Can your body’s biological clock determine how receptive you will be to treatments and therapies? Some evidence suggests yes. A number of recent animal studies and early clinical trials have shown that certain medical interventions, from vaccines to immunotherapies, can be more effective when timed to a person’s circadian rhythm, the body’s internal clock that drives essential biological functions such as sleep, eating, metabolism – and immune activity. And researchers are trying to harness the connection between circadian rhythms and the immune system through an approach called chronotherapy.
“Everything you’re looking at is probably oscillating to some degree in your body, and almost any drug you can think of will probably benefit some time in the day,” says Zachary Buchwald, a radiation oncologist and physician-scientist at Emory University.
Buchwald is currently leading a study on timed immunotherapy for people with skin cancer called the TIME trial. He and others are trying to understand whether there is solid biological evidence to make the case for customizing therapies based on a person’s unique circadian rhythm—or finding ways to change their internal clock to ensure that treatment works effectively. Scientific American spoke with Buchwald about how circadian rhythms are linked to the immune system, what ongoing clinical studies are investigating and what potential limitations the field must consider if timed therapies become the norm.
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(An edited transcript of the interview follows.)
Tell me a little about the history of chronotherapy.
Much of this research was carried out by many other investigators who have been working on this for decades. The paper I came across that got me particularly interested in this topic was from a colleague of mine named Christoph Scheiermann in Geneva. He showed, in mice, that there are fluctuations throughout the day in where the immune cells are located. If you think of the immune parts of the body as different compartments – the blood and the lymph nodes – at one point in the day, there are more white blood cells, or T cells, in the lymph nodes. And then, 12 hours later, there are more immune cells in the blood. So it fluctuates in a 24-hour circadian cycle.
This finding has been confirmed by others and shown to some extent in humans. To confirm that in humans, you’d have to take out lymph nodes serially over a 24-hour cycle, which we don’t do for obvious ethical reasons. But you can draw blood many times in a 24-hour cycle, and there are changes linked to the time of day: data show that the frequencies of different T-cell subsets in the blood fluctuate throughout the 24-hour cycle.
How did you become personally interested in investigating these time-related effects for cancer treatments?
I had studied lymph nodes quite a bit in the lab, and we’ve known that the lymph node that drains the tumor is very important for response to immunotherapy and cancer. And lymph nodes are super important for the response to anti-PD-1, which is a widely used antibody that helps stimulate the immune response against cancer.
In Scheiermann’s mouse study, he also showed that if you synchronize the timing of a vaccine with the circadian-induced peak of T cells in the lymph node, it leads to a more robust immune response. I was fascinated by it.
Given these findings, I hypothesized that something similar might happen with antibody administration for the treatment of cancer. To test that idea, we did a very simple retrospective analysis and asked the question: If patients receive more of their antibody infusions at a particular time of day, do they live longer? We published the first study in Lancet Oncology in 2021. It showed that if patients receive several of their infusions very late in the day, they live for a shorter time.
“I wouldn’t be surprised if there are many other research areas and contexts where circadian rhythms could have significant implications.”
—Zachary Buchwald, oncologist, Emory University
What is the basis for TIME test are you running now?
It is a phase 2 randomized trial for patients with advanced melanoma receiving an immunotherapy called ipi-nivo, or ipilimumab plus nivolumab – two drugs that are standard treatment for patients with that diagnosis. Participants are randomized to one of three time blocks during the day, which dictate when the drug is infused into the arm. The three time blocks are 08:00 to 11:00, 11:00 to 14:00 and 14:00 to 17:00
I have no data to report yet, but I would say patients seem very receptive to the question being asked.
So if people get the therapy later in the day, how might it affect them? What about people who have circadian rhythms that favor a night cycle?
The short answer to that question is: I don’t know. But the longer answer is this: in the first retrospective studies, we included all 299 participants. And even though we took a broad population of people – without any data on their circadian rhythms or sleep habits – we still saw a significant effect. It suggests that person-to-person variability may be important, but the effect is still large enough to overcome person-to-person differences, at least in the earlier retrospective analysis. In our randomized study, we collect individual daily data on all registered patients, so hopefully we can get more answers.
How does the circadian rhythm affect other types of diseases?
Because I am an oncologist, most things that enter my mind are in the field of oncology. There are patients who receive what is called cell therapy, which is an infusion of immune cells to fight cancer. In another paper from (Scheiermann and his colleagues), they showed, in mice, that the time of day they infuse the immune cells seems to make a difference in how well the cells get into the tumor. Very nice articles have also been published about bone marrow transplants and the importance of time of day.
John Hogenesch (a chronobiologist at Cincinnati Children’s Hospital) is very well known in this area for trying to implement circadian findings in clinical scenarios. Specifically, he has worked on changing the lighting in (hospital settings) to fit more appropriately with a patient’s underlying circadian rhythm. I am not involved in this work, but the goal is ultimately to align medical care, in general, with the inherent circadian rhythm we all have, and that can include the environment a patient is exposed to, but also the medications the patient receives.
I would not be surprised if there are many other research areas and contexts where circadian rhythms can have significant implications.
What are some of the limitations of the research that researchers still need to address?
I think there is a healthy amount of skepticism about whether this phenomenon is real – whether timing antibody administration with your own circadian clock can affect response to the drug. And I think that skepticism is based on solid assumptions and ideas about how the antibody works. For example, if the antibody has a very long half-life (time in the body), why does it matter when you infuse it if it’s going to be floating around for several circadian cycles? But that idea, while valid in one context, does not fully address how the antibody might interact with the T cells within a 24-hour cycle. If the data shows that there is no effect, then there is no effect. But if it is, I think it’s an area that hopefully others will be interested in pursuing.
What can chronotherapy look like in hospitals and clinics? What judgments must clinicians still make?
We and others in different countries at different institutions demonstrably show that earlier infusion is associated with better outcomes for patients with different types of cancer. If that’s the case, I’d imagine there would be a broader push from at least some clinicians and, most likely, patients to get infused earlier in the day. This is going to create a significant logistical problem for infusion centers around our country and, potentially, around the world. It can also exacerbate socio-economic disparities, because people with poorer means may not have as much flexibility to come at a particular time of day – or may only come later in the day.
The broader, long-term goal, in my mind, is not just to find an optimal time of day to infuse medication, but to actually find a way to medicate the circadian rhythm itself so that a patient can come at any time of day.
