'Living Drug' That Fights Cancer by Harnessing Immune System Clears Key Hurdle

http://www.npr.org/sections/health-shots/2017/07/12/536812206/living-drug-that-fights-cancer-by-harnessing-the-immune-system-clears-key-hurdle

by daegloe • 9 years ago

423 141 9 years ago

npr.org

ceejayoz5• 9 years ago

Another big concern is the cost. While Novartis will not estimate the price it will ultimately put on the treatment, some industry analysts project it will cost $500,000 per infusion.

Welp, guess my insurance premiums aren't stabilizing anytime soon.

seibelj• 9 years ago

There won't be that many people who need this drug, and supposedly it's a one-time cure that isn't a life-long drug treatment. I'm a layman when it comes to biotech, but my hope is that longterm the prices come down for this and other drugs that use a similar technique to treat diseases. I'm happy researchers are focusing on cures rather than "living-with" a disease.

Also, shoutout to Boston (and Cambridge) which I don't think gets enough love on HN. #1 in the entire world for biotech, #2 for software, #1 for higher ed, #1 for healthcare, you can actually afford to live here, solid public transportation, amazing skiing / hiking / beaches, NYC in 4 hours. If you are tired of SF think about Boston

im_down_w_otp• 9 years ago

You lost me at "amazing skiing" ;-)

rhexs• 9 years ago

You can afford to live there? I was looking at 1 br apartments in Cambridge and it was pretty darn close to SF Bay. Interviewers I was talking to said they commuted in 45 minutes just so they could own a house.

numbsafari• 9 years ago

Funny... Weren't these studies done in Philly, not Boston? And isn't the Novartis lab based out of Switzerland? I missed the part about Boston in this article...

pinaceae3• 9 years ago

how much is getting cured of cancer at a very young age worth? dying vs. living another 80-90 years?

less than a Tesla? more than a house?

interesting questions arise around immuno-oncology.

should Apple be the most profitable company - or someone that literally cures cancer?

orbitur2• 9 years ago

how much is getting cured of cancer at a very young age worth? dying vs. living another 80-90 years? less than a Tesla? more than a house?

It's worth so much that a person shouldn't be required to pay for it. Like a right.

ceejayoz5• 9 years ago

how much is getting cured of cancer at a very young age worth? dying vs. living another 80-90 years?

A tough question, made tougher by the side effects of doing so. $500k per infusion pays for quite a few mostly-healthy low-income uninsured kids to get basic pediatric care. The US healthcare system is already priced too high for a lot of people - I pay $2,002.25/month for my family.

should Apple be the most profitable company - or someone that literally cures cancer?

Should healthcare really be a for-profit endeavour?

woofyman• 9 years ago

"should Apple be the most profitable company - or someone that literally cures cancer?"

Nobody needs an Apple product. Life is a basic need.

shallot_router• 9 years ago

They deserve to be profitable but in a way that doesn't require bleeding dry the cancer patients themselves.

pinaceae3• 9 years ago

getting downvoted for asking questions.

HN sometimes really can fuck right off.

Symmetry• 9 years ago

The US federal government has basically standardized, in terms of public health and safety measures, on treating doing those interventions that will save lives if they will save lives for less than $7.5 million on average (it's been going up over time). This is for stuff like lead abatement, public safety commercials, pollution controls, etc.

That doesn't apply to medicine but it looks like this treatment is well worth it compared to the money the government spends, e.g., cleaning up lead paint. And since the number I gave is for an average life when saving a child we should be willing to spend more.

gozur883• 9 years ago

This won't affect your insurance - the patient population is too small.

Now, if a similar treatment gets approved for, say, prostate cancer... that's going to affect your insurance.

zamalek4• 9 years ago

the patient population is too small.

I think that cancer is one of the great filters. At some point a species will develop an unreliable way to treat cancer (chemotherapy); at which point cancer becomes a genetic problem as natural selection is displaced by medicine. Over many generations, this will kill a species unless a reliable cure is found - we seem to have that cure. Our cure is symptomatic (cancer being the symptom) but the same technology could eventually be used for designer genetics.

Essentially, more and more people are going to rely on this treatment until we are able to completely eradicate hereditary cancer. Probably not in our lifetimes.

philjohn4• 9 years ago

Eh, probably not for prostate cancer, very treatable if caught early, and a lot of people have "watchful waiting" as it does less harm to leave it in for a while than take it out.

Now, if there was a gene therapy for breast, colon or liver cancer, then it would be a problem.

eatbitseveryday3• 9 years ago

NYTimes also covers the story (https://www.nytimes.com/2017/07/12/health/fda-novartis-leuke...) with more discussion about individual patients.

From the NYT article:

The panel recommended approving the treatment for B-cell acute lymphoblastic leukemia that has resisted treatment, or relapsed, in children and young adults aged 3 to 25.

Why so young?

skadamou• 9 years ago

A couple of things really surprised me about this article.

First, I'm sure that there is other evidence the FDA is using to determine whether or not to grant this drug FDA approval but a 63 person drug trial seems like an exceedingly small sample size to work with. Perhaps because this disease is so rare they could not put together a larger trial?

Also, it seemed a little bizarre for an FDA panel to receive comments about a decision it is trying to reach from the families of those involved in the drug trial. I suppose there is nothing wrong with that, per se, but shouldn't these types of decisions be reach on the basis of scientific evidence and strive to be devoid of any kind of sentimentality?

Either way, it's always excellent to see new cancer treatments on the market, particularly when they are as groundbreaking as this one.

gumby4• 9 years ago

It's an orphan indication which has special rules to promote development. Otherwise, the thinkingngoes, nobody would develop treatments for uncommon diseases.

epmaybe3• 9 years ago

It's not that small, if the statistics look good. And they really do look better than most everything else on the market.

Also, the approval isn't for patients newly diagnosed yet, it's only for patients that have relapsed or resistant to current therapies. You'll see a larger phase IV trial later, most likely.

Now, off topic from your comment, I'm worried about cost. I know that the R&D for this kind of therapy is exceedingly high, but these therapies need to get cheaper for us to be able to justify using them in a larger population.

ekianjo2• 9 years ago

a 63 person drug trial seems like an exceedingly small sample size

Sampling is basically decided on 1) recruitability and 2) effect size. If your effect is extremely large, even with a relatively small base size you can demonstrate the benefits of your drug.

Basically very, very large trials are mostly useful to demonstrate benefits that are not that large to begin with.

kurthr• 9 years ago

Apparently, it's not uncommon for pharma to coach the families that comment to the committee either... And in another orphan drug case with small sample size, that of Sarepta/eteplirsen, in which several evaluating scientists seem confused and the majority were overridden (for approval) by the FDA director in charge. Comments included, “serious irresponsibility” (by selectively publishing data during the whole process) and saying that the drug was a “scientifically elegant placebo”.

http://blogs.sciencemag.org/pipeline/archives/2016/09/20/sar...

This new leukemia treatment is a really interesting, and perhaps the effect size is large enough for the small trial size, but we seem to have some problems in the review process (ignoring data) and incentive structure (coaching parents) for these "orphan drugs".

http://blogs.sciencemag.org/pipeline/archives/2017/05/19/im-...

ceejayoz5• 9 years ago

Why so young?

It's a cancer commonly found in children.

https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia

Acute lymphoblastic leukemia is seen in both children and adults; the highest incidence is seen between ages 2 and 5 years. ALL is the most common childhood cancer, constituting about to 30% of cancers before age 15.

eatbitseveryday3• 9 years ago

If someone over 25 gets it, then this method is not approved for them? That's how I read this.

jozzz• 9 years ago

Isn't 25 supposedly the magic age when more cells die than are created, i.e. when you start 'aging'.

dghughes• 9 years ago

Then again every seven years all the cells in your body are new so is the new you now aging faster as a "cellularly younger" person?

JoeAltmaier• 9 years ago

From the article:

   "Scientists use a virus to make the genetic changes in the T cells, raising fears about possible long-term side effects"

Is this a real risk? Is 'using a virus' in this way, still risky at all? or is it just the word 'virus' that makes writers put this line in every article about gene therapy?

{edit: real risk}

Sir_Substance• 9 years ago

A virus is a machine for replacing DNA in a cell with other DNA. Seems like the right tool for the job.

gumby4• 9 years ago

It's a standard tool. In fact a virus is not necessary a living device: there's a DNA delivery wrapper (looks like. Little lunar lander with a big spike coming out) and a payload (DNA).

A virus can't reproduce but it can inject its payload into a cell and have the cell's DNA copy/execution capabilities copy the DNA for the virus, making new delivery machines until the cell explodes and emits a cloud of new dlivery agents into the organism.

But if you remove the payload and replace it with your own, that payload presumably won't make more viruses

eatbitseveryday3• 9 years ago

It's a standard tool. In fact a virus is not necessary a living device: there's a DNA delivery wrapper (looks like. Little lunar lander with a big spike coming out) and a payload (DNA).

Just a slight correction. Not all viruses look like what you describe. [0] Others, like the HIV, are circular. [1]

[0] https://en.wikipedia.org/wiki/Virus#Structure

[1] https://en.wikipedia.org/wiki/Structure_and_genome_of_HIV

aabaker99• 9 years ago

The virus is inactivated HIV. The risks about long-term side effects pertain more to gene editing than the use of a virus as a delivery mechanism.

jfarlow10• 9 years ago

Which are risks similar in nature to the risk of getting cancer after one has been infected with any other virus that integrates into one's genome.

wdbbdw• 9 years ago

Not only are viruses a cool (if somewhat nefarious) DNA-delivery system (though, HIV being a retrovirus probably means that it delivered RNA instead of DNA), but it can be targeted. HIV viral particles attack human immune cells, which just happen to be the general cell type that needs to be treated in this case! Using something like hepatitis or HPV probably would do the trick here since those viruses wouldn't have the keys to unlock the doors to get inside of the T cells.

nerdponx2• 9 years ago

Not to be flippant, but isn't a "virus that cures cancer" exactly how the Will Smith movie I Am Legend starts?

HillaryBriss4• 9 years ago

ok, sure, the pessimistic among us can accentuate the negative aspects of this medical therapy, but it did solve the NYC subway crisis. and don't forget the wildlife habitat expansion.

these things aren't all bad.

philjohn4• 9 years ago

Yes.

agumonkey• 9 years ago

Virus retroviral internal machinery has been used for ages.

freeflight• 9 years ago

"Scientists use a virus to make the genetic changes in the T cells, raising fears about possible long-term side effects"

Isn't that the plot of Resident Evil/Biohazard? ;)

AnimalMuppet• 9 years ago

A real risk compared to, say, dying from cancer that you already have? What, are they worried it might give you cancer in 10 years? If the cancer you have now is going to kill you, that still sounds like a good deal.

(This is not hypothetical. My wife's grandfather had radiation treatment for cancer. 20 years later, he got cancer again, plausibly from the radiation. That's still a net win of 20 years.)

sjbase• 9 years ago

Does anyone know: what are the failure rates like for the gene editing technology being used for this? Thinking like a software engineer, are there transposition errors (GATC --> GTAC) , atomicity issues (GATC --> GA)? Mutations afterward?

jfarlow10• 9 years ago

In this particular case the therapy is being applied to cells that have been extracted from a patient. That allows a reasonable error rate where errors can be filtered out, and success verified before the cells are reimplanted. This is a strategically nice intermediate before having to run a therapy on a living organism. The technology in use here is not quite the same kind of 'DNA editing' as is found with tools like CRISPR, but rather a much more therapeutically mature (if technologically blunt) form of viral 'insertion of a block of code'.

With respect to actual code fidelity, errors in DNA come from a number of different sources. Every time DNA is copied (a cell divides) there is an inherent fidelity rate of the copy (on the order of a single mistake per billion writes). The payload here is on the order of a few thousand base pairs so copies should have a very high fidelity.

In this case a viral protein is 'inserting' its DNA randomly into the genome of the target cells. Imagine inserting a library of code randomly into a codebase. Certainly not ideal, and an issue that CRISPR technologies promise to help improve. However, given that the therapy is only being applied to immune cells that are only running the 'immune' section of the human codebase, and no progeny of those cells will ever have to become a brain or skin or run any of the other programs, the chance that the inserted DNA disrupts the 'immunological' code in the codebase is relatively small. And if there is disruption to some cells' genomes those cells could be screened out if they really distort something they should not.

With respect to DNA generally, common errors arise from undesirable but common chemical modifications to the code itself. The DNA can become damaged (by reactive oxygen, UV light, and through other chemical reactions), and while there are significant systems to repair that damage, oftentimes since there is only a single backup (DNA is 'double-stranded'), it's often impossible for that machinery to determine whether the error is on strand1 or strand2, so 50/50 chance of 'repairing' into the error.

stillfinite• 9 years ago

The significant thing about CAR-T cell therapy is that it's not very specific to the type of cancer - all cancer cells have damaged DNA that leads to the productions of antigens. Leukemia is the low-hanging fruit because it's easy to inject the T-cells back into the body right where the cancers cells are. It's hard to tell whether you could get enough T-cells to diffuse out of the bloodstream to have an effect on something like prostate cancer. It would be a real breakthrough if you could overcome that hurdle, because then you would have a treatment that works on many different cancers without much modification.

hwillis• 9 years ago

Real, actual question: would it not work to just inject t-cells deep into my taint in that case?

HillaryBriss4• 9 years ago

i second that question. if they can carry out needle biopsies of the prostate and other cancer locations, if they can surgically remove cancerous tissue -- why can't they also get these modified cells to the cancerous locations somehow?

Cerium• 9 years ago

What I got out of the article was that the approach here seems to be that you create a small number of improved t-cells and inject them. Then these improved t-cells will respond correctly upon contact with cancer cells. At that point they will multiply to meet the required demand. The initial injection would be more like a vaccine than a drug.

vibrio2• 9 years ago

"local' anticancer treatment is achievable but not really effective. the promise in the CAR-T is persistence of the cells and systemic distribution so they can surveil for micro metastases and minimal residual disease, hopefully eliminating it. I'm not sure injecting a ton of cell into ones taint would give the cells the best opportunity to persist and provide systemic prevention.

scottLobster• 9 years ago

I wonder though if just having these types of cells in the bloodstream could limit or even prevent cancers from metastasizing. That would provide a massive increase in survivability in and of itself.

jfarlow10• 9 years ago

The other 'cool' part about CARs is that 'without much modification' is not near so large a challenge as it is for small molecules. Certainly there are regulatory barriers, but scientifically, the ease with which you could just (genetically) pop on a custom nanobody/binding domain is many many orders of magnitude less than trying to find a small molecule to hit a different target.

In a decade or two, I wouldn't be surprised if CARs were being deployed that were entirely customized to a patient's cancer, where the scaffolding was 'FDA approved', while the binding domain was cultured to specifically react to this patient's cancer, encoded into DNA, printed and designed within the space of a few hours or days. The kind of customizability that comes from a genetic therapy opens a lot of new doors.

tcbawo• 9 years ago

Perhaps we'll even be able to generate individualized tissue samples in order to test out side effects prior to treatment

suddenseizure• 9 years ago

The downside with adaptive immune system therapy (like CAR-T therapy) is that it doesn't work as well with cancers with fewer mutations that the T cell can detect as anomalous.

My wife has brain cancer and has been reading about all the immunotherapies available. Unfortunately brain cancer tends to have much fewer mutations than say, lung cancer. However there are innate immune system therapies being researched that might be more promising in those cases.

sjg0072• 9 years ago

So sorry to hear this. It sounds like you guys are doing the right research. Being in a similar boat, I think that the checkpoint inhibitors look very promising. I try to keep up with the field as best I can. The hard part is you have to find an appropriate clinical trial for whatever you and your doctor think is best... Also, just as an FYI, the NCI is starting up a new precision medicine trial (NCI-MATCH) to target specific pathways instead of tumors... but I'm more of the opinion you have to do combination chemotherapy and modalities unless the drug is super effective. But then again I'm not an oncologist or a doctor.

inlined2• 9 years ago

Very sorry to hear about your wife. I assumed one of the other problems would be the blood brain barrier. Could this therapy overcome that too?

jfarlow10• 9 years ago

Congratulations! The Chimeric Antigen Receptor (CAR) deployed here is very much unlike the standard 'small molecule' drug that 'disrupts a bad thing', and much more like a rationally engineered tool using the body's very own technologies to overcome a particular limitation. In this case, it gives the patient's own immune system a notion of what the cancer looks like.

If you want to build your own 'living drugs' we've built a digital infrastructure to allow you. Though we just made public our generic protein design software (thanks ShowHN! [1]), we're employing the same underlying digital infrastructure to build, evaluate, and manage CAR designs in high throughput [2]. The drug approved here was painstakingly designed by hand, while we think the technology now exists to permit many more such advances to be created at a much more rapid pace.

[1] https://news.ycombinator.com/item?id=14446679

[2] https://serotiny.bio/notes/applications/car

Design your own 'living' protein drugs here right now: https://serotiny.bio/pinecone/ (and let us know what you think, and how we can make it better!)

skummetmaelk2• 9 years ago

3...2..1.. Prion disease!

Seriously though, how would you prevent such automated designing from having unintended side effects?

jfarlow10• 9 years ago

The software is useful because it allows you to have some idea of the function of each component prior to their assembly. Further, at this point, the software is designed for R&D far far upstream of being put directly used as a therapeutic. Finally, if a design causes some problem, we want to know that - we allow that undesirable property to be discovered in the laboratory, annotated, and communicated so that others know to not use such designs.

e40• 9 years ago

3...2..1.. Prion disease!

Can you explain that?

pishpash• 9 years ago

Also a totally new class of bio weapons.

snakeanus2• 9 years ago

Is there any plan to open source the software?

jfarlow10• 9 years ago

Not at the moment. We do love open source and have an interest in seeing what we can make open. But currently we simply don't have the resources to do so.

There is the Synthetic Biology Open Language (SBOL) that is being developed to make this kind of information interoperable. The standard is young, eager and important work that we appreciate and follow. http://sbolstandard.org/

kristiandupont• 9 years ago

This is fascinating! As someone who knows nothing about this domain whatsoever, could someone point me to some (easy to digest) introductory material? I signed up now, but the terminology is completely alien to me..

jfarlow10• 9 years ago

Proteins are the machines produced to atomic specification by a genetic blueprint encoded in DNA. The are the tools life uses to accomplish most of its tasks. Proteins are formed like 'beads on a string' - a chemical single-dimensional chain, where twenty different chemical 'amino acids' are mix-and-matched. The amino acids are strung from an 'N' terminus to a 'C' terminus in order to produce nearly every machine all biology uses for every task a cell might need to survive - structural, chemical, metabolic, energetic, sensation, etc. Once produced, the chain of amino acids folds in on itself in 3D, and many 'motifs' or 'domains' have particular functions as sets of tens to hundreds of amino acids. The software, Pinecone, allows you to characterize and then mix-and-match those domains to produce protein machines with novel function. It is essentially a 1D CAD program that outputs 3D atomically defined objects, but compiles down to DNA that nearly any organism can read. It's not all that different from a molecular Kerbal Space Program - a hardware store for protein domains - but one where you can press 'print' and get your DNA delivered.

- Protein Domains: https://www.youtube.com/results?search_query=protein+domains

- How proteins are made: https://www.youtube.com/watch?v=gG7uCskUOrA

- Visualization of protein machines in use: https://www.youtube.com/watch?v=wJyUtbn0O5Y

- Economically, socially & therapeutically valuable Proteins: https://serotiny.bio/notes/proteins/

The basic concepts and terminology are a mix of biochemistry and molecular biology and are describing organic machines that are thousands to hundreds of thousands of atoms, and a couple of nanometers in length on a side.

aaronbrethorst• 9 years ago

"While Novartis will not estimate the price it will ultimately put on the treatment, some industry analysts project it will cost $500,000 per infusion."

Meanwhile, the latest version of the US Senate's healthcare bill includes the so-called Cruz Amendment[1], which would allow insurance companies to offer health insurance plans without essential health benefits, which would allow lifetime caps on insurance[2], which could mean that your six year old with recurring leukemia gets pulled off their treatment when they're halfway through. Not because you did anything wrong, per se, but because maybe your employer refuses to spring for health care plans with more than an $x dollar cap. Or you never anticipated something so horrific and catastrophic happening to your family.

[1] https://www.nytimes.com/2017/07/13/us/politics/senate-republ...

[2] https://www.brookings.edu/2017/05/02/allowing-states-to-defi...

logfromblammo• 9 years ago

You could always pay the alternate price of kidnapping a Novartis executive's child until the treatment is completed, and then surrendering yourself to a lengthy prison term afterward. I can't pay $500k out of my own pocket, but I can buy a roll of duct tape and rationalize the hell out of an ethically tricky situation.

That's one of the classic posers to gauge someone's level of ethical maturity, isn't it? Your child is dying, and you cannot afford the treatment. Would you steal it instead of buying it? Why?

sloppycee• 9 years ago

That sounds horrible.

Although, I do wonder what effects there would be if a cancer cure-all were discovered.

Since nearly everyone would need the treatment at some point, it wouldn't really be insurance anymore; more like a mortgage.

PeterisP4• 9 years ago

We're already at this stage - we have many life-extending (there's no life saving, only extending it for smaller or larger amounts) treatments and procedures, and the amount is growing. For pretty much every patient who dies currently we could extend their life a bit more (not they'd always want that, mind you) if we put in more resources in that patient.

It's tautologically clear that it's not possible to do everything for everyone, i.e. a community 100% composed of doctors and nurses wouldn't be able to provide all the possible life-extending things (especially late in life/close to death) to everyone of themselves. So one way or another we need a process to decide where we stop, i.e. what life-extending things will not be provided to which people.

Of course, there's a major practical difference between in a process that takes/costs one day of labor and extends life expectancy by a year, and a process that takes/costs a year of labor and extends life expectancy by a day - but there's no conceptual difference, and we have options all along that scale to find where the tradeoff starts/stops making sense.

Young_God• 9 years ago

A friend of mine is alive today because he was part of one of the early trials. He had been told by his doctor, just before he was accepted into the trial, that he should start putting his affairs in order.

judah• 9 years ago

Is this the same CAR-T treatment that Juno Therapeutics tried and scrapped[0] after 5 trial patients died after receiving the treatment?

[0] http://www.xconomy.com/seattle/2017/03/01/after-trial-deaths...

ksenzee• 9 years ago

No. From the article:

In the past, a handful of patients who were getting similar treatments developed by other companies died from serious brain swelling. Although those sorts of complications did occur in some patients receiving CTL019, the patients recovered and there were no fatalities, the company says.

known2• 9 years ago

Isn't this how vaccines work?

jfarlow10• 9 years ago

Vaccines work by previewing a foreign object, that if seen again, the immune system will attack. The big difference in treating cancer is that there is nothing 'foreign' about cancer - it arises from one's own cells. Cancer is an unproductive or even malicious mashup of material already found in the human body, very much unlike a viral or bacterial infection. There are no natural differences in kind that can be detected by an immune system that would not otherwise attack healthy tissue as well.

In this case there is essentially a synthetic sensor designed and provided to the immune system that is precisely tuned in the lab to detect the (very subtle) differences between a cancer cell and a healthy cell.

known2• 9 years ago

  it will cost $500,000 per infusion

dajohnson89• 9 years ago

Making the choice between being indebted for your entire life and just dying is surprisingly hard for me.

'Living Drug' That Fights Cancer by Harnessing Immune System Clears Key Hurdle

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