Timing cancer drug delivery around our body clock may boost survival

They say timing is everything, and treating cancer may be no exception. Researchers have found that simply shifting when people with cancer receive immunotherapy drugs could improve their survival, adding to evidence that our body’s internal clocks influence how well cancer treatments work.

The activity of our cells and tissues works on 24-hour cycles, known as circadian rhythms, which coordinate everything from hormone release to the timing of cell division and repair. These rhythms are often disrupted in cancer cells, which tend to divide continuously, rather than at set times.

This has prompted efforts to reduce the side effects of chemotherapy, which targets rapidly dividing cells, by administering it when healthy tissues are least active. Increasingly, however, researchers are exploring whether the effectiveness of cancer drugs might also be improved by giving them at particular times.

One such group of drugs is immune checkpoint inhibitors, which help immune T-cells recognise and attack tumours more effectively. “T-cells and other immune defenders are naturally more active in the morning; primed to respond,” says Seline Ismail-Sutton at Ysbyty Gwynedd hospital in Bangor, UK, who wasn’t involved in the study. “Administering immune checkpoint inhibitors during this window may amplify anti-tumour effects and enhance efficacy.”

Earlier this year, Zhe Huang at Central South University in Changsha, China, and his colleagues reported that giving the checkpoint inhibitor pembrolizumab alongside chemotherapy to people with advanced non-small cell lung cancer (NSCLC) before 11.30am was associated with nearly double the survival rate seen in those who received most of their treatment in the afternoon.

To investigate whether timing treatments around circadian rhythms – known as chronotherapy – might also benefit people with small cell lung cancer, a faster-growing and more aggressive form of the condition, the same team analysed data from 397 people treated with the checkpoint inhibitors atezolizumab or durvalumab alongside chemotherapy between 2019 and 2023.

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

After adjusting for multiple confounding factors, earlier administration was associated with a 52 per cent lower risk of cancer progression and a 63 per cent lower risk of death.

Zhang believes this effect probably exists for other tumour types, pointing to hints from studies of renal cell carcinoma and melanoma. As to why this dosing regimen has this effect, the NSCLC trial showed that morning administration boosted circulating T-cell numbers and activation, while late-day dosing had the opposite effect. Studies in mice have also shown that tumour-infiltrating T-cells vary in function over 24 hours, and that the circadian clocks of nearby endothelial cells can regulate when immune cells enter tumours.

Although randomised controlled trials with larger sample sizes are needed, this study “further supports the growing number of reports from all over the world describing better results with early time of day of immunotherapy drugs administration,” says Pasquale Innominato at the University of Warwick, UK.

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

Still, treating everyone early in the day isn’t practical, says Robert Dallmann, also at the University of Warwick, and individuals’ internal clocks differ. “The difference in biological time between ‘early birds’ and ‘night owls’, for example, can be many hours.”

But biomarkers to 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 shift in timing that unlocks a new dimension of precision medicine,” says Ismail-Sutton, who recently published a perspective on this approach.