilimab) before 3 p.m., and the other received them after that, four times every three weeks. Both drugs are PD-1 immune checkpoint inhibitors.
Immune checkpoints are a way of marking so that T cells do not attack normal cells. When the PD-1 protein on the surface of a T cell binds to PD-L1 on a normal cell, the T cell passes by. The problem is that cancer cells also produce PD-L1 to masquerade as normal cells. The anticancer drugs administered in this study use antibody proteins that bind first to PD-1 on T cells so they do not mistake cancer cells for normal cells.
The researchers followed patients for 29 months after the first treatment. In the trial, patients treated before 3 p.m. survived a median 28 months, while those given anticancer drugs late in the afternoon survived 17 months. Francis Lévi of Université Paris-Saclay, a corresponding author of the paper, said, "It is a striking result with survival nearly doubled."
Progression-free survival, when the disease does not worsen, was 11.3 months in the early administration group and 5.7 months in the delayed group. The risk of disease progression fell by 60%. Patients who received earlier anticancer injections had more cytotoxic T cells in the blood that attack cancer cells, and their activity was higher.
Dozens of studies have reported that administering immune checkpoint inhibitors, a type of anticancer therapy, earlier in the day markedly reduces the risk of death for cancer patients. But all were post hoc analyses of treatment outcomes. This is the first time patients were randomly assigned and a clinical trial was conducted that varied the timing of anticancer drug administration.
◇ Treatment strategy aligned with morning-type immune cells
The team explained that the stronger treatment effect in the early administration group was because the targeted T cells gather around tumors in the morning. As time passes, T cells gradually move into circulation. Administering anticancer drugs earlier lets T cells attack more cancer cells. In other words, it is like issuing the signal to concentrate fire when friendly forces have encircled the enemy.
Many of the patients in this clinical trial are still receiving treatment. Continued follow-up is needed to assess the long-term benefits of early administration of anticancer drugs. Although an increase in T cells in the blood was confirmed, there is also the limitation that changes in tumor tissue have yet to be analyzed.
Lévi said, "We need more research to see whether administering at a specific time, such as 11 a.m., is better than setting a broad time window for anticancer drugs." Because circadian rhythms vary somewhat by person, the optimal time to administer anticancer drugs may also differ individually. Lévi noted, "Morning people and night owls can have immune systems that change distinctly over the course of a day."
Another task is whether the findings apply to other cancer treatments. Pasquale Innominato of Warwick Medical School in the United Kingdom said, "For cancers such as melanoma or bladder cancer where immune checkpoint inhibitors are effective, we expect similar results, but the likelihood is low for prostate or pancreatic cancers that do not respond to this therapy."
◇ COVID-19 vaccines are more effective in the afternoon for younger adults
Vaccines also appear to be influenced by circadian rhythms. A team led by Elizabeth Klerman of Harvard Medical School and Jane McKeating of the University of Oxford reported in the Journal of Biological Rhythms in 2021 that antibody levels after COVID-19 vaccination were higher when doses were given in the afternoon than in the morning.
During the COVID-19 pandemic, the researchers evaluated neutralizing antibody levels after vaccination in 2,190 health care workers. In general, those vaccinated in the afternoon showed higher antibody responses. The team explained that immune cells have a greater learning effect to vaccines in the afternoon.
Vaccines work by introducing viruses or bacteria that have been detoxified into the body to trigger an immune response. It is like experiencing a small enemy force in advance and preparing, so that when a large-scale attack comes later the body can respond immediately. The immune system is designed to prepare for invaders such as viruses and bacteria during the day, when external activity is high.
Dendritic cells, the scouts that recognize viral or bacterial proteins (antigens), move to the lymph nodes, the rally points for immune cells, in the afternoon. The densities of T cells and B cells that attack invaders also peak in the lymph nodes in the afternoon. Therefore, if a vaccine arrives then, it can be seen as the most effective time for the body to establish a state of readiness.
The researchers also divided COVID vaccines by product from Pfizer in the United States and AstraZeneca in the United Kingdom. The Pfizer and Moderna vaccines deliver messenger ribonucleic acid (mRNA), the genetic material that makes the virus's spike protein, directly into the body, while AstraZeneca delivers the spike gene into the body via another virus that is harmless to humans.
Antibody responses were higher among recipients of mRNA Vaccine, women and younger adults. This contrasts with earlier trials in older adults in which influenza (flu) vaccines were more effective in the morning. The researchers explained, "COVID vaccines and influenza vaccines work by different mechanisms." Because COVID vaccines fight a completely new virus, afternoon vaccination, when immune learning is stronger, is better; but for influenza viruses that older adults have experienced over many years, morning vaccination aligns with the immune system's scouting time.
References
Nature Medicine (2021), DOI: https://doi.org/10.1038/s41591-025-04181-w
Journal of Biological Rhythms (2021), DOI: https://doi.org/10.1177/07487304211059315