Patient Number One in a new cancer treatment
nautil.us
nautil.us
In essence, the tumor infiltrating lymphocytes (TIL) adoptive cell therapy was as follows:
1. The doctors removed a melanoma tumor that was growing in my neck.
2. In the lab, white blood T cells (T lymphocytes) that were attempting to attack the cancerous tissue in my tumor were isolated into at least five different petri dishes. The white blood cells' growth was stimulated using IL-2.
3. Those samples that grew the most and attacked the cancerous tissue (2 of the samples, in my case) were then expanded to a total of 130 billion lymphocytes in the lab.
4. I returned to NIH for a week of immune system preparation, specifically the almost complete suppression of my own active immune system using harsh chemotherapy. This was to allow my body to accept the new lab-grown immune system.
5. Once my immune system was sufficiently suppressed, I received all 130 billions of the lab-grown lymphocytes. The immune system was then stimulated by having five large doses of IL-2 every eight hours over a two day period. (Note: This was hellish.)
6. After a week or so, my immune system had recovered and I was released from the NIH Clinical Center to return home. I was given an anti-biotic to take for 4 to 6 months to reduce the possibility of contracting a specific pneumonia (PCP).
7. I returned to NIH monthly for scans monthly for the first three months. After month one, my tumors had shrunk 33%. After month two, 66%. After month three, they were almost complete gone. My immune systems had essentially been immunized against some of the mutations contained in my cancerous melanoma cells.
8. I was declared NED (no evidence of disease after 15 months) and a complete responder to the treatment after 21 months.
Now, almost five years post-treatment, I have had CT scans and brain MRIs every six months with still no signs of melanoma. My doctors have told me that I'm likely cured.
Immunotherapy works. I chose this trial because the I liked the fact that my own immune system was being boosted to fight my cancer.
Further info: https://en.wikipedia.org/wiki/Tumor-infiltrating_lymphocytes
My doctor is Dr. Steven Rosenberg of the National Cancer Institute.
>I'm certain that Big Pharma doesn't like these treatments.
You would be certainly wrong on that part. Immuno-oncology has been "Big Pharma's" major focus for the past 5-10 years, inspired in no small part by the work of Rosenburg and many others. One of the most recent approvals discussed on HN was for a CAR T-cell targeted against CD19. Big Pharma would also be very happy to sell immune checkpoint inhibitors for use in combination therapy with adoptive cell transfer.
I do know that my specific trial at NIH was sponsored by Lion Biotechnologies as part of that company acquiring a license to reproduce the laboratory processing for the TIL ACT.
Paywalled, but a good review of the 100 in trials right now: https://www.ncbi.nlm.nih.gov/pubmed/27613725
It's not like there's a shortage of maladies people would be willing to pay a lot for treatments for.
(though you can probably fly to Mexico or Canada and fly back with a good amount of it for cheaper)
The price in Australia is AUD$30 (~USD$24) for a 12-pack of 100mg tablets [1]. That's totally unsubsidised, although you do need a prescription. How on earth could they literally cost thirty times more in the states?
[1] http://www.chemistwarehouse.com.au/buy/61362/Viagra-100mg-Ta...
I really hope if we don't catch one of these in stage one that I will be able to get treatment like yours.
With regards to big pharma as far as I understand the problem seems to be a little different namely that it's not a pill or a treatment as such but a combination of things which means big pharma wont necessarily be investing heavily in it as they can't turn it into a product (again as far as I understand).
Last but not least. Congrats on the lucky outcome.
About 20-30 minutes after receiving a dose of IL-2 by infusion, my body would undergo violent bed-shaking rigors for 10-20 minutes. I had the worst chills I've ever had, followed by breaking out in a hot sweat when it had passed. This was very unpleasant.
After each successive dose, the effects would worsen.
Essentially, the doctors were trying to take my body to the brink of experiencing a cytokine storm (https://en.wikipedia.org/wiki/Cytokine_storm) to jump-start my immune system.
This was a pretty miserable part of the treatment, but (in the end) obviously worth it.
In my specific case, they weee concerned that I might have a heart issue that was unknown (I don't). For the sake of my own safety, I was given the treatment in ICU. For most patients, this is unneeded.
Actually, my biggest risk was contracting a superbug with my severely weakened immune system. The last NIH patient who died from the superbug was a few rooms away in ICU at the NIH Clinical Center at the same time as me. (I knew the doctors were taking extra precautions with me, but I was totally unaware of was what happening down the hall from me.)
https://www.google.com/amp/www.nbcnews.com/health/health-new...
I am told that the treatment and follow-ups cost the research program budget at least a million dollars per patient.
Nobody said cheap. People (me included) actually expect immunotherapy to be expensive. A course of Perjeta/Herceptin can go to $188k (per [1]). But many are already outraged by this number. A course of Rituxan can be about $14k to the patient, and you could say it's dirt cheap compared to Herceptin, but it appears the cost to the manufacturer is $300 ([2]).
As for superconductors, antimatter, and all other sci-fi sounding things, the cost of an PET scan is about $7k, and of an MRI scan is less than half that, so that can't explain the million we're talking about here.
I think we simply became insensitive to hearing big numbers in the context of healthcare. The birth of my second son cost my insurance about $130k (they covered 90%, but I still had to fork out about $15k), and he didn't have any surgery, or anything major. So yes, I can understand $1MM for cancer treatment, but allow me to be mindblown all the same. I don't think $130k was reasonable for a delivery, and I don't think $1MM is reasonable for immunotherapy (which again, does not involve surgery).
[1] http://www.fiercepharma.com/regulatory/fda-approves-roche-s-... [2] http://consumersunion.org/outrageous-health-costs/cancer-dru...
The hospital charges make sense too as you're under supervision by trained nurses and living in a room built with specialized equipment.
I had an appendectomy recently. Everything included (surgery, hospital charges, drugs etc.) came to ~ $55k. Insurance paid most of it and I was ultimately charged around $5k. With that in mind $130k doesn't sound unreasonable for a delivery of a baby.
While I'm accustomed to hearing this kind of thing from the USA, know that for citizens of any other developed country, that is an absolutely absurd amount, to the tune of 10x or 20x the proper cost.
I've recently had friends in both Japan and Australia, hardly countries with poor healthcare, give birth and in both cases the cost was around USD$5k. That's private, by the way - public would have been free (ie covered by the system paid for by the 2% medicare levy in the case of Australia).
No, the prices are only explainable by profound inefficiency and corporate rent-seeking. The US is paying hugely inflated prices for (at best) similar outcomes to its peers - now that's market failure!
Needless to say I expect the US will adopt a single payer healthcare system within the next 10-20 years, like every single one of its peers, simply because the current system is unsustainable.
[1] https://journal.practicelink.com/vital-stats/physician-compe...
[2] https://en.wikipedia.org/wiki/List_of_countries_by_quality_o...
Congratulations on your recovery!
Can you maybe elaborate a little on how they selected the cells to lab-grow? Step 2 and 3, in particular. By what criteria did they divide them between petri dishes and how did they test how efficient they were at destroying cancer cells? (Did they feed them parts of your tumor or something?)
Essentially it has 3 parts:
- Extraction of tumor to test against.
- Extraction of immune cells, to which a genetic therapy is applied that grants them a new tool to home in on the above tumor.
- After testing the immune cells against the extracted tumor, reimplant the 'upgraded' immune cells.
He said he had chemo to suppress his immune system before he got the new one.
We need more of this.
Congrats on being NED.
I work in biotech and a very successful CEO of mine once told me "When I'm evaluating new (bio)technologies, always bet on tech that replicates/take advantage of a currently working biological system. Tech where everything is synthetic/relies on a custom designed system/etc is much more likely to not work in the long run."
How was the treatment?
Because of its depth into the skin tissue, I had a wide excision (where more skin tissue is removed) and a sentinel lymph node biopsy which removed four lymph nodes that were most closely connected to the tissue that was removed. Of the four nodes removed, three were negative (clear) and one had a micro metastasis (micromet) sized 0.18mm. This placed me at Stage IIIa.
The melanoma developed as tumors in my lung just over a year later, putting me at Stage IV.
The primary symptom I had was the mole. I felt completely normal.
As far as the treatment, read my answer about the "hellish" nature of it in another reply.
Congrats on the success :)
If that's the worst of it, I can handle it, especially considering the alternative.
However, I do know that my seasonal allergies have changed slightly since treatment–they've actually moderated. I don't know if that's due to the treatment or just an age-related occurrence.
Congratulations byteCoder!
I've had to witness my brother in law dying because of cancer. It's horrible.
It's really cool to see the patient's side of the journey though - and I'm very glad things turned out well for you. Thanks for sharing :).
Small question: How do you get into a trial like this? Did someone choose you? Are trials like this announced somewhere and you did apply? Word-of-mouth? Someone related who works in this field?
It's hard to imagine how it feels to be diagnosed with cancer but I guess in many cases, if the outlook looks dim, a trial like this would make the most sense? Or not?
Excuse me for the basic questions,I have no experience in Biology or how antibiotics work.
Our immune system is a force to be reckoned with for any cancers - we don't have figures on how many cancers our immune system clears before it meets one it cannot clear.
So for cancer to survive, it has to thwart our immune system somehow, and one of the ways it does this is to use signalling pathways which dampen down the immune response. It communicates to the cancer 'calm down, don't call your friends'. The immune cells don't go away - instead they switch to a mode where they control rather than clear the cancer.
Adoptive TIL therapy (which is not the same thing as the article is talking about, though they are both T cells) takes the immune cells from the cancer. These cells recognise the cancer as being foreign ('non-self') and in need of clearing, but they have been suppressed by signals from the cancer. In the lab the cells are selected and bred so that you have a pool of hyped-up cytotoxic T cells, which when transfused back into the patient are so aggressive even the suppressive signals from the cancer don't stop the killing.
In fact, it's the mutations in the cancer which allow this therapy to work. Mutations are what makes the cancer 'non-self' - the more they have, the more attention they get from the immune system. If they try to hide their mutations (all cells must present the products of their DNA on the cell surface), they get removed by natural killer cells (so called because they naturally kill cells unless they display what they are meant to on the cell surface).
The article actually talks about another type of treatment called CAR-T cell therapy. This is a bit different. What you do in this case is you take a T cell from the patient (not a tumour-infiltrating T cell - instead you want an effective T-killer cell), and they graft an antibody which is specific* for the tumour onto the cell. There are a few other steps to make sure that the cell survives in the patient, but essentially when you infuse this cell (ok they give more than one) into the patient, it recognises the target (hopefully the tumour), divides and kills, divides and kills etc etc until the tumour is gone. Then hopefully it stops dividing, or you end up with a T cell tumour.
In this case - your question is right on target. The cancer can and does mutate to avoid this therapy. In this particular case the antibody is for CD19/CD20 (I can't remember), and it was able to clear the tumour before it could evolve to drop CD19/20 from the cell surface. In other patients subsequently treated, a proportion of them have relapse with tumour cells not displaying CD19 on the surface.
In fact, this is the achille's heal of CAR-T cell treatment. It is essentially a very powerful antibody, but for it to work it needs a few things - 1. The tumour must have the target marker on all of its cells - i.e. it can't evolve out, 2. You must be happy to lose any healthy cells which also have this marker.
In this case the patient lost all of his B cells. This is a powerful component of the immune system, but actually, you can get away without it, thankfully. This treatment wouldn't work for a T cell leukaemia/lymphoma. Removing all of your T cells gives you AIDS, which is no better than having a terminal cancer (when it's not caused by HIV, that is).
In that case, would any cell that mutated to avoid there treatment, de-cancer itself?
Predicting what sort of antibody or T cell receptor will bind a specific mutation (more technically a piece of protein with the mutation in it - about 10 amino acids long) is hugely difficult - it requires a very good understanding of how all the amino acids fold and interact in a 3D spatial model, and we simply aren't there yet.
Your last question really depends on the mutations. Further mutations would stimulate more of an immune response, but a mutation could, for example, increase the ways a tumour cell hides from the immune system. On the other hand, it would be hard for the tumour cells to de-mutate itself to avoid TILs already specific for that mutation.
As you say, there are many reasons why cancer isn't self - neo-antigens are just a facet of that. Are cancer associated antigens the same thing as cancer-testis antigens? To be honest, I've never really groked CTAGs - they don't make sense to me. Why does the thymus not expose T cells to them? Why does cancer produce them? To many questions..!
If you want to build your own chimeric antigen receptors we've built a digital infrastructure to allow you [1]. Though we just made public our generic protein design software (thanks ShowHN! [2]), we're employing the same underlying digital infrastructure to build, evaluate, and manage CAR designs in high throughput [3]. The drug approved here was painstakingly designed by hand [4], while we think the technology now exists to permit many more such advances to be created at a much more rapid pace.
[1] https://serotiny.bio/pinecone/
[2] https://news.ycombinator.com/item?id=14446679
The plasmid DNA is then used as a reagent to manufacture the physical retroviruses that are used to transduce the extracted T-cells which are then reimplanted into a patient.
Practically, multiple plasmids, each containing a single component of a synthetic retrovirus are given to 'viral manufacturing cells', and the output is pool of virus that is infectious only once, and has DNA that encodes the CAR design as its payload. That virus is then given to the extracted T-cells, where it infects them with the viral payload and integrates its genetic payload into their genomes. Once integrated, the cells are tested to ensure they are not further infectious, then reimplated - newly 'upgraded' with DNA that encodes a synthetic CAR protein that is now capable of homing in and killing the target cancer.
Getting all that payload into a plasmid is certainly an art. A lentiviral capsid has a physical pressure capacity such that it can hold <13kb of DNA. This is precisely why it's so important to have good ways of testing/pruning/evaluating new protein designs so that you can prune down a theoretical design into precisely the minimal design required for effect.
<fairly obvious outcome> is likely to be "large increase in incididence of autoimmune disorders"
Right now immune ablation is pretty rough chemotherapy, but has nonetheless been shown to put multiple sclerosis and type 1 diabetes into remission. There are new approaches to targeted cell killing under development now (such as Oisin Biotechnologies' system) that should be much better, with minimal side-effects. Couple that with a cell therapy to accelerate replacement of immune cells and it looks pretty promising.
But if the immune system over reacts, it can run out of control and kill you.
I have a relative with stage IV melanoma. She was included in a research trial that used a pair of immune stimulating drugs in an attempt to get her own body to fight the cancer.
What they didn't realize is she had a latent, undiagnosed autoimmune condition called vasculitis.
Unfortunately, while vasculitis is normally isolated to a particular part of the body, hers was systemic. What followed was an immediate halt of the drug regimen and massive doses of steroids to get it under control. If that hadn't have worked, it would have killed her. Full stop.
The condition is now fortunately under control, but she has 30% kidney function, and the steroids pushed her over to full non-insulin-dependent diabetes. She's now on a targeted therapy that, for now, has pushed her into full remission, but it's only a matter of time before the melanoma becomes resistant to the drug.
The reality is, doctors do not fully understand the immune system. Period. These treatments are in many ways astonishing, but they can turn frightening very very quickly. And they don't always work, either.
Unfortunately, there are no miracles, here. Not yet.
There was a chance that his immune system would go into overdrive, and there was a chance that the edited T-cells wouldn’t be as potent as they expected. The medical team just really couldn’t be sure what would happen.
That article goes on to note all manner of side effects with this style of therapy: fever, tremors, convulsions, encephalitis... and right at the end we have this quote:
He had an atypical skin growth, a chronic cough, a sinus infection, a puddle of fluid at the bottom of his lungs, a virus in his right eye, and bad heartburn.
Of course, as far as side effects go, this is pretty minor. But there's no understanding of why these types of things happen in the first place because our understanding of the immune system in vivo is just not very good.
My general understanding is that they are so difficult to address because we don't really understand them.
I have a condition that gets partly explained as "overactive immune response." I really hate the concept of autoimmune diseases and I hope that someday it will be mocked as "god, what those barbaric idiots believed back in the day."
But under that umbrella the reason cancers are 'hard to treat' (from the perspective of a pharmaceutical education/industry/knowledgebase that had a century of success curing invading diseases) is because cancers do not present a 'differnece' that can be exploited biochemically. Cancers are by definition a mashup and amalgamation of the components that make up a human - again very much unlike a bacteria, viral or fungal infection.
You are correct though that there is still a lot for us to learn. The technologies in this article are very much a glimpse of the next steps though.
I don't really know how to effectively engage you, but I stand by my initial statement of:
I would like to see a more elegant means to boost the immune function, without so much of the Dr. Frankenstein element. I think supporting the immune function is the way to go, but I think we need a lighter hand, not a heavier one.
I don't really feel you are making points that invalidate that desire. Perhaps we just don't understand each other. If so, it is probably best to stop here rather than keep digging a deeper grave.
Considering that by some measures we have made hardly a dent with our 40-year war on cancer (https://blogs.scientificamerican.com/cross-check/sorry-but-s...), I feel confident that this is but the start down the road of immunotherapy.
Most people don't seem to realize the kind of progress that's been made in recent years with CRISPR etc. These problems are becoming data problems rather than biology/chemistry problems. The public (government) should certainly be funding many teams with small amounts of money ($10,000 to $100,000 say) rather than pouring billions/trillions of dollars into "proven winners" (big pharma) that mainly come up with therapies rather than doing basic research.
Honestly I think the same argument applies to so many areas of the economy: alternative energy, space travel, growing food, and so on. We could be finding so many "cures" for relatively modest investments that our current system has actually become very expensive due to the opportunity cost of not doing so. I've spent most of my life asking what we are all working for and towards but have come to the conclusion that keeping everyone busy is the goal now, not progress.
https://www.forbes.com/sites/jacobsherkow/2017/02/21/how-muc...
http://www.nature.com/news/why-the-crispr-patent-verdict-isn...
This could discourage smaller companies from picking it up (ex. to build upon it, from which in the long run everyone will profit, see open-source) and make CRISPR-based treatments more expensive / unavailable (ex. large companies owning the patents artificially inflating the price, may be even more than the old technology it replaces).
I lost my health insurance, again, to Obamacare. But it doesn't matter because no one in my state (ks) is willing to sell individual health insurance next year... I think there are three states headed this way last time I read.
So yes, the repeal of Obamacare does need to happen sadly :/ I'm hoping for a partisan solution, but at the moment members of Congress are busy promoting their political parties instead of working together.
No, we do not have any national health exchange. That was proposed by the Republicans instead of the original Obamacare bill but was rejected.
Then again, not all people are very capable of rational thought.
I mention this because it seems HIV is the Alucard of immunological treatments: a terrifying incurable disease which we now use as a potent weapon to fight other diseases. The thing that made it so terrifying -- its tendency to attack immune cells -- also makes it incredibly fit to purpose.
With growing global density and antibiotic abuse, it's the things like MRSA and syphilis that are likely to never disappear.
Everyone is afraid to over-hype this, but take a moment and consider that we're now re-wiring the human immune system to fight things it previously couldn't. That's incredible.
Obligatory xkcd on the topic: https://xkcd.com/938/
CARs (& protein biotherapetuics) :: human diseases (misregulation/cancer)
Whoa... what is the probability that you'd get all of these without being exposed to a carcinogen?
>retired corrections officer
I wonder if the prison he was working in was built near a superfund site.
http://www.alternet.org/environment/americas-toxic-prisons-e...