The paper published in Nature is paywalled past the first page, but is available in full on scihub using DOI 10.1038/s41591-018-0040-8. NCI press release is at [1] and links to clinical trial info at [2].
Articles related to immunotherapy and TILs/CAR-T cell have been appearing in the mainstream media for the past five years. And each one of them has hailed one or two miracle cures.
For patients (as well as their immediate caregivers) who are dealing with advanced/metastatic breast cancer, these articles tend to do more harm than good. The reason is because for an informed patient who is vulnerable, such pieces tend to strongly start influencing treatment decisions.
My sister completed her journey with advanced breast cancer in April. And she was on immunotherapy for 8 months. She was also evaluated for TIL based treatment at MSKCC.
An earlier extremely similar article had strongly influenced our decision making. Now we realise that information such as this influences families a lot. I really feel the tone and underlying theme of the article should not be to convey it as a revolution. There is a reason why certain thresholds of success are built into clinical trials. Articles such as these should be written by guest oncologist and not journalist, as they tend to overemphasize the optimism and underplay the risks.
What's interesting about this approach (TIL expansion) relative to other leading cellular immunotherapy approaches (CAR-T/NK and TCR) is that it doesn't rely on gene editing. Long term, I think genetically "programmable" cellular immunotherapies are more likely to win (e.g. because they can be programmed to overcome tumor immune suppression), but it's impressive that a durable response is achieved here with clonally expanded TILs.
My Mom was diagnosed with two kinds of stage III lymphoma just after Christmas last year. She started chemo a few months ago. Three treatments in, all of the tumors were no longer visible in a PET scan.
I'm still trying to emotionally accept that the nightmare is over. It seems almost too easy, like it's just setting us up to let us down. It can come back, of course. But she's in remission now and totally done with treatment.
Whenever I think of oncologists, I always imagine how much it must suck to tell people they have cancer every day. I'd never really considered the other side of that. To get to tell someone you have completely cured them of a disease that would surely have killed them. It must be an incredible feeling, like beating Death at his own game.
I imagine the joy is tempered by the lack of 100% confidence. "Your cancer is gone...but we really can't say that it won't reappear, because we can't say if ALL the cells are gone, they are just too few for our technology to see. So go forth and be joyous and I definitely won't be nervous that this all turns out to be false hope that results in you back here again, feeling doubly betrayed".
There was a thread on reddit a while back asking cancer survivors what the worst part of it was. One person said that when they got diagnosed, it brought a black cloud into their family that will never leave. Even in remission, it will always be there in the back of the minds of their loved ones, forever.
I understand this personally but I temper those thought by the fact that anyone can be killed randomly by anything at anytime. So live each day regardless.
A creature can not live with this realization not supressed.
You cant take credit.
You cant have a loved one go on a journey alone.
If you where fully aware of you mortality, you would cower in a bonker like a nomad crab in its shell.
Maybe one would storm outside from time to act in fits of panic.
And yes, those edgy adults, claiming to be aware of death/mortality and accpeting, usually have created lightning rods in theire conciousness for these fears.
Like believe systems, that reroute this fear into believe of immortality, or in the atheist case a feeling of superiority for living your life to the max, while all those others do not. Those fully aware are in asylums
This is true of any cancer treatment. You're never cured of cancer. You just go into remission. The 5 year mark has historically been the point when complete remission is deemed a cure, but that doesn't mean recurrence is impossible.
At the limit though this argument works for broken legs too. Oh sure the leg seems better now, but it could break again. I think with a broken leg you'd accept that's just a different break, even if it's the same leg.
I had Hodgkin's Lymphoma many years ago, in my final follow up they said the radiation damage means there's a higher than normal chance I'd get some entirely different cancer later in life, but as to Hodgkin's there's no difference from the rest of the population. If I get Hodgkin's again it isn't because the treatment stopped working, it just means the same or similar freak DNA change happened. Like if I broke the same leg again.
I don't know about other cancer types but around here they do that for non-hodgkin-lyphoma. The first two years after remisson the screening is every 3 months. Year 3-4 every 6 months and year 5+ once every year.
Yep. Last year my mom's cancer returned two years after she was told she only had an 8% chance of recurrence. She's at least lucky in that it's apparently a non-aggressive type that can be treated with meds that have minimal side effects. Unlucky, however, since (barring new treatment options) she'll need to continue treatments for the rest of her life.
Just like a weather forecast, the prediction was right. Your mom just happened to be one of those 8 people who get it out of every hundred. Doesn't feel like it though.
My mom had small cell lung cancer 10 years ago. She died in about 4 years, there was no immuno-therapy available for her then. This kind of thing is a miracle. It's another sign for those that need them that we do get payoff for decades of cancer research. It's really why we need to support fundamental research. We have put a lot of resources into cancer, will we be able to apply them to other areas, or move funding over eventually? Many kind of psychological issues are thought to have significant brain functioning causes or at least impacts, I hope we can eventually make similar progress there. Or on diabetes or whatever.
I'd have given anything to help mine. I'm happy your mom was able to get that treatment.
This is also why we should have low marginal tax rates, including for the wealthiest. Immuno-therapy tech was basically angel invested by Facebook's Sean Parker https://www.parkerici.org/our-model/ It is important for society to have significant resources outside of the control of politicians and bureaucracies.
Imagine in the near future [+] when telling someone they have cancer is the same as telling them they have strep throat: a minor inconvenience. We're still in the dark ages of treating cancer (ie radiation, chemo, and surgery).
You could be right; it's totally possible that in 20-30 years telling someone they have [antibiotic resistant] strep is the same death sentence as telling them they have cancer.
We'll be eating genetically engineered meat. As in lab grown muscle tissue, no need to even raise and then kill a cow. We can use the land reclaimed from animal husbandry applications.
While this is probably (hopefully) an exaggeration, I think you're dead right. The downvotes seem reflective of a delusion in the tech community that we will find a technological solution to any and all of the global problems we are likely to face soon. I wish people were more concerned about this.
If you think sea level rise is the only problem and, if it were, you think 10m is not enough to lead to complete societal meltdown in some places, then we clearly need more hyperbole.
I'm not really sure. Many forms of cancer are treatable if detected early. The question is mostly around how early they are discovered. Certainly many kinds of cancer are more likely to be discovered when they are already advanced. :-(
Dr. Rosenberg has been investigating CAR-T and other immunotherapies for decades (originally at the national cancer institute, more recently at the university of pennsylvania). I believe he (and his collaborators) will be on the short list for the Nobel Prize in Medicine eventually.
For people interested in immunotherapy more broadly, the American Society of Clinical Oncology meeting is currently underway. Originally just a medical society meeting for oncologists it has become sort of the oscars of biotech in recent years as immunotherapy has gained steam
You can check out abstracts on the ASCO website as well as follow biotech news outlets like Endpoints News, Stat news to get highlights. Also twitter is a good source of info: follow people like brad loncar, the above mentioned news sites as a start
People tell me that research in Autism has yielded few fruits or treatments to improve quality of life for those severely affected. They feel betrayed perhaps because the complexity of the causes and phenotyping of autism has turned out to be much more complex than realized 15 years ago.
I bring this up because people felt the same way about cancer. For decades and decades, there were glimmers of false hope, claims that a cure for cancer was just a few years away, surely solved in the next decade, and time after time they were proven wrong. People felt betrayed perhaps because the complexity of cancer made the problem so very difficult to solve. And YET: Here we are. Real, tangible progress.
The hard problems take huge efforts over many years, but we are solving them. If we put the effort and funding and time into understanding autism, other neurodevelopmental disorders, depression, longetivity, and so on, we will prevail.
Its not game-changing. That said, its a great step forward.
The T-Cell treatments or CAR-T cell treatments is one of the most promising lines of research in cancer treatment. Fred Hutch is doing a lot of research on right now. Seattle Cancer Care (which is associated with Fred Hutch) has an entire floor devoted to CAR-T trials.
https://www.seattletimes.com/pacific-nw-magazine/the-hutch-i...
The interesting bit is that this is a successful trial on a solid tumors. CAR-T has shown that its most effective on non-solid tumors or blood based cancers. A few months ago there was a Stanford press release on them doing a combination of injecting solid tumor CAR-T and alcohol, which caused a singular tumor to be attacked and removed.
It is a spectacular proof of concept, but it's not exactly game-changing in any way that will revolutionize cancer care around the world in the near future. This was incredibly labor- and capital-intensive procedure that involved extracting tumor material, sequencing its genes, determining which main mutations appear in the material, finding immune cells that attack that specific mutation, replicating those immune cells, and then injecting them into the patient. Since most cancers carry unique or nearly-unique mutations, this treatment would need to be tailor-made for every single patient, meaning its use would only be limited to those with a lot of resources.
Agreed that this process would need to be tailor made for each person, but there are a lot of efforts out there at industrializing and streamlining this process.
The process itself is extremely difficult with lots of ways that it can go wrong. But as with other areas of molecular biology, there's hope that the consistency of automation may improve that.
Current cancer treatments that are used in practice can easily make it in to tens of thousands per month of treatment. That provides a lot of wiggle room for doing expensive things.
Once there's a reason to produce thousands or millions of individualized cell therapies, it's likely that the process could be made economically feasible.
Gene-sequencing costs just keep getting cheaper and cheaper.[0] If this result is replicated, there will be strong incentives to streamline and automate other steps in the process as well.
Gene sequencing is a small part of the costs. The first approved car-t cell therapies are priced at ~$500k, took hundreds of millions to develop and cost over $30k per batch to make at scale. These more personalized approaches that are still unoptimized in terms of manufacturing process might cost $60k plus per batch
The manufacturing process is logistically and technically very difficult. You are engineering live cells, an extremely complex and delicate "process". Things that shouldn't affect product quality for simpler drugs like proteins end up totally changing the biologic function of the product
There's been effort to automate this but it's been difficult. Innovation here would be incredibly valuable
Out of curiosity why is engineering live cells at scale impossible? Is it because there is a huge probability that things will go wrong? Is it logistically and technically more difficult than manufacturing say a microprocessor?
Almost everything we do these days is automated to some degree at some point. Is it mostly a question of large sums of capital to develop the tooling necessary?
I don't think it's impossible, it's just really hard. I have no experience with microprocessor manufacturing so can't really speak to that. I also dont have experience in the lab but have provided operations / admin support to cell therapy manufacturing processes
Part of the challenge is just that live cells are complex living things. They interact with their environment in difficult to predict ways. You can only measure so many cell characteristics at a time, certainly not enough to get a full picture of everything that's going on, which makes in-process quality testing very difficult. A manufacturer we worked with said "process is product", which means we dont know how to measure product quality that well so we have to basically reinvent the process every time it changes. I think getting the right tooling to measure quality would help but that would require some really breakthrough innovation.
Another challenge is shelf life. You need to get these cells to patients quickly once they leave the lab, often requiring climate controlled air shipment if the patient is far from the lab. And you dont want to build too many labs, as transferring a process from one lab to another is very expensive and fickle.
Investment in cellular meat could go along way to bringing down the cost since this is one of their major barriers. If we can bring the cost of media down to $5/L and control a large batch process, I’m sure a lot could carry over to lower cost cancer treatments.
The numbers we were looking at were probably 50-80% labor, depending on how much was done in house vs 3rd party. Culture materials was most expensive piece of the materials cost but prob under 5% of total cost of manufacturing.
Once you have the gene sequenced, could you automate the part where you pinpoint the mutation? And then couldn't you automate which cells you need to engineer in order to attack that mutation? That seems like it could take out at least some time/money, though I know the biggest issue would be in engineering the cells.
Discovering which mutations are important is hard, but once you know what mutation to target, finding it is relatively straightforward and is done by software. You can actually test for 500K+ specific mutations for a few hundred dollars with a gene chip, you dont even need sequencing if you know what you're looking for. But to discover what mutations matter you need a lot of training data including expensive / hard to access tumor samples, and high quality clinical data showing how patients with different mutations fared.
The process of selecting cells to engineer is pretty complicated and labor intensive. Basically you have to get a patient to a clinic, draw blood (or biopsy), process the sample for shipment, ship it to a lab (often have just a few hours to get this done), then you do a number of steps to isolate the specific cell types you want. A lot of this is manual but isn't really novel, the techniques are pretty well established and straightforward, some probably could be automated but im not sure how much, and it would be expensive to automate. I think a few large manufacturers probably invest heavily in automation but most small companies or academic labs probably cant afford it
I’d say that cellular meat is still a hard and expensive process, let alone something that needs to be very precise and is more complex. Cellular meat is the MVP that can help get there.
Indeed; I can imagine machines performing all of the more laborious steps, with doctors just needing to verify the results and perform the procedures. Mass-produced tailor-made treatments.
Let's be optimistic, but cancer is a very broad and difficult problem. Many treatments are overhyped by the press office of the hospital/university.
The article has a few good cautious warning, in particular:
> But experts caution that the treatment has only proved itself in one woman and that the clinical trials are needed to see how effective the therapy could be in other cancer patients.
People who are down voting you probably aren’t aware the comics you link to are public service specials written by a scientist (I think?) in the first case, and the life partner of a cancer survivor in the second. They are actually very good overviews of the depth of problems involved in “curing cancer,” and the uncertainty involved in real instances of cancer recovery, not captured in TFA headline.
That is really cool. Anybody who is better versed in the subject matter have any intuitions about how much effort it would take to replicate? And perhaps whether a streamlined process would be possible to make this available for all?
There has been a ton of investment in the area of identifying tumor mutations and re-engineering patients own cells to fight the tumors. This is called "autologous cell therapy". Autologous meaning using a patients own cells and cell therapy meaning cells rather than small molecules or large molecules like proteins are the "ingredients" of the drug
The 1980s saw the introduction of proteins as therapies using genetically engineered organisms to make drugs. Previously drugs were either extracted and purified from natural sources of chemically synthesized. Only small molecules could be synthesized, not proteins, so the ability to make therapeutic proteins -- much larger and more complex than traditional small molecule drugs -- enabled a new class of drugs and companies like Genentech and Amgen
Cell therapies potentially represent another massive leap in ability to treat disease. There are a few genetically engineered cell therapies approved today, kymriah and yescarta. They are engineered to attack cells that express a molecule called CD19. This molecules is found mostly on B cells in the blood. So naturally these drugs are used for B cell lymphomas
It has proven difficult to make these cell therapies work in other cancers, especially solid tumors. Solid tumors are more difficult for immune cells to penetrate (denser and surrounded by a complex mass of fibroblasts, blood vessels and immune cells called the tumor micro environment), they have more defenses against immune attack, and they have fewer good molecules to target -- while CD19 is pretty specific to B cells and thus a good target, most solid tumor targets are either expressed on healthy tissue (so targeting these targets would attack healthy cells as well) or are not consistently expressed across cancers
The approach in this article represents an effort to solve the latter problem. There has been a lot of investment in this space by VCs and to a lesser extent pharma. There are basically two approaches, each with a set of delivery options:
Neoantigen targeted therapies: these aim to find novel tumor mutations and target them with drugs. The advantage here is that you'd have mutations specific to a tumor. The disadvantage is that you'd have to tailor each therapynto each patient which would be insanely expensive. There are many efforts to find shared neoantigens that could be used to treat a variety of patients, from what I've heard this isn't going super well. Neon therapeutics, gritstone oncology, moderna and several others are active here
Another approach is targeting "wild type" antigens (i.e. Not mutants) that are specific to cancer and not other tissues. Advantage is that you'd need less customized therapies. Some common shared tumor antigens people are focused on are NY-Eso-1, mage-A4 (or a3 or a1, don't recall). Several companies are in the clinic here but still not clear if the approach works. Aduro, immune design, biontech, moderna, neon, gritstone, 3t biosciences and others are involved
Delivery options are most commonly autologous cell therapy but this is super expensive and it is very hard to get consistent product. The manufacturing process itself contributes a ton of variability. Even using a different brand of the same type of flask can lead to a final product with vastly different biological function. Basically you draw cells from a patient, ship them to a lab, process them and ship them back. Nobody really knows if this process can scale to anything beyond just a few super rare cancers into something like say diabetes. Also the approved drugs to date have had major side effects which would prevent their use in any but the most devastating disease
Another approach is off the shelf allogeneic cell therapy. Here you just make cells that work in any patient. Immunogenicity is a potential concern
Others are using bacteria, viruses or non viral vectors to deliver mRNA encoding for the antigens to dendritic cells, which are cells that tell T cells which antigens to attack. Biontech is a leader here. This is sort of a "bounce shot" approach. If it works it would be amazing but it is very technically challenging and I don't really know if the exact details of the mechanism are that well understood. There are many clinical studies ongoing so well know soon
Overall this is a really promising development because solid tumors are just really tough. There will be a lot more to see in this field the next few years
Anyone know what type of breast cancer was treated? My mother recently passed away from Metastatic Inflammatory Breast Cancer and I wonder if this treatment could have helped her.
And men. Although cancer is usually referred to by its location, this is actually much less relevant to its treatment than the type of cancer it is. Although men only get breast cancer rarely, this treatment method will be applicable to many other cancers.
> even if men were not at all subject to the advancement personally
That seems like an impossible hypothetical, really. People will always have relatives and friends of all sexes so there's no way to stop people of one sex from benefiting from the health of the others.
It's already known what the expected pricing for CAR-T therapy will be, considering the first of these therapies was approved last year for pediatric leukemia (KYMRIAH/tisagenlecleucel). Expect around $475,000.
Seeing as more is spent on marketing than on drug development, and pharmaceutical marketing is heavily restricted in many other countries, I suspect the only subsidization which is happening is from US consumers to US marketing companies.
>“I had resigned my job and was planning on dying. I had a bucket-list of things I needed to do before the end, like going to the Grand Canyon,” she added. “Now, I have gone back to normal everyday life.”
I find this sad. For one brief, glorious moment she was alive, going to fulfil her bucket list and live her life to the fullest.
The therapy, while groundbreaking, didn't make her immortal, she's still going to die as are we all. But going back to her 'normal everyday life' instead of fulfilling her dreams she may as well have just died anyway.
[1] https://www.cancer.gov/news-events/press-releases/2018/immun...
[2] https://clinicaltrials.gov/ct2/show/NCT01174121