Immunotherapy drug clinical trial results: half of tumors shrink or disappear
rockefeller.edu475 points by marc__1 4 days ago
475 points by marc__1 4 days ago
https://www.sciencedirect.com/science/article/pii/S153561082...
I’m both sad and incredibly happy to read this. I lost my wife recently to a recurring metastatic melanoma. She was treated at MSK by an amazing team. It was a terrifying diagnosis and literally would have been a guaranteed death sentence in 2017. In 2023, she had a very real chance of pulling through due to immunotherapy. Unfortunately some complications led to the worst outcome and we lost an amazing woman. I remember that my wife said once that the everything she had on that journey was on the shoulders of those before. So maybe in some small way she helped with the research and a future mother, sister, wife, husband, son, dad will have hope where there was none. I lost my wife before they developed sickle cell treatments recently. Knowing the pain she went through everyday, makes me grateful that children soon will not have to know that pain. Thank you for sharing your story. I remember that my wife said once that the everything she had on that journey was on the shoulders of those before. Very true and profound, I'm sorry for you loss, what an inspirational thing to say. That this message passes on is testament to our loved ones spirit carrying on in ours and others hearts and minds That sucks, man. I wish I had something I could say that made a difference. So sorry to hear that. Im not sure the loss gets easier but Im going to start sharing your hope in better future outcomes. I got goosebumps reading your sad story. So sorry, and I hope you recover from this. Having lost my mother to melanoma over 20 years ago, it is very encouraging to see the progress that has been made against this terrible disease. Very sorry for your loss. I’m so sorry for your loss and thank you for sharing your wife’s story. As a husband, father, and son starting treatment for melanoma tomorrow, your words mean a lot. It’s humbling to think of how much today’s progress is owed to courage of those who came before Sincerely, I’ll be thinking of you tomorrow. Best wishes with your treatment, give it hell. Be strong, be well, and always be comfortable asking for help. Best of luck to you. I am a walking, talking, laughing, smiling result of the effects of immunotherapy. I was on Pembrolizumab on a six week cycle across eighteen months, administered at Charing Cross Hospital in London, after diagnosis in early 2022. It effectively dealt with my lung and brain cancer, with minimal side effects. This year, I returned to the gym and am sucking up every last opportunity to extract as much fun as I can with my wife. I am amongst the luckiest of souls, and feel deeply sorry for everyone who is losing to or has lost someone to cancer. That's my wife's current medication. We just had our 6 month CT and her largest tumor was reduced to half it's original size. 10 years ago, this wasn't an option. 5 or so years ago it wasn't a treatment for her cancer (metastatic renal). I'm so thankful this treatment is available and that the genetic testing lined up. My sister was part of an immunotherapy trial years back. She was given weeks to live; the trial gave us years. Tailored medicine is truly a marvel. My mother had immunotherapy treatment last year for lung cancer. It caused a lethal arrhythmia within 24 hours that they could not treat. She was dead by the end of that day. The cardiologist said this was a known side effect (he muttered 5% as she lay there). It's still not a perfect solution. To be fair, not knowing your mother's age or cancer, 5% is right around the mortality rate for major surgery in the elderly too. Things are just dangerous as you approach end of life and there are no good solutions for anything. What are the odds of chemo sucking every moment of joy out of your life and then you die anyway. I think I could deal with 20:1 odds if I had a clean before and after. Tell everyone you love them, hope to see them soon, then take your 95% chance of having an extra few years. That's pretty much what happens when you get a stemcell transplant. Luckily there is steady improvement in the survival rate. This is a very old therapy by now of course. But let's hope the various form of immuno therapy take the same trajectory, getting a little better every year. Hank Green just did a follow-up about a question about “who has the most DNA”, where he back pedaled heavily on his previous attempt to answer. I learned, as he had, that sometimes bone marrow transplants don’t take and one option is to administer another, or several, which could make you much more chimeric than the average stem cell recipient. But I don’t understand how the marrows don’t end up fighting each other in a death match. Is that a special property of marrow? I'm really sorry for you loss (and the way it happened). That said, we all know that these are not perfect solutions. They save some more, they don't save all. Friend was told he had 12 months to live maybe 20 years ago (some rare form of melanoma). Him and his wife committed hard to tons of clinical trials and is still alive to this day and has no indication he’ll be dying anytime soon. He’s the very first patient on a number of studies, which he thinks is pretty cool. Direct study link: https://www.sciencedirect.com/science/article/pii/S153561082... > Fc-optimized CD40 agonistic antibody elicits tertiary lymphoid structure formation and systemic antitumor immunity in metastatic cancer > CD40 agonism enhances antitumor immunity but is limited by systemic toxicity and poor efficacy. Here, we present a phase 1 study (NCT04059588) of intratumoral (i.t.) 2141-V11, an Fc-engineered anti-CD40 agonistic antibody with enhanced binding to the inhibitory receptor FcγRIIB. Among 12 metastatic cancer patients, 2141-V11 was well tolerated without dose-limiting toxicities. Six patients experienced tumor reduction, including two complete responses in melanoma and breast cancer. 2141-V11 induced regression in injected and non-injected lesions, correlating with systemic CD8+ T cell activation and mature tertiary lymphoid structures (TLSs) in complete responders. In CD40/FcγRs humanized mice bearing orthotopic tumors, i.t. 2141-V11 promoted de novo TLS formation, facilitating i.t. CD8+ T cell effector responses independent of lymph node priming. The resulting local immune responses by 2141-V11 mediated abscopal antitumor effects and sustained immune memory. These findings demonstrate that i.t. 2141-V11 is safe and promotes immune-privileged tumor microenvironments that promote systemic and durable antitumor immunity. As a young person with Multiple Myeloma, these articles give me hope but I know a cure is a long way off. I feel like I'm at the stage where Ill be one of the last people to die from it or I'll be one of the first to be cured of it. I'm watching companies like Deepmind with great interest. It's my hope that these AI tools speeds up a cure before it's too late. While promising, be VERY skeptical about efficacy claims of these early stage research drugs. Tons of drugs in the pipeline that goes after these promising receptor targets. PD-1/PD-L1, CD47, CD40 (as mentioned in the article) etc. Keytruda (PD-1) is an incredible success both clinically and commercially, but there are many many other drugs buried in the clinical trial cemetery that initially showed promising results. Medicine is really hard. > but there are many many other drugs buried in the clinical trial cemetery that initially showed promising results Mot many that showed such dramatic results across different types of cancer with very low toxicity. Even if it turns out this drug kills 10% of patients outright, it would still be useful. Can anyone comment on near term success of the prostate cancer trial? Asking for a friend. > The findings have sparked a number of other clinical trials that the Ravetch lab is currently collaborating on with researchers at Memorial Sloan Kettering and Duke University. Now in either phase 1 or phase 2 study, the trials are investigating 2141-V11’s effect on specific cancers, including bladder cancer, prostate cancer, and glioblastoma—all aggressive and hard to treat. Collectively, nearly 200 people are enrolled in the studies. Waiting for the Derek Lowe post, but... if this is legit, it's a 'holy flipping s**' moment. That kind of success in Phase I human trials is incredibly rare. Had to look this up, seems like Derek Lowe is a reputable blogger[0] in this space Look at the photos in the study that show the disappearing melanoma. Incredible. The fact that they were only testing a tiny group of patients (to make sure the treatment would not do more harm than good) with such astonishing remissions for two different very aggressive cancer types warms my heart. With an autoimmune solution I worry that you have to test on a vast number of people to determine the actual safety. And maybe even to come up with a way to determine if a candidate is in an at risk group. And then god forbid it turns out to only work for a couple of major ethnic groups and then is starts to look like eugenics if you don’t immediately plow all the money into creating versions that work properly for everyone else. Low toxicity, effective against many cancers, it's almost unbelievable. If clinical success holds in phase 2 and 3, this is the next Keytruda. The day after tomorrow I am driving 12 hours across three states to get my dog the second shot of his immunotherapy treatment for hemangiosarcoma. It’s only available in trial (this is a yale study). Results for him are too early, but the standard prognosis with chemo is 3-6 months. This feels like we are on the cusp of profound medical breakthroughs treatment of cancer. My thanks to everyone who contributes to this kind of medical and scientific progress. Just remember that you could be at risk for three kinds of cancer. Cancer is the thing that will get you if nothing else does. And then there are the cancers that are truly unfair. That try to jump the line. Go after kids, mothers, professional athletes. If we can fix those, our relationship with cancer will change. Hope those are the ones we can fix first. Or best. why professional athletes? Presumably because they're otherwise very healthy. They are rarely at peak healthy. They are just in peak physical shape. Depending on the sport - strain on muscles, joints, heart (clarifying my earlier Q, addressed to hinckley) "..cancers that are truly unfair. That try to jump the line. Go after kids, mothers, professional athletes" Why group athletes with kids and mothers as "unfair" victims of cancer? Higher sun exposure, extended exposure to chemicals like pesticides on fields, lots and lots of reasons beyond what most people assume (steroid/ PED use). Those tend to be the ones that “get you” at an older age. I’m sure there are going to be a lot of retired athletes interested in the metastatic melanoma results here of course, but bone or testicular/ovarian cancer hitting 25 year olds (eg, Lance Armstrong) is just kinda brutal. And childhood leukemia is the biggest dick of them all. Funded primarily by US taxpayers via 6 NIH grants from the National Cancer Institute and NCATS, with additional support from private foundations including the Robertson Fund, V Foundation for Cancer Research, Breast Cancer Alliance, and Beckman Foundation. My wife had Crohn's disease since a teenager, and was diagnosed with metastatic gallbladder cancer aged 52. A death sentence. She chose to do aggressive chemo to prolong her life from a few weeks to a few months. She suffered a great deal before she died. An immunotherapy treatment was discussed, and it could possibly have helped a lot, but it carried a somewhat high risk of causing a disastrous Crohn's flare that would kill her immediately. The doctor was unwilling to try this because it might kill her. So she died inevitably without it. It was a classic medical ethics case right there in our crisis. We did a lot of interesting and intense things in those months before she died. Fuck. >An immunotherapy treatment was discussed, and it could possibly have helped a lot, but it carried a somewhat high risk of causing a disastrous Crohn's flare I'm really sorry to hear about it playing out that way man. What a horrible dilemma to have to be in. Also, want to ask because I have a few people close to me with Crohns: Obviously there's a lot of nuance and detail in this kind of combination of two illnesses and a specific, very complex medicine, but would you mind sharing a bit more detail of why the immunotherapy was so risky for such a deadly flare? I know immunotherapies are sometimes used to even treat autoimmune diseases, so I'm very curious for this reason too. The problem is that the cancerous cells are themselves descended from healthy cells; other than the small differences that make them cancerous, they are in fact the same thing. Many of the cutting edge immunotherapies for cancer essentially teach the immune system to target the cancerous cells. However, in combination with an autoimmune disease like Chrons where the immune system has already learned to react to healthy cells, there is a much higher chance that an immunotherapy intended to target only cancerous cells also causes the immune system to target more healthy cells. Yes, exactly. The specific risk for Crohn's is that the amped up immune system will rapidly kill ALL the gut cells that they've been pissed about for decades. For the unfamiliar: Crohn's is to guts what eczema is to skin. They are both autoimmune diseases where the immune system attacks a specific kind of healthy cell. Unhelpful. It sounds like the most vicious possible dilemma to find yourself in. Cancer treatment has a way of doing that. I’m very sorry for your loss. One of the hugely important takeaways of this study is that even though the therapy was applied at the site of the most significant tumor, the immune response appeared to trigger against presumably ALL tumors throughout the body. Is that worrisome if they thought they could control bad consequences by keeping the treatment hyperlocal? > “The melanoma patient had dozens of metastatic tumors on her leg and foot, and we injected just one tumor up on her thigh,” Ravetch says. “After multiple injections of that one tumor, all the other tumors disappeared. The same thing happened in the patient with metastatic breast cancer, who also had tumors in her skin, liver, and lung. And even though we only injected the skin tumor, we saw all the tumors disappear.” Bring it faster, I beg you. Defunding NIH and gutting the public research pipeline, best we can do. I am very much against the defunding of the NIH and CDC and I think RFK Jr is a very dumb person who is the worst person on earth to put in a position like that. That said, fortunately the US is not the only place on earth that smart people can work on medicine. It’s frustrating to me as an American to see the republicans so ecstatic to force a brain drain, but these researchers didn’t suddenly lose their knowledge, they’ll likely just move somewhere else and this research can keep going. Of course science can happen elsewhere, but science is struggling to get enough funding already. With a major rich country pulling funds, cancer research worldwide is affected. This particular study was funded in part by an NIH grant: https://reporter.nih.gov/search/3JOZ-0aY0EOBJOb7uLdbzA/proje... and https://reporter.nih.gov/search/3_aBusrtpki2R0Moj7ntjg/proje... Part of the research was also funded by this grant: https://reporter.nih.gov/search/lW12o2Q2CEe6M9PKMITWWQ/proje... and seemingly this grant: https://reporter.nih.gov/search/gjjBtikE4Uuyy875NUyiog/proje... I count $3,043,276 in funding from the first NIH grant plus $10,515,749 from the second. I don't know how where the funds for the "Robertson Therapeutic Development Fund Early Clinical Development Award" and "The V Foundation for Cancer Research" came from and how much of the broader grants were spent on this research, but this particular research seems to have been funded mostly by the USA. This is a good development. Who's going to have access to this medication if it comes to market? Will it be for the wealthy or will the poor have access to it? Some of it depends on the cost of manufacture. If it’s tailored to each individual and scaling it is difficult but the drug is effective then it’d likely be costly. If scalability is easy then it’ll be relatively affordable. If all tumors would randomly grow or shrink, then half of the tumors will shrink indeed. They usually grow :( . Anyway, this is only a phase 1 trial, that is designed to test if the new proposed drug is safe and check the safe dose range. In later trials there is a control group that is important to check how often there are weird cases where the tumors mysteriously shrink. (For example, bad measurement methods, diet change, leftover cure from a previous treatment, a lucky mutation, divine intervention, whatever, a double blind randomized controlled group include all those cases.) My mother is currently battling stage 4 GBM. We are trying out a an immunotherapy vaccine developed Germany. It's still in trials and doesn't cure anything, but if it prolongs her life that would be the best case scenario, so we took the chance. Really hoping to see a breakthrough in immunotherapy drugs in the next few years. Related topic: http://timesofindia.indiatimes.com/life-style/health-fitness... Claims today of "100% Efficacy Vaccine" The russians have been selling Герпетическая вакцина within russia since the 1990s. Is it approved outside russia? No. Is there any real evidence that it works? No. Is HSV cured in russia? No. Were there systematic reviews or meta-analyses in credible journals to support its effectiveness? No. Is there any reason to believe in claims of medical breakthroughs in russia? No. Maybe this is just my Western sensibilities shining through, but is there reason to trust the reporting coming from Russia? I'm genuinely interested to know if that's just my own bias or if there's something to that. It is mostly your own bias, yes. That said publications about cancer breakthroughs ought to be taken with at least as much salt as those in western mass media. Some information about the Russian drug from the main (I think) oncology research institute in Moscow: https://new.nmicr.ru/en/pacientam/metody-diagnostiki-i-leche... I had a quick search and the news is apparently about results of a stage 1 trial and an earlier news article from February guessed it would take at least 2.5 years for this to become available assuming all trials were successful. I have not found any official announcements about results of the trial, only some somewhat shady (mostly-foreign) news sites reposting each other. According to the registry of clinical trials (https://grls.rosminzdrav.ru) the ЭнтероМикс phase 1 trials run Nov 24 - Oct 26 so I strongly suspect this is scummy clickbait reporting, Downvoted. The mental leaps to connect the two are very very large. If you distrust western medicine's process then let's discuss, but trying say we collectively shouldn't because "look at Russia!" isn't it. Out of 12, only 6 saw their tumor shrink and 2 were tumor free. Thats 17% saw a complete response, 33% a partial response and 50% no response. It’s not particularly striking results, though any progress is welcome. University press releases aren’t exactly the most unbiased sources of scientific information. A 50% occurence of systemic improvements across various cancer types is pretty great. If it has only minor side effects when treating agressive cancers, it could be a huge quality of life improvement for patients compared to other treatment options. Worth noting that all 12 were already metastatic cancer patients, so they probably already had a rather low 5-year survival chance. I'm under the impression that seeing even a partial tumor response is pretty striking. As others pointed out, these are stage I trials and these are patients that have had other treatments already. In particular the melanoma patients had already had other immunotherapy - which is known to work for 50+% of cases - so this could help plugging the gap for the rest. I get the impression that the study involved about patients that normally have no chance of recovery. But it's worth noting the relatively low effectiveness means that someone who has the option of using an "ordinary" treatment with a known, higher effectiveness should do so. Please note that these were metastatic patients after unsuccessful earlier treatments, not a random group of freshly diagnosed patients whose tumors would be less aggressive on average. I don't see any reason to be dismissive of this result. It is, indeed, striking to have half of terminal patients respond to a new treatment and two completely healed. It is also striking that this treatment works on multiple cancer types. Overall - striking, yes. N == 1, but I am awestruck. Let us hope that the larger trials won't disappoint us. That's not the way to look at the numbers. First, you'd want to talk about whether the results are statistically significant. Second, when dealing with a fatal disease, people are pretty happy if their odds of survival go up by a few %. Melanoma grows from incredibly fast. Like you can watch it grow fast. That type of response is pretty incredible. The details of each patient isn’t known, and obviously there is a lot of work to do. But this is an amazing result and a future drug will save lives. Watch it grow over what timescale? Visually… a millimeter or more in 3-4 weeks. It accelerates from there and doubles every couple of weeks. > University press releases aren’t exactly the most unbiased sources of scientific information. Can you blame them? They're always looking for funding for their research, and the current climate is not the best. I don't blame them for trying to get funding - but I do blame them for over hyping scientific breakthroughs which leads to headlines where a correlation being noticed is reported as a causation has been discovered and people should stop doing whatever immediately (or start eating some new fad diet) The system is well broken, and the outcome of the over hype is the MAHA movement - people who have not understood the reporting really means "We have found an interesting new avenue of research" not what they hear which is "We've cured disease" which inevitably then leads to "Science is false, they told me they could cure disease, but it didn't, eat more Vitamin C instead" I blame them. The bad headlines didn't star this year, so it's not about the current climate. In the university we don't allow the students to cheat. We don't allow researchers to make creative titles of research papers (in spite I've seen a few) or just lie inside the papers (in spite I've seen a few). So I think the university press office has a responsibility to give a simplified but accurate report. Whom are they lying to? Investors take a look at the data or get professional advice. Grant founding committees read the papers (or at least they shoud) and in particular care more about the grant proposal than the press release. So a bad tite only confuse the layman, that after a few clickbait titles that disappear start to doubt that a university professor is more reliable than the guy from Ancient Aliens. Any treatment with a low likelihood of disqualifying other treatments is worth having in the toolbox. So the question is not percent efficacy but percent side effects. Given this is a phase one trial, and the prognosis of the patients in question, those are still pretty striking results.
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