Administering immunotherapy in the morning seems to matter. Why?

https://www.owlposting.com/p/the-time-of-day-that-immunotherapy

by abhishaike • 1 year ago

239 194 1 year ago

zevets• 1 year ago

This is bad science. Patients schedule when they go to immunotherapy appointments. People who go in the morning are still working/doing things, where once you get _really_ sick, you end up scheduling mid-day, because its such a hassle to do anything at all.

vhanda• 1 year ago

From the article -

this paper was not a retrospective study of electronic health records, it was a randomized clinical trial, which is the gold standard. This means that we’ll be forced to immediately throw away our list of other obvious complaints against this paper. Yes, healthier patients may come in the morning more often, but randomization fixes that. Yes, patients with better support systems may come in the morning more often, but randomization fixes that. Yes, maybe morning nurses are fresher and more alert, but, again, randomization fixes that.

tines6• 1 year ago

What does randomization mean in this context, and why does it fix those problems?

leereeves• 1 year ago

Yes, maybe morning nurses are fresher and more alert, but, again, randomization fixes that

How does randomization fix that?

gus_massa• 1 year ago

How many dose this treatment has? How many between them?

How many patients dropped out? (Or requested a schedule change) Do they count like live or dead?

vibrio• 1 year ago

"Forced to throw away" biases is strong. If run well, RCTs surely help manage potential biases, but it does not eliminate them. The slides saw available on X-itter didn't show a Consort diagram (accounting of patient count between screening and endpoint) or the balance of patent characteristics between the arms. This seems to be a single site study, which is significant caveat IMO. The lack of substantial mechanistic explanation, and alleged study redesign mid-stream are also caveats. All that said the reported effect is very large, and I'd like to see a more detailed reporting and analysis. If the effect that size is real, it should be able to be found in some relatively quickly retrospective studies (yes, many caveats there, but that could probably provide very large numbers rapidly in support of the RCT).

majormajor• 1 year ago

I always have seen mid-day appointments as also a luxury for those doing well (at least professionally/financially). If you have to go first thing in the morning, it's often because your boss wants you in relatively early and won't let you take time mid-day. If you're in a position where you can go in at 2PM and not have to sacrifice sleep to do so, that feels healthier.

Given the highly-evident strong circular nature of the body, a hypothesis that it has something to do with that seems highly likely, certainly worth following up on.

detourdog2• 1 year ago

I can schedule appointments whenever I want. I'm an early riser and prefer my appointments first thing in the morning.

JumpCrisscross2• 1 year ago

mid-day appointments as also a luxury for those doing well

Irrelevant to this study given randomization.

pbhjpbhj2• 1 year ago

Surely your boss legally has to let you attend a health appointment? Though they might not have to pay you. That seems like a very basic workers right, the sort of thing you'd have a general strike over if it didn't exist??

munchler2• 1 year ago

The appointment schedule was randomized, so your objection is incorrect.

abhishaike• 1 year ago

Writer of the article here: randomization fixes most of this, but the other commenters are correct in that doesnt fully account for the clinic performance (e.g. nurse performance, which does dip during the night according to the literature). I previously thought it wasn't a major issue for clinical trials, since a separate team independent from the main ward are giving the drugs, but there isn't super strong evidence to support that. I will update the article to admit this!

This said, I am inclined to believe that this isn't a major concern for chronotherapy studies, since I haven't yet seen it being raised in any paper yet as a concern and the results seem far too strong to blame entirely on 'night nurses make more mistakes'. Fully possible that that is the case! I just am on the other side of it

rendaw3• 1 year ago

I'm doing CedarCure. You're required to not exercise or bath/shower for 2h after taking, which is fairly difficult in the morning, so I asked the doc if I could do it in the evening instead (despite explicit instructions to do it in the morning). The doc said it was fine, confirmed by the pharmacist.

I should know better by now than to trust doctors to act based on research and not gut feeling, but I hope this doesn't mean the last year of taking it was a wash...

detourdog2• 1 year ago

I looked up CedarCure and what I found is that it is a pesticide. What is the treatment about?

rendaw3• 1 year ago

It's an immunotherapy drug for cedar pollen allergy.

iamtheworstdev2• 1 year ago

looks like a sublingual immunotherapy treatment for allergies to japanese cedar pollen.

tines6• 1 year ago

OP is an insect going in for assisted suicide.

annoyingnoob• 1 year ago

https://synapse.inc/medicine/9101/

justsomehnguy• 1 year ago

There is always an option what taking it in the evening is magnitudes better than not taking it in the morning at all because you skipped it because you need a shower.

Always remember what you are just an another patient with your own quirks.

tialaramex2• 1 year ago

For the drug I take every day (Levothyroxine), research found that evening was worse, but the explanation was poor compliance - people forget to do it more often compared to the morning. Same reason the contraceptive pill is less effective than you'd expect in real populations, compliance is poor. If you're the sort of person who can actually take it on time, every day, without fail, it's extremely effective, if you aren't, not so much. The choice to include "dummy" pills is because of improved compliance - remembering to take it every single day on the same schedule is just easier, so adjust the medication not the instructions.

iamtheworstdev2• 1 year ago

a brand new study comes out and you're mad the doctors didn't know about it a year ago?

do you carry any of the blame on yourself since you knew there were explicit instructions but apparently waiting to shower or exercise was too much of an inconvenience for you?

tomcam4• 1 year ago

Where did they say they’re mad?

rendaw3• 1 year ago

If the medicine instructions didn't state that they should be taken in the morning it might be reasonable, but presumably the producer had some reason for including that instruction. Furthermore, the linked study implies that this effect was suspected before but not confirmed - it's possible and even likely that the CedarCure makers knew this and specified the instructions as such.

There’s a really interesting phenomenon in the immunotherapy field that has been going on for what seems to be several years now
All of this culminated in a really incredible review paper

(review paper references papers from multiple years prior)

And no, it's absurd to imply I do carry blame here. I'm not a medical professional and that's exactly why I asked two specialists for help understanding the criticality of the instructions... that's the point. Even if they didn't know, they could have deferred to the written instructions rather than coming up with an original conclusion.

mjevans2• 1 year ago

Explicitly clear, but otherwise not overly specific, medication instructions would be best.

Say exactly what matters.

E.G. 'Take once a day at a similar time.' VS overly specific but not required 'take in the morning / evening / lunch / some other assumption that doesn't matter.' HOWEVER maybe "Take once a day with your first (full) meal." OR "Take once a day with your primary meal." might make more sense for medications that interact with food.

Nevermark• 1 year ago

I could do it in the evening instead (despite explicit instructions to do it in the morning)

Have either you or your doctor identified the reason for the morning recommendation?

Maybe restart consideration of timing there?

Doctors are going to take your practical need to break one part of protocol, to maintain the rest of the protocol, seriously. They can't resolve the practicalities of patients' lives.

HexPhantom5• 1 year ago

Yeah, that tension between convenience and protocol is so real and frustrating

aitchnyu2• 1 year ago

From a lazy search, the measures are to trigger a reaction, but not intense enough send you to hospital. Fasted state (first thing in morning) can enhance absorption and avoid interference with food. (hot) showers cause vasodilation and exercise causes increased heart rate, both which increase allergen absorption enough trigger adverse reaction. If you have taken it for a year, your doctor may probably not worry about a too-intense reaction.

I'm also taking dust mite immunotherapy and assumed this article applies to me.

amluto• 1 year ago

If the reasoning in the OP is right, then one might infer that the evening is the right time to take it. The goal of cancer immunotherapy is to convince your body to treat the cancer as harmful. The goal of allergy immunotherapy is to convince your body to tolerate allergens. If you are more likely to consider antigens harmful in the morning and tolerable in the evening, then evening is better.

As a giant confounding effect, it seems that allergy immunotherapy might work, at least in part, by convincing your body to make large amounts of IgG antibodies to the allergen, and IgG antibodies are in the “kill it but don’t sneeze at it” category, which isn’t same thing as having your T cell population tolerate the antigen.

uselesswords7• 1 year ago

I think you are misunderstanding a couple of things. The label for Cedarcure doesn’t have timed dosing, just says take it during the day. Furthermore this research article would actually indicate it’s better to take it in the afternoon for your particular drug, if there really is any connection. Which is still a crazy connection to make because you are complaining about a specific immumotherapy regimen finding not being applied to an allergy-style medication. Why not apply this logic to every drug that interacts with the immune system (which is all of them)? Furthermore as other comments pointed out, you’re mad your doctor didn’t know about a brand-new study that didn’t exist when they made a recommendation?

Doctor’s have a wide discretion and often get things wrong. But in your case, that’s not what happened. If anything your doctor actually got it right either by chance or intuition.

jmward01• 1 year ago

I wonder if other basic processes could be at play here like when patients go to the bathroom. If you do this in the morning they may be more likely to not need that for a while while in the evening they may do that immediately. I'm not saying this is the mechanism, just pointing out that there are a lot of timing dependent things in a person's schedule that could be a factor here. It is a great thing to point out though. I hope a lot more research goes into the idea of timing and integrating medication into a schedule most effectively.

HexPhantom5• 1 year ago

We tend to treat the body like a static system when it's actually dynamic across the day

unnamed76ri2• 1 year ago

I used to be on a chemo drug and had to take folic acid every day to stop it from doing bad things to me.

I had awful ulcers in my mouth from the chemo drug and had been taking the folic acid in the morning. Through forgetfulness I ended up shifting the folic acid to the afternoon and the ulcers went away and never came back.

tomcam4• 1 year ago

Thanks for sharing, and I’m very glad you are here to discuss it.

HexPhantom5• 1 year ago

How many side effects people just accept because no one thought to tweak the schedule

cenamus• 1 year ago

And to think about how often such things are figured out individually, but go unnoticed, because there's basically 0 chance for the average person to get anyone to do a study on it.

Laaas• 1 year ago

Light affects us deeply. Very probably true for more than immunotherapy.

NotGMan• 1 year ago

Perhaps it's due to overnight fasting, that people in the morning don't eat yet/as much?

Autophagy is increased during fasting, it usually takes 3 days of water fasting to fully ramp up to its maximum, so no food overnight might just slightly start it up.

I watched a youtube video of guy who did low carb and fasted at least 24h before and after chemo (or even 48h, forgot which) and he didn't experience the negative side effects of chemo as much.

levocardia2• 1 year ago

Hazard ratio of 0.45 seems implausibly high, especially when it's just the exact same treatment dichotomized to before/after 3pm. My money is on something other than a real circadian effect: either the result of a 'fishing expedition' in the data, or some other variable that incidentally varies by time of day. Maybe breaking randomization, leaving the drugs out for too long at room temp, etc. If you really believe this is an important and biologically plausible effect it should be a top candidate for a replication attempt.

trhway2• 1 year ago

some other variable that incidentally varies by time of day.

glucose level? low in the morning, and cancer likes glucose (among other effects of low glucose a cancer site would probably have lower local acidity, and the high local acidity is one of the tools used by cancer to protect and spread itself) .

levocardia2• 1 year ago

AM/PM glucose differences are probably going to be swamped by mundane stuff like who has a snack before treatment vs. who doesn't. Are you not supposed to eat before immunotherapy? If so, maybe (non)compliance with that requirement is what's underneath.

egocodedinsol2• 1 year ago

Here’s a link to the abstract: https://ascopubs.org/doi/abs/10.1200/JCO.2025.43.16_suppl.85...

apparently it was prospective and randomized. I’m a little shocked by the effect size.

munchler2• 1 year ago

This paper was not a retrospective analysis, it was a randomized clinical trial.

egocodedinsol2• 1 year ago

Yeah I’m checking - I saw several other oncologists suggesting song a separate discussion.

raylad4• 1 year ago

My father was on chemotherapy with fludarabine, a dna base analog. The way it functions is that it is used in DNA replication, but then doesn’t work, and the daughter cells die.

Typically, patients who get this drug experience a lot of adverse effects, including a highly suppressed immune system and risk of serious infections.

I researched whether there was a circadian rhythm in replication of either the cancer cells or the immune cells: lymphocyte and other progenitors, and found papers indicating that the cancer cells replicated continuously, but the progenitor cells replicated primarily during the day.

Based on this, we arranged for him to get the chemotherapy infusion in the evening, which took some doing, and the result was that his immune system was not suppressed in the subsequent rounds of chemo given using that schedule.

His doctor was very impressed, but said that since there was no clinical study, and it was inconvenient to do this, they would not be changing their protocol for other patients.

This was around 1995.

sixo• 1 year ago

Amazing. And shameful (for them.)

ch4s34• 1 year ago

It’s not shameful, it’s how evidence based medicine works. One case is interesting but not a basis for changing a protocol by itself. Tons of things could have influenced the outcome and you need a proper study to know that.

vkou5• 1 year ago

And shameful (for them.)

1. A single positive outcome with N=1 should generally not be the basis for making a medical recommendation.

2. It takes a mountain of research work to go from that to a study that you can draw meaningful conclusions from.

3. The hospital is not in the business of doing research, it's in the business of treating patients.

bravesoul22• 1 year ago

What's the p value? 0.5?

irrational• 1 year ago

Is it the time of day or how long the patient has been awake that matters? It seems like someone could change their sleep cycle to match the doctors schedule if the latter.

HexPhantom5• 1 year ago

It's frustrating (but not surprising) that even with a clear positive outcome, the system couldn't adapt without a clinical trial to back it up

taneliv• 1 year ago

Isn't it also quite understandable? Otherwise we risk the new way working well for half the patients and killing the other half, to exaggerate.

bloqs• 1 year ago

As a younger person what are the best habits to get into to maintain optimal long term immune health?

ReptileMan• 1 year ago

Normal weight and enough sleep.

throwaway290• 1 year ago

Don't compromise it chronically. Protected sex etc.

goda90• 1 year ago

Sleep, exercise, a balanced diet of mostly whole fruits and vegetables, and a moderate amount of whole grains, legumes and fresh meat/fish/eggs if you're not choosing a vegan lifestyle. Avoid ultra processed foods, cured meats, alcohol and other recreational drugs. Make sure you get enough vitamin D, which can be hard with certain diets if you're not supplementing, or getting the right amount of sunlight(latitude and time of year matters).

Try to stay low stress, spend time out in nature, maintain good relationships, etc.

Edit: caveat to spending time out in nature: be vigilant of ticks. A tick-bourne disease can mess up your immune system pretty well

stronglikedan• 1 year ago

Don't be a germaphobe. Don't wash your hands a lot. Give your immune system a little work out each day by not babying it.

Try not to take any medicines unless you absolutely need them, and stay away from hand sanitizers. If you do need to clean anything, soap is more than enough and water is usually enough.

I thought it was normal to be over 50 and not take any medicines, but all the doctors and staff were surprised by this when I got my colonoscopy recently.

mschuster91• 1 year ago

- Get vaccinated fully and regularly. Any kind of infection is much harder to deal with for the body than a vaccine. Particularly important are the measles and Covid shots, an infection with either of the actual pathogens can wipe out your immune system history and you lose a lot of protection.

- practice safe sex, get tested regularly (even if both you and your partners are exclusive) and get that HPV shot. Yes, even if you're male. Cancer on your bits ain't pretty.

- keep the drug consumption reasonable, especially smoking and alcohol

- the better quality the food, the better your health. Should be a no-brainer and I know about food deserts, lack of time etc

bregma• 1 year ago

You want to live a long time? Avoid any of the things that make it worthwhile.

jcims3• 1 year ago

You were obviously on to something and it's frustrating yet completely expected to see all replies with pat dismissals that anything like this gets when there is some real potential innovation in healthcare.

Google 'chronotherapy' with some chemo/cancer/immunotherapy related terms and you'll find a ton of research being done. Given that most of it seems to have evolved in the last 8 years my guess is that the concept was 'vetted' by a nobel prize in 2017 for molecular circadian clock, so people feel safe putting their name on studies in this area.

refulgentis• 1 year ago

? The other replies don't dismiss it...

Gravityloss• 1 year ago

I've heard similar things about fasting.

BDGC• 1 year ago

If you’re interested in circadian biology, which underlies chronoimmunotherapy, please check out UCSD’s BioClock Studio. We create tutorial videos and other media to teach circadian biology concepts: https://bioclock.ucsd.edu/

owenthejumper4• 1 year ago

Sicker patients get emergency treatment in the hospital in the afternoon while healthier ones in the morning in the clinic

Spooky233• 1 year ago

Cancer treatments typically don’t happen in an inpatient setting.

owenthejumper4• 1 year ago

Of course they do

anthuswilliams• 1 year ago

The article is reporting on randomized clinical trials, which are not subject to this dynamic.

georgeburdell• 1 year ago

Not a medical doctor. Does this also have implications for other immunotherapy like allergy shots?

parsabg• 1 year ago

I wonder if the same would also be true for immunosuppressants administered for autoimmune conditions. Given they mostly interact with the signaling pathways, I guess in theory they should also be more effective in the morning if there is more immune cell activity going on.

more_corn2• 1 year ago

Because the immune system sleeps at night and wakes up in the morning?

Kiyo-Lynn2• 1 year ago

I once accompanied a family member through immunotherapy. The treatment times were mostly arranged by the hospital, and the doctor suggested doing it in the morning. We just thought it was to avoid the afternoon rush. Looking back, though, they really did seem to feel better with morning treatments. Now I realize the timing itself might actually affect how well it works. I really hope that in the future, doctors will consider not just the drug and the dosage, but also when it’s given.

Spooky233• 1 year ago

They do - for metastatic melanoma, the goal is before 4:30, which is linked to higher survival rates.

Kiyo-Lynn2• 1 year ago

I didn’t know there were already examples like metastatic melanoma where the timing is clearly defined. It makes me wonder if other treatments could also benefit from getting the timing right. Thanks for sharing this. I’ll definitely look into it more.

EricPhy• 1 year ago

“Let’s pretend you have very early-stage cancer. The dendritic cells are in their normal cycle of desperately presenting tumor fragments to T cells, the T-cells rightfully getting upset, activating themselves, and going off to hunt the cancer. But cancer simply shuts them down by expressing an immune blocker protein: PD-L1. In response, the T-cell mostly shuts down, wanders back to the lymphatic system, and gets a little bit more ‘exhausted’. It believes that it activated itself for no reason, and thus will require a much higher bar for doing anything else in the future. The more times this occurs, the more exhausted the T-cell becomes, the more unwilling to ever activate again. In the limit, it will simply kill itself. Hence why you need immunotherapy to revitalize these cells!”

That’s a powerful analog for depression and burnout in humans.

cluckindan• 1 year ago

And not necessarily just an analog, given how there is an immune component to stress.

agumonkey• 1 year ago

Yeah, so many things use the same memory response curve to adjust their behavior, but that model can fail rapidly in these conditions. Very interesting to read though.

HexPhantom5• 1 year ago

In a way it feels like we're scratching the surface of a new layer of treatment optimization

OrderlyTiamat• 1 year ago

They changed the study target effect (which hour range), design (interventional vs observational) and inclusion/ exclusion criteria multiple times.

I don't really care at that point what their conclusion says, because I have no idea how to interpret the statistics in a theoretically sound way now.

Noelia-• 1 year ago

A while back, a colleague told me his doctor always scheduled his immunotherapy infusions for the morning, saying it would be more effective. I thought it was just something they said, but seeing all this new data, I’m realizing there’s actually real science behind it.

aitchnyu2• 1 year ago

If a hospital cannot serve everybody in the morning, should they create a dorm with only artificial light that has sunrise at 12 pm and sunset at 12 am to shift circardian rythms?

pmlnr• 1 year ago

Body meridian clock, that's why.

s1mplicissimus• 1 year ago

tl;dr

Administering immune system related drugs in the morning improves success rate. This is because the immune system is more receptive in the morning, due to evolutionary adaptation. The authors even seem to have isolated the gene sequence that leads to the "sensor" which generates the necessary "data" for the immune system to optimize on.

Really cool research imo

ImHereToVote• 1 year ago

Fasted state?

Administering immunotherapy in the morning seems to matter. Why?

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