If I understand correctly, this is an infusion of cells that are engineered to kill cells with a certain antigen on their surface along with an injection that makes some non-cancerous cells express that antigen on their surface. Wouldn’t that result in killing a lot of those cells?
My brother made it through CAR-T but ended up succumbing to the effects of a massive tumor that did not respond to the treatment. Essentially all the soft spots and flare ups in his bones went away, but a hard tumor in his abdomen survived. It grew uncontrolled until his kidneys failed.
Part of his treatment was “reseting” his immune system with a leukemia regiment to give the CAR-T a fighting chance to augment the native immune system. I don’t think this new CAR-T would affect the treatment plan, especially since CAR-T is generally prescribed after other treatments fail. CAR-T is a little spooky because sometimes it just kills the patient and they don’t know specifically why.
The big win here is that in January of this year they told my brother there was nothing they could do to treat the hard tumor. Maybe next January that conversation goes differently.
Yes. This makes it significantly better than most existing cancer treatments, which simply kill all dividing cells, thereby killing cancer faster since it divides faster. (Specific cancers have better treatments, but those treatments are one-per-very-specific-cancer and sometimes -per-cancer-per-person, which is very expensive and limited and not available for all cancers.) This treatment targets a type of cancer that is very hard to treat otherwise, and can actually treat several types of cancer!
It's important that the CARVac (mRNA vaccine) part of the treatment targets specifically (though how specific, I dont know) dendritic cells which are "professional" antigen-presenting cells in the immune system. During an immune response, dendritic cells gobble up antigens and present them on their surface to help train the immune system so it's more trying to hijack that (very important) part of the immune response rather than training the immune system (and resulting in the death of the "infected" cells) in the way we're used to understanding mRNA vaccines.
Quoting from it: “ And that's what you see with the intramuscular dose as well: a good part of the dose goes to the liver, but in that case there's a substantial effect in the muscle tissue itself, and it's longer-lasting (out to about a week of protein expression)”
So, yes, an mRNA vaccine (the current ones, anyway) likely causes a fair amount of Spike protein to be expressed in your muscle tissue, but no one has noticed it causing the death of large amount of muscle tissue [0], and despite some searching, I haven’t found any evidence that anyone really understands what’s going on.
[0] People produce cytotoxic lymphocytes that detect bits of spike protein displayed by MHC1, much like CAR-T cells detect whatever they’ve been engineered to target on the surface of cells. Yet CAR-T (sometimes) kills massive numbers of tumor cells, and mRNA COVID vaccines apparently don’t cause the death of massive numbers of harmless cells that took up some of the vaccine. I’m curious why.
It’s been a while since I’ve been deep in the field, but the basics are you’ve got a first order action and a second order action.
T cells in this instance are directly cytotoxic. They find the ligand they bind to, and they begin lysis of the cell to kill it.
Meanwhile the intent of the mRNA vaccines that so many of us received over the last several years was to get B cells pumping out immunoglobulins which would soak up virus, reducing severity/duration of illness and allowing time for the bodies other defences to swing into action.
They’re not the same mechanisms of action (or at least they don’t rely on the same levers at the same strengths). Like everything in the human body, it’s a stochastic process so bits of everything are happening at once
Regardless of the intent of the vaccines, the evidence is fairly clear that they induce a CD8+ response, and the manufacturers seem fairly proud of this fact. Here a paper I found in a few seconds of searching:
We are talking about incurable (refractory) cancer cases in which, after treatment, 95% saw either stabilisation or regression of the disease, and 59% showed significant regression or reduction. This is absolutely awesome news.
Note that this trial is an early trial primarily designed to investigate safety of the treatment. It’s absolutely good news but they need to do a stage 3 trial with a much larger N to convincingly show that it has such a large effect.
As someone who isn't very familiar with how the clinical phase process works, is it fair to say that before Phase 3 clinical trials, companies can cherry pick patients that look like they will respond well to the treatment? and then Phase 3 is more general?
For P1 (which is only to prove safety) this may be the case, but for pivotal studies in P2 and later, participants are almost always randomized so cherry picking shouldn't be possible.
But sure, the study design and primary/secondary endpoints are always levers to increase likelihood of admission. There are often long discussions with the FDA and other regulators on how the endpoints and study population should look like.
Can someone more knowledgeable on the subject please clarify if this proposed therapy requires personalization for each patient or if it can be (eventually) mass produced? Thanks!
There are two kinds of personalization in a [CAR] [T] therapy:
1) using the patient's own cells [personalization of T Cells]
2) customized therapeutic genetic payload, per patient [personalization of the CAR]
There are current competing factions for #1 - where cells are from just the patient ["Autologous"] (safer, slower, more expensive), and where the cells are from a universal donor ["Allogeneic"] (possible immune response, but can be manufactured at scale).
The therapeutic payload is a DNA sequence encoding a synthetic chimeric receptor ["CAR"]. This sequence is customized based on the details of the patient's particular cancer, but are common across many people. If the cancer has an excess of "Protein X" on it, then the CAR sequence is designed to target Protein X. All patients with a similar cancer profile receive the same CAR sequence as a payload to the T cells. This too could be personalized, to not just profile the _class_ of cancer, but particular to that _specific patent's cancer's profile_ - but this is not yet feasible given the turnaround time to build, test and evaluate a new genetic payload in the context of a person's specific tumor cells.
This particular therapy has the cells be from the patient (personalized), but the CAR sequence provided to the cells is common for all people that have the same cancer profile (semi-personalized). In this case, the cancer profile includes those that have an abundance of the protein called Claudin-6.
Somewhat related: I wonder how much next-generation biotech is essentially complete, but waiting in regulatory queues? As a layperson, it certainly felt like we got mRNA COVID-19 vaccines _shockingly_ quickly after governments decided they were a priority. The BioNTech website shows 36 technologies in their pipeline that have passed the "preclinical phase".
Trials take by far the longest time in drug development. During COVID, those went rather quickly not only due to accelerated bureaucracy and practically unlimited funding but also the sheer volume of COVID patients speeding inclusion and event rates up way beyond rates normally seen. Getting enough patients enrolled is easy if you have six figure daily infection rates.
Not an expert at all but I'm preparing to go through assisting someone with CAR-T therapy soon. This is just from what I've seen with their treatments and visits so far.
In the previous chemotherapy it was dosed at regular intervals and they could make adjustments to the speed of the dose, supplemental medication, and maybe dose size(?) but the close supervision was more or less right around infusion followed by 3 weeks without medical care. With the CAR-T we're looking at about a week of 8 hours every day in the clinic, followed by 3 weeks of slightly fewer days each week. In addition the caretakers (family/friends) are to monitor the patient at all other times for signs of cytokine release and the neurological effects. There are steroids used to reduce the impact of both but they need to be applied fast enough. The patient is supposed to be monitored 24/7 for a month, and for patients who live more than a hour from the clinic they have to stay in a hotel and cannot go home.
It seems more serious than the initial chemo cycle but it seems to me that part of that is because they inject the modified cells then just watch.
Following CAR-T studies earlier from Novartis, I recall that cytokine release as an adverse event was also highly predictive of the treatment's efficacy. So terrible as it is, it's also an indication of the immune system at work.
"Four-day extracorporeal blood purification resulted in complete resolution of immune effector cell-associated neurotoxicity syndrome and greater than 95% reduction in interleukin-6 levels without side effects"
I mean yeah, its about balancing risks. I'm guessing that a ~2% chance of a cascade would mean that its not likley to be given as a first like of defence.
In a lot of cases we don't have other first line options. it may be no treatment die in 6 months, standard treatment die in 10 months, or this where 2% die in 1 month but 98% are cancer free 1 year later. All numbers above made up, but those are often what we are dealing with.
Of course where we have other cancer treatments that works well those should be a first line (at least for now - who knows how this will advance), but all too often we don't have good options.
The huge accrued warchest from their Covid-19 vaccine plus the proven creativity and technical expertise of their team makes BioNTech an interesting long-term bet.
As a kidney transplant patient, I'm particularly interested in the latent virus vaccines like CMV, and EBV vaccines. Those who have an organ transplant have to deal recurrence of CMV, EBV and BK virus because they are quite common and latent in the body from past occurrences. I don't know if these vaccine will work on me anymore since I'm already immunosuppressed but there is hope. I'm dealing with both BKV and CMV right now. Treatment is mostly to cut back on immunosuppressants to let your immune systems fight back but that has its own risks. And I never had CMV before while so I'm dealing with those from my donor organ. There are some companies doing trials on antibody treatments right now.
There's also a real chance that the various latent viruses are responsible for some significant percentage of alzheimers, dementia, and general cognitive decline so vaccinating against them is not just good for acute infections.
I think they will come to the conclusion that the benefits of the therapy outweigh the possible risks in this case, in a way they did not for the covid vax.
>Personally most people I know who don't want the covid vax reached that conclusion after weighing the risk/benefit
This has to be a class/geographic thing because all but one of the 2 dozen or so people I have met that told me they didnt get the covid vax(rural area, southern state), said they did so for reasons that revolved loosely around " i dont want the demon-crat drug changing my DNA and causing a WHO mass population culling". You could definitely claim that only those types of people are the ones being vocal about it, but the actual demographic breakdown of opinion on the covid vaccine....
only 40% of Republicans view the covid vaccine as safe, as of sept. 23. last month. they STILL dont think its safe. compared to 80% for democrats, a lot of that likely to due any loading of the word "safe".
It's very hard to say, but IMHO the best thing that governments and public health officials could have done (and could do) with this whole scenario is just ... lay off ... on these people once the majority were vaccinated and Omicron came on the scene and the vaccines were shown not to be "sterilizing" against it. Putting pressure on past Jan 2022 or so simply became counterproductive.
To be clear: I think the vax skeptics/opponents were wrong. I've had every one of them I could get as have my kids. And I've still not caught COVID, over 3 years on (or if I did it was so mild as to be undetectable.) I think the vaccines are great.
But these people have been backed into an ideological corner, and they're behaving like anybody when they're cornered. It is now best to back away, because we are now dealing with another kind of contagion because many anti-vaxxers became ripe pickings for formerly unrelated far right, conspiracy type radicalization.
I think there are many lessons for public health officials here for future campaigns.
There was basically nothing any public official in the US could do to steer the ship in any kind of direction, once the political leader of 75 million Americans had hijacked the entire disease, public health measures to address it, and medical treatments of it, for some pretty over the top and insane political pivoting.
The timeline really highlights the volume of avenues he took that damaged the public health apparatus around COVID.
its no big deal, itll go away soon, i took hydroxychloroquine, masks dont work, "If we didn’t do testing, we’d have no cases", stop shutting down, kids with the sniffles are classified as COVID, and a near constant name drop and slamming of Fauci.
The guy undermined HIS OWN public health officials constantly and turned them into conspiracy scapegoats. The battle was lost well before the vaccine was even released. What did he think his supporters would do when Fauci came out and said "take this vaccine"? Hell, Trump has been supporting the vaccine for at least 2 years now, and even he cant fix the mess he made.
It's a bit more complicated than this (disclaimer: I followed the trials and vaccinated earlier than most).
The current wave of anti SARS-CoV-2 vaccines skepticism has multiple facets and is also country dependent.
First, the risk profile of the disease meant that the best solution would be vaccinating those at risk immediately and leave the rest for judgement of the individual. However, people took the infamous Israeli study about 94% reduction of risk of asymptomatic infection (hence transmission affecting) at face value (the 5MM people from that study weren't swabbed regularly; it was an extrapolation), which meant that some tried to follow the dream of impossible elimination (impossible since March 2020) so they thought everyone needed to be vaccinated. Previous evidence on other CoVs was largely ignored.
Second, many vaccinated to go back to a normal life. Imagine the reaction when those people were faced with more lockdowns, masks, restrictions... Some thought they were made fun of.
Third, the government officials absolutely hated good news as they thought fear was good to achieve compliance, at least in UK and Italy. In Italy, not the nutjobs, but respected members of medical society unwillingly questioned the efficacy of vaccines ("half-work", someone said). This confused the general public even more
Fourth, adverse reactions are to be expected and with loads of inoculations, some are bound to appear even if very rare. Even more with these vaccines which are highly reactogenic. The confused reactions on the AZ vaccines when there were cases of thrombosis were eloquent. Also, risk vs benefit ratio was not considered. Children have very low risks but have a higher incidence of (rare) adverse events. Given this, the ratio isn't favorable, but it was pushed anyway without solid data (the confidence intervals on FDA documents for pediatric versions of these vaccines are horrid).
Fifth, some countries went out of their way to make the lives of those not vaccinating very miserable. In Italy you could not even work without three doses. Children without three doses > 12yo could not take the bus legally. And the whole Canadian truckers matter.
While antivaxxers are a very loud but small minority with no real power (they're extremists) the whole matter was a massive failure at scientific communication. Also because governments wanted to treat citizens like stupid peasants that needed guidance by the enlightened. Well, not all of them, but in Europe there were many.
However, it's impossible to prove that Covid is more harmful than the vaccine in every particular cohort of a population.
Anti vaxxers perceive themselves to belong to a cohort that are less likely to be harmed by the illness, because of youth, behaviour, or physical fitness or luck or religion or whatever.
On the other hand, they have plenty of evidence that people belonging to the same cohort have been adversely affected by the vaccine, therefore it's entirely logical from their point of view to not get vaccinated.
Yes I'd agree that it is impossible to prove something to someone you don't share common ground with.
I'll never be able to prove ghosts don't exist to someone who believes they do.
I might however be able to prove the absence of any evidence for the existence of ghosts, provided that the person I'm speaking to has the same perception of what constitutes evidence.
I don't think the cohort of antivaxxers belongs to a cohort of people that thinks too deeply about what cohort of people they belong to and what cohort of people should take the vaccine vs what cohort of people shouldn't take the vaccine. It's mostly a cohort of people that want to agree with each other so they can all be in the same cohort.
I think human existence is uniquely tragic in the sense that we can see the cancer right there in the CT scan and yet we can’t do anything about it. We can’t point a finger at the blob and tell our brain to get its shit together and ignore the cancer’s mimetic countermeasures. We first have to completely understand how cancer and our body works and then invent magical chemicals to force our body to intervene like we rationally know it should
Nah, the unique tragedy is that some humans want to live forever in a mushy world where everything complicated will eventually crumble and rot. Cancer has been right there for millions of years and the pretty slick biological "intervention" was to just continually be spinning up new generations with a clean slate of cells. It seems to work great on the level of humanity as a whole, and countless tools have been offered to help individuals wrap their head around their individual material mortality. No understanding of cancer or bodies required; no magical chemicals needed; no violated "shoulds" involved.
That you may now stare at a cancer and panic isn't a universal part of "human existence", it's just a struggle that some individuals see themselves trapped in when they've lost sight of the bigger picture.
That's not to say that medical inventions aren't cool, or that they shouldn't be enjoyed, but the starkness of what they're set against is a very personal and subjective thing. What's tragic is that so many people seem cursed to stare at that darkness these days and lack insight into there even being some very robust alternatives to doing so.
I think it's a little weird to assume that's how everything is "supposed" to be just because that's how it's been. There's really no "supposed to"; there's what there is, and what we can do and change and build.
I do agree that some people take this to far: worrying so much about death that they forget to enjoy life, pouring their lives into life-extension measures and leaving precious little time to live. (Then again, the people who pour their lives into life-extension could end up benefiting countless others; how's that for big-picture thinking?) But I'd hardly call it a "tragedy" that humans want to live longer (or even forever).
I don't particularly fear death, I don't think (at least not any more than your average human), but I am supremely bummed out that (assuming humanity doesn't destroy itself first) I'm going to miss out on things like advanced spaceflight, viable long-term colonization of other planets and moons in our solar system, and -- if we can figure out that pesky speed of light issue -- travel to and colonization of other solar systems. And that's without getting into more "out there" stuff like mind uploading and catoms and whatnot. Humanity has so much potential, and we're still a childishly young species that has so much room to grow. To me, the tragedy is that I won't get to see what happens with all that.
I think the bottom line is that we should stop judging people for how they use their time. I'm sure there are some people who would scoff at some of the things you or I do with our time; who are we to criticize someone for working to lengthen the human lifespan?
You responded to a lot of things that I didn’t write and wouldn’t write, but your insights are good at articulating why medical technology and life extension can be so exciting!
If your expectations don't align with reality, only one of those things are substantially mutable. If this misalignment causes you distress, there's only one thing you can do to fix it. It's simply unreasonable to be "bummed out" that you won't get to see the distant future. We're biological organisms with all the limitations that implies, and there's not any substantial indication that will change anytime soon. This leaves the rational you with one option: only allow yourself to be concerned with things you can influence. Your mortality is not in this category.
Yup, and maybe this'll be a help to some. My comment is not pushing back against medical technology, it's pushing back against the idea that human existence is somehow damned to be bleak until some fantastical medical utopia arrives and delivers immortality. You can both enjoy life-extending technology and acknowledge the inevitability of death without all that fretting and drama; many do.
My point is that many people undergoing cancer treatments are trying to avoid having their lives cut short rather than extend them unnaturally. Children with cancer is an example of this, but it applies to adults as well. Dying of cancer before you get to enjoy a full lifespan IS bleak. And not just for the afflicted person, but also for their friends and family.
Once again I want to profusely thank the HN'er who posted the story about BioNTech and their herpes vaccine in pre-Wuhan Flu October 19. At the time of that story, one could invest in its ipo @ $13.
More than proof of concept if they went with such a statement to the press. Also, ongoing Phase 1/2 means that by 5-10 years this therapy may become commercial, the initial target being refractory/relapsing tumours as stated in the announcement. It may take some time for the therapeutic target population to be expanded, but this is not a minimal achievement.
My view is that this being an autologous therapy (the patient's very own leucocytes are being engineered: the entire manufacturing cycle [I speculate 30-50 days] is done for just a single patient), this will be very expensive and probably only covered on an insurance basis in certain countries only. Still better than nothing, and even science has to make money. The real breakthrough will be arriving to heterologous therapies, where healthy donors leucocytes can be engineered and administered to any patient.
In the next five years, how many people will die of a cancer that this could have prevented? Why do we accept this, and aren’t willing to bring it to market faster?
This is only one side of the question. There are thousands upon thousands of potential therapies, all with varying degrees of evidence that they work, with varying degrees of match between the available evidence and the true reality of the potential of that therapy.
We need some process to distinguish between what works and what doesn't work.
The question isn't merely "how quickly can we get this one thing to market" it's "how can we prove that it works as quickly and cheaply as possible, without biasing us to treatments that don't actually work, and with giving all options their proper due."
For a while in machine learning there was a field called "active learning" (might still be ongoing?) that was all about how to choose the most informative questions to ask to learn as quickly as possible.
We face that same question with cancer therapies. Every patien that is on one trial can not be on a trial for a different therapy, so that's one limited resource for how quickly we can learn. But the other limited resource is of course how much we want to spend on validating therapies versus deploying existing, working therapies to a broader group of humans.
Because people can be killed by unexpected side effects of treatments that are incautiously rolled out too soon. People can also die because the money went into treatments that turned out to be ineffective when the resources should have been spent on searching for things that actually worked.
Liability. This is a perverse incentive structure, but it's not an easy problem.
If people die due to your inaction, you are not liable.
If people die due to your actions, you very much are.
Even a minor issue can end up being harmful. If you have a cancer treatment that's safe and effective, but you haven't fully vetted it and it turns out to be less effective than another available option, then your drug would cause harm.
It's safer to test these things, otherwise you get sued, go to jail, your company folds, and nobody gets cancer treatments anymore.
I think it should be allowed that, for people with illnesses that end up inevitably fatal in a high percent range, they be allowed to get early access to experimental medication once it's passed some sort of verification.
Right now, only those very rich have that chance, they pay the pharma companies (and a host of outright quacks)... I'd love to see cancer medication being accessible for everyone, no matter the amount of money on their bank account.
If you have an effective way to streamline trials, I think people would be very very interested in it, regardless of the liability argument (of which I am very very skeptical). Already trials are usually pushed to be as fast as possible, because the patent clock runs out on treatments, so a faster answer is usually the best answer to achieve for investors.
Cancer is a pretty major health concern for most people and the idea of this general treatment is interesting even if it’s understood to be a very hard problem. HN also has a lot of people who have worked in or adjacent to scientific research so I think there’s always an appreciative upvote for something which starts to look like positive results from something generations of scientists have worked towards.
Any major examples? I've heard a lot about animal trials succeeding and then the human trials failing, but would love to read into it if you have any sources.
But what makes this unique versus the hundreds of other early studies that show "encouraging results"? The technique of CAR-T isn't exactly groundbreaking any more with 3 products already on the market. And the ORR of 59% is kinda of in line with current CAR-Ts.
I'm going to ESMO and this would be interesting but certainly not the highlight of the data releases.
Don't get me wrong, this may turn out to be very exciting, but it's very early data, and similar to other development programs has a 90% chance of failing.
Your initial question was why the link was getting upvotes. I don’t think anyone is claiming it’s a medical revolution but a lot of people have or know someone who has been affected by cancer, and anything which offers hope for the future is going to get attention. I don’t mind that, it’s a pleasant change from yet another JavaScript framework.
“BNT211 continues to show encouraging antitumor activity in patients with CLDN6-positive relapsed or refractory advanced solid tumors” <- interesting because they finally demo some effect in solid tumors in humans
“Follow-up of efficacy data at 1x108 CAR-T cells with or without CARVac shows an overall response rate (“ORR”) of 59% and a disease control rate (“DCR”) of 95%, with the CARVac cohort demonstrating a prolonged persistence of CAR-T cells” <- interesting because those are high response rate. Let’s hope it lasts and they can increase those rates but as a patient, you would take this.
It’s interesting to HN because BioNTech uses techniques to update a running (biological) system with analogues of patch files, temporarily lived cellular rootkits, etc.
Because cancer is one of the most common most deadly and least treatable diseases out there. I've lost loved ones / family to cancer. Haven't lost any to Covid e.g.
Whatever we can do to treat the various cancers out there, the better it is for humanity. I'd much rather have money flow in this that in the next financial / crypto scam.
