Timing cancer drug delivery around our body clock may boost survival

They say timing is everything, and cancer treatment may be no exception. Researchers have found that simply changing when people with cancer receive immunotherapy drugs could improve their survival, adding to the evidence that our bodies’ internal clocks influence the effectiveness of cancer treatments.

The activity of our cells and tissues operates in 24-hour cycles, called circadian rhythms, which coordinate everything from the release of hormones to the timing of cell division and repair. These rhythms are often disrupted in cancer cells, which tend to divide continuously rather than at specific times.

This has prompted efforts to reduce the side effects of chemotherapy, which targets rapidly dividing cells, by administering it when healthy tissue is least active. However, researchers are increasingly studying whether the effectiveness of cancer drugs could also be improved by administering them at specific times.

One such group of drugs is immune checkpoint inhibitors, which help immune T cells recognize and attack tumors more effectively. “T lymphocytes and other immune defenders are naturally more active in the morning; ready to respond,” says Seline Ismail-Sutton of Ysbyty Gwynedd Hospital in Bangor, UK, who was not involved in the study. “Administering immune checkpoint inhibitors during this window may amplify antitumor effects and improve efficacy.”

Earlier this year, Zhe Huang of Central South University in Changsha, China, and colleagues reported that giving the checkpoint inhibitor pembrolizumab alongside chemotherapy to people with advanced non-small cell lung cancer (NSCLC) before 11:30 a.m. was associated with a survival rate almost twice that seen in those who received the majority of their treatment in the afternoon.

To determine whether timing treatments based on circadian rhythms – known as chronotherapy – could also benefit people with small cell lung cancer, a faster and more aggressive form of the disease, the same team analyzed data from 397 people treated with the checkpoint inhibitors atezolizumab or durvalumab alongside chemotherapy between 2019 and 2023.

“Compared to patients treated later in the day, those treated before 3 p.m. had significantly longer progression-free survival and overall survival,” says team member Yongchang Zhang, also at Central South University.

After adjusting for several confounding factors, early administration was associated with a 52 percent lower risk of cancer progression and a 63 percent lower risk of death.

Zhang thinks this effect likely exists for other tumor types, pointing to indications from studies in renal cell carcinoma and melanoma. As for why this dosing regimen has this effect, the NSCLC trial showed that morning administration increased the number and activation of circulating T cells, while late administration had the opposite effect. Studies in mice have also shown that the function of tumor-infiltrating T cells varies over 24 hours and that circadian clocks in neighboring endothelial cells can regulate when immune cells enter tumors.

Although randomized controlled trials with larger sample sizes are needed, this study “confirms the growing number of reports from around the world describing better outcomes with earlier administration of immunotherapy drugs,” says Pasquale Innominato of the University of Warwick, UK.

But could hospitals realistically implement this? Compared to adding treatments, “adjusting infusion time is a simple clinical decision that adds virtually no cost,” says Zhang.

Yet treating everyone early in the day is not practical, says Robert Dallmann, also at the University of Warwick, and individuals’ internal clocks differ. “The difference in biological time between “early risers” and “night owls,” for example, can be several hours.

But biomarkers that can accurately determine people’s chronotypes are being developed. Once tested and validated, chronotherapy “could represent a low-cost, resource-efficient innovation, with the power to profoundly improve outcomes: a simple change in timing that opens a new dimension of precision medicine,” says Ismail-Sutton, who recently published a perspective on this approach.