Timing cancer drug delivery around our body clock may boost survival

They say timing is everything, but treatment is Cancer may not be an exception. Researchers have found that simply changing the timing of cancer patients taking immunotherapy drugs can improve their survival, adding to evidence that our body's internal clock influences the effectiveness of cancer treatments.

The activity of our cells and tissues is based on 24-hour cycles known as circadian rhythms, which coordinate everything from hormone release to timing 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 that targets rapidly dividing cells by administering it at times when healthy tissue is least active. However, researchers are increasingly examining whether cancer treatments are effective. drugs can also be improved by giving them at specific times.

One such group of drugs is immune checkpoint inhibitors, which help immune T cells recognize tumors and attack them more effectively. “T cells and other immune defenders are naturally more active in the morning and ready to respond,” says Celine Ismail-Sutton at Ysbyty Gwynedd Hospital in Bangor, UK, who was not involved in the study. “Administration of immune checkpoint inhibitors during this period may enhance the antitumor effect and improve efficacy.”

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

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

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

After adjusting for multiple confounders, earlier introduction was associated with a 52 percent lower risk of cancer progression and a 63 percent lower risk of developing cancer. death.

Zhang believes this effect likely exists in other tumor types, pointing to hints from studies renal cell carcinoma And melanoma. As for why this dosing regimen has this effect, a study in NSCLC found that morning administration increased the number and activation of circulating T cells, whereas late-day administration had the opposite effect. Mouse studies also showed that tumor-infiltrating T cells vary in function over a 24-hour period and that the circadian clock of nearby endothelial cells may regulate when immune cells infiltrate tumors.

Although randomized controlled trials with larger sample sizes are needed, this study “further confirms the growing number of reports from around the world describing better outcomes with early initiation of immunotherapy drugs,” he says. Nameless Pasquale at the University of Warwick, UK.

But can hospitals actually implement this? Compared with adjunctive treatment, “adjusting infusion time is a simple clinical decision that requires virtually no additional cost,” Zhang says.

However, he believes that treating everyone early in the day is impractical. Robert Dallmannalso at the University of Warwick, and people's internal clocks vary. “The difference in biological time between early risers and late morning people, for example, can be many hours.”

But biomarkers are being developed to accurately determine people's chronotypes. Once tested and validated, chronotherapy “may represent a low-cost, resource-efficient innovation that can significantly improve outcomes: a simple shift in time that opens up a new dimension of precision medicine,” says Ismail-Sutton, who recently published perspective on this approach.