30+ Years in Immunology and This Immunotherapy & Keytruda Finding Still Caught Me Off Guard

Nobody told you this about your immunotherapy infusion. The data will surprise you.
#keytruda #immunotherapy #radiationtreatment

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Episode Description:

Your oncologist scheduled your infusion.

But nobody asked about the time.

It turns out that matters more than anyone told you.

• There's a biological reason checkpoint inhibitors work better at certain times
• The data is consistent across 20+ trials and multiple cancer types
• Not a single study found the other timing to be better

One question at your next appointment could change everything.

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info@elevatingcancertreatment.com

https://elevatingcancertreatment.com

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Disclaimer:
The information provided in this podcast is for educational and informational purposes only, and does not constitute medical advice. It is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have heard or read in this podcast or on this channel.
Reliance on any information provided by Dr. Jay Chaplin or Elevating Cancer Treatment is solely at your own risk. Dr. Jay Chaplin is a scientist and drug developer, not a medical doctor providing patient care. The content presented here reflects general scientific understanding and research, and may not be applicable to your individual health circumstances. Individual medical conditions and treatments vary, and no two situations are exactly alike.
Always consult with your personal healthcare provider before making any decisions about your health or treatment plan.

Transcript

SPEAKER_00 0:00

Alright, in part one of this series, we covered circadian timing for chemotherapy, chrono chemotherapy, morning drugs, afternoon drugs, and why the timing of your infusion matters at a biological level. If you haven't seen that video yet, I'd recommend watching it first. The link is right here. Today I'm covering the finding I teased at the end of that video. And I want to be honest with you, this one surprised even me. And I've been in this field for over 30 years. Hello, and welcome to Elevating Cancer Treatment, where we explain the science and debunk myths to help you navigate your health journey. My background is a little different. Beyond educating about cancer, I'm actually designing new drugs that are defining the future of oncology. This direct hands-on experience offers me a very different perspective of how these cancer treatments work on the body, interact with the cancer cells, and cause side effects. And these are insights that I'm excited to share with you. If that sounds interesting, make sure to like this video, subscribe to the channel, and hit that notification bell so you never miss an update. And please share it if you find it useful. I'm Dr. Jay Chaplin. An important reminder, I'm a PhD, not an MD. The information in this video is education and it's not medical advice. Every cancer is unique and no general information applies to everyone. Please remember that. Always consult with your healthcare provider for guidance on your specific situation. And two quick things. First, as a thank you for being here, I've created a free resource, 10 things to Elevate Your Chemo Journey, which you can download from the link below. And second, by signing up, you'll also get updates on that innovative cancer treatment I'm working on. I'm confident it represents a significant advancement in immunotherapy. So please take a moment, download your free guide, and join us in shaping the future of cancer treatment. So the answer and the surprise is that timing doesn't matter where I expected it to, but it matters enormously where I had expected little difference. Again, these approaches are very well tested with over 20 clinical trials and absolutely consistent results. It's peer-reviewed, it's frequently published in Lancet Oncology, it just probably hasn't made it to your infusion suite yet. This video is for you if you're receiving or planning to receive either radiation treatments or immunotherapy infusions, things like Ketruda, Optivo, or Urvoi. It's also for you if you want to minimize side effects and improve your outcomes. It's for you if no one has ever talked to you about treatment timing, because it does matter. And finally, this is also for you if you're a caregiver trying to squeeze every last little bit of advantage out of the treatment your loved one is already going to be on. So if any of those apply, please keep watching. I review treatment plans, genomics reports, and clinical trial data as part of my consulting work. And I will tell you, timing of treatment administration is rarely documented or discussed in a treatment plan. It just isn't. It's almost never listed as a variable you can optimize. It gets assigned based on the clinic's scheduling and their convenience, not on biology. And that is a big gap, and it's a gap I really want to close for you right now. So let's do a quick review of the biology again to make sure we're on the same page. Every cell in your body, and I mean every single one, runs on a daily molecular clock. There are actual clock proteins in your cells, believe it or not. The master regulators are literally called BMOL1 and clock. There you go. They keep time with remarkable precision, cycling through 24 hours regardless of whether you're awake, asleep, fed, fasted, or in a windowless room for months. They just keep time. Now here's why this matters for cancer treatment. That clock controls approximately 10% of all of the genes in your body. And many of the genes in that 10% are directly involved in things cancer treatment depends on. Specifically, things like drug metabolism, DNA repair, and cell division timing. So when the drug gets cleared, when healthy cells can repair themselves, and when cancer cells are most vulnerable. That's the mechanism for chemotherapy. That's what's happening behind chrono chemotherapy, and it makes a lot of sense there. And I had expected radiation treatments to be as time sensitive for most of those same reasons. So here's the finding I promised you. This is the data that honestly caught me off guard when I first reviewed it. You would think that immune checkpoint inhibitors, drugs like Kitruda Opduvo and Urvoi, would be completely timing insensitive. These drugs have very long half-lives, two to three weeks. Once you infuse them, they're circulating for a long time, months on end. Why would it matter whether you get your infusion at 9 o'clock in the morning or 3 o'clock in the afternoon? It shouldn't, should it? And yet it matters enormously. And the effect sizes are both larger and more consistent than anything I've seen in chemotherapy, chronotherapy. And here's the likely mechanism, not the one that you would have thought, not the one that I thought. So the targets of the checkpoint inhibitors, proteins like PDL1 or the PD1 protein, or CTLA4, those don't particularly oscillate, maybe a little bit, but not a huge amount. Yeah, not a whole lot. So it's not the targets. But the immune cells that actually do the killing, those do oscillate. It's not that they appear and disappear, they move. The CD8 positive T cells, killer T cells, that checkpoint inhibitors are trying to unleash, have a circadian trafficking pattern. They home to lymph nodes overnight and emerge into the bloodstream during the day. They're most accessible for priming by those antibodies during daytime hours because they're out in circulation. And they're most able to home to tumor sites and do their job killing cancer cells during the day because they're already moving. This appears to matter the very most during the first three or four treatments, the initial priming phase, though the effect is present throughout. It's sort of like getting a vaccine. If you get a vaccine at a time point where you have a good response, it primes everything down the line. So the clinical data is striking and very consistent. One study found survival rates going from 38% up to 65%, based solely on whether infusions were given before or after noon. Another study with a much more treatment-resistant cancer saw efficacy go from a very measly 3.3% up to 16.9%. Across more than 20 clinical trials, four major cancer types, and one large pan-cancer analysis. Not a single reversal, not one study where afternoon dosing was better. Morning is always better, with the cutoff appearing to be somewhere around 11 o'clock to 1 p.m., right around noon. A 2024 study published in the European Journal of Cancer, linked below as usual, specifically examining early morning immune checkpoint blockade, confirmed the survival advantage in patients with metastatic cancer of multiple different types. The authors noted that the benefit was consistent across cancer types and drug classes. It didn't matter which cancer, didn't matter which antibody. It always worked. It always worked better to infuse in the morning than in the evening. Let me say that again clearly. Again, we're not talking about a new drug, not a new dose, not a new combination. This is just changing the time of your infusion appointment from afternoon to morning and having in some cases a doubling of efficacy. That is as large or larger of an effect than adding another strong drug to your regimen. Now again, I had expected radiation treatment to also have a strong timing component, mostly because the DNA damage induced by radiation is more easily repaired in normal healthy cells at specific times of day, usually in the afternoon. There is a hint of that effect, but overall there's enough variability between types of radiation exposures, doses given, and specific tissues targeted that there really is no clear and easy result. This is very similar to what we saw with doxorubicin in part one, where there was far too much context dependence to have an easy, straightforward answer. So again, I want to be realistic and very clear about what's actionable here, because I know the way infusion centers work. For immunotherapy infusions, this is the most immediately actionable advice for the most people. Just request a morning slot. Please, just request a morning slot, specifically beginning before noon, every time. If you can't get all of them scheduled early, please try to get the first four sessions scheduled early, as those seem to make the most difference. The data is consistent and the effect is large. There is no good clinical argument for an afternoon infusion of a checkpoint inhibitor if morning slots are available. Now, again, as I said last time, for those of you who are shift workers or night owls, your circadian clock is probably shifted. The times I've given are based on a standard day-night schedule, going with sun exposure. If you do shift work or have severely disruptive sleep patterns, your optimal timing windows are probably shifted. Maybe by several hours, and not necessarily in the way that you would expect. This is a meaningful variable and worth discussing with a physician who understands chronobiology, or you can give us a call. You can track this for yourself by tracking your temperature cycles. Take your temperature once an hour, every hour, for three or four days. Higher temperatures correspond to your daytime hours. Map that onto a normal day, and you can figure out where your morning window actually falls. So, unlike the chrono chemotherapy, for women, the immunotherapy timing effect is not sex-dependent at all. This matters just as much for you as it does for the men. So again, please, women, if you're taking immunotherapies, please request the early infusions. It makes a difference. It makes a difference for you. So, why hasn't your oncologist mentioned this? Again, that's the obvious question, and the honest answer is likely just ease and cost for the infusion centers, for the hospitals. The field requires infrastructure changes, flexible scheduling that most infusion centers really don't have and don't want, because they'd rather spread out workload and staffing, make it even completely throughout the day. If you do that, makes it easier and more straightforward for them. In oncology, changing what time someone gets their infusion isn't as obvious or as easy to explain to a patient as just prescribing a new drug. So they don't really have a reason to do it, they don't really have a drive from you, and it's not an easy conversation, they'll just skip it. But none of that makes it okay for them to leave this on the table, though. This could be a huge benefit for you, and a really easy one. So, the next time you sit down with your oncologist or your infusion nurse, please ask this specific question. Can I move my immunotherapy infusion earlier? That's it. Zero cost, zero additional toxicity, no new prescriptions, just changing the clock and getting better efficacy. Why not ask? If this opened your eyes to a variable your medical team has never mentioned, please like this video. It helps get the information in front of people who really need it. Subscribe if you want Science Ford cancer content every week. And please share this with someone on immunotherapy who has never heard that their infusion time could matter this much. And finally, if you're willing, please leave me a comment down below. Has your infusion center ever offered you a morning slot, or has timing never even come up as a variable? Again, I genuinely want to know how many of you have had conversations about that, and how many have never even heard that timing could matter or that you could adjust it. You can make careful, informed, biologically grounded decisions about your treatment. That's exactly what this channel is here to support. And again, if you missed part one on chemotherapy timing, that video is right here. I'll see you in the next one.