
'Living Drug' That Fights Cancer by Harnessing Immune System Clears Key Hurdle - daegloe
http://www.npr.org/sections/health-shots/2017/07/12/536812206/living-drug-that-fights-cancer-by-harnessing-the-immune-system-clears-key-hurdle
======
jfarlow
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](https://news.ycombinator.com/item?id=14446679)

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

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

~~~
skummetmaelk
3...2..1.. Prion disease!

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

~~~
e40
_3...2..1.. Prion disease!_

Can you explain that?

~~~
jfarlow
Prions are 'misfolded' proteins [1] that, in their misfolded form actually
cause other proteins to also misfold - a physical viral cascade. A really
crazy concept not too dissimilar from a kind of biological 'grey goo' \- and
in real life actually happens to cause diseases like 'mad cow'. The
implication is that blindly engineering a protein might create such a physical
virus. I would suggest that the likelihood of accidentally creating such a
virus is very much like accidentally creating stuxnet. Possible, but
extraordinarily unlikely. And further, would such a thing be made, we'd like
to know about it while it's still in the lab and can be contained, learned
about, and prevented in the future.

[1] [https://en.wikipedia.org/wiki/Prion](https://en.wikipedia.org/wiki/Prion)

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

~~~
Cerium
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.

~~~
inlined
The t-cells would multiply? I thought they were created in the bone marrow. Do
bloodstream t-cells go through meiosis?

------
Young_God
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.

------
eatbitseveryday
NYTimes also covers the story ([https://www.nytimes.com/2017/07/12/health/fda-
novartis-leuke...](https://www.nytimes.com/2017/07/12/health/fda-novartis-
leukemia-gene-medicine.html)) 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
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.

~~~
epmaybe
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.

~~~
jlg23
> I know that the R&D for this kind of therapy is exceedingly high

Do you have a source for that? I happen to be involved (genetically only - my
family) into medical research and everyone I know agrees that costs are vastly
inflated:

* Marketing for a new drug is not "research".

* Reformulation of trial-targets is not "research", it's re-shaping of the test settings so you can get $drug to market ASAP.

* When the government/"the people" pay for research (through co-operations with universities), it's not your "R&D cost".

* When you do basic research, it's incredibly easy to claim "10k hours". Ok, but can we please claim those 10k hours only once? Not for every variation of the substance you research again and again?

~~~
doctoring
(I'm a physician who used to work with large pharma companies on trial design
and trial innovation.)

I think the cost of R&D in pharma that we hear about is sometimes vastly
inflated and sometimes pretty accurate, but definitely oftentimes misapplied
(especially by pharma).

On the whole, trials are expensive. Sure, there's the pre-clinical stuff --
basic research that you're alluding to. There's the stuff that is R&D but
fails in the pipeline at some point. There's animal studies.

But in most cases, most of the cost comes from human trials (Phase I-III, and
mostly Phase III), which can sometimes span dozens of countries and tens of
thousands of participants. For some drugs, the Phase III trial(s) account for
over 80% of the total R&D cost. Even when they are relatively small trials (as
in this CAR-T therapy trial), the administrative and logistical effort to
implement something like this is immense. The whole point of these trials is
to collect data, and so that data is subject to the highest amount of scrutiny
of any data in any medical enterprise. If you come into my clinic for a pre-op
before surgery and I measure your blood pressure to be 140/85, give or take a
few (oh wait maybe I used the wrong cuff size, lemme try again, oh it's pretty
close), that's fine. But if you come into my clinic because you're a
participant on a trial for drug X, and I measure it to be 140/85... I better
be damn sure that's right (and the study coordinator at my clinic, and the
pharma company, and the FDA), even if drug X isn't a blood pressure drug.
We've seen cases where certain innocuous data discrepancies trigger central
study monitors (study employees) being flown out to remote clinics to manually
verify paper records or equipment logs to confirm/reconcile errors.
Inaccuracies can cause you to miss things, or patients to be harmed, or can
cause a study or a clinic or a hospital to be shut out from performing
research again. And of course it can make the difference between a drug
approval and failure. It's a lot of resources around the idea of data
integrity.

So even small versions of these types of trials can be very expensive.

Now, is it TOO expensive? We often hear about the cost of bringing a drug to
market to be around $1B. (Some studies have put it over $2B when you account
for failed drugs, etc.) This may or may not be right, but let's not forget,
the pharma industry makes more profit than just about any other industry. And
the way CMS and insurers agree to pay for medicines... well, pharma has a lot
of freedom in pricing (upwards).

You've hit on a lot of things that make the release of some new
drugs/devices/therapies _less_ expensive than we are commonly led to believe:
reusing previous data, getting new approval for a specific enantiomer of a
previously approved racemic drug, making cosmetic updates to existing devices,
the tricks go on and on and on. And pharma keeps saying "R&D is so expensive!
This drug should definitely be 2X more expensive than the one we're
replacing." Planned obsolescence is a pain with your smartphone; it's a lot
worse with your insulin pump or even the insulin itself! And one outcome of
the high cost of large trials is that pharma does more of these types of un-
innovation in some cases, which (due to the patent and regulatory and
reimbursement systems) simply give pharma a free pass at making easy money off
of our backs.

The high cost of trials also leads to really high prices of "true" innovation,
such as in CAR-T trials. This type of therapy (like a lot of new oncology
therapy) is highly customized, and no longer simply some chemical compound you
make in a factory and then ship all over the world. You have to take a
patient's own cells/fluid/materials/etc, process them, and then make
modifications (in some cases unique to the patient), and then return the
processed product (to the same patient). This is indeed highly costly on top
of the cost of performing a lengthy trial, where for certain rare and/or
terminal diseases your study endpoints are pretty tough to capture (um, did
the patient die? uh, how long do we wait?).

~~~
jlg23
> most of the cost comes from human trials (Phase I-III, and mostly Phase
> III), which can sometimes span dozens of countries and tens of thousands of
> participants

Uhm. Yes. Again, I'd rather have an actual break down of the costs involved
here. At least in Germany insanely overpaying doctors for conducting phase III
trials replaced the [at least] $3-4k/day budgets pharma companies had to
accommodate relevant practitioners at congresses when it was outlawed.

When the head of a public hospital in a western country can legally triple
his/her income by conducting a study for 4h every Saturday morning, I file the
costs under marketing, not R&D.

~~~
refurb
It's not that hard to estimate clinical trials costs. Last I checked you were
looking at $10-20K per patient per year. It all depends on how much monitoring
you are doing.

Now run the math. For a broadly used drug, you might need a trial of 20,000
people over 3 years (if you're looking for a long-term benefit). That's what a
lot of the statin drugs did. That alone would be $1.2B at the high end, $600M
at the low end.

And you have to run a minimum of two phase 3 trials. Follow on trials are even
more.

------
JoeAltmaier
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}

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

~~~
HillaryBriss
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.

------
aaronbrethorst
"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...](https://www.nytimes.com/2017/07/13/us/politics/senate-republican-
health-care-bill.html)

[2] [https://www.brookings.edu/2017/05/02/allowing-states-to-
defi...](https://www.brookings.edu/2017/05/02/allowing-states-to-define-
essential-health-benefits-could-weaken-aca-protections-against-catastrophic-
costs-for-people-with-employer-coverage-nationwide/)

~~~
sloppycee
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.

~~~
PeterisP
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.

------
ceejayoz
> 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.

~~~
pinaceae
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?

~~~
orbitur
> 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.

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

It can't be a right. That would mean someone has an obligation to provide it.
I would say it's worth so much that a monopoly on it should not be allowed.

~~~
ceejayoz
> It can't be a right. That would mean someone has an obligation to provide
> it.

By that logic, voting can't be a right, because someone has to register
voters, run the polling booths, count the votes, etc.

~~~
njarboe
If the health care system was mostly staffed by unpaid volunteers, I might
agree. As it stands health care is 17% of US GDP (10% global) and growing.

------
sjbase
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?

~~~
jfarlow
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.

------
judah
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...](http://www.xconomy.com/seattle/2017/03/01/after-trial-deaths-juno-
pivots-and-scraps-lead-car-t-therapy/)

~~~
ksenzee
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.

------
known

      it will cost $500,000 per infusion

~~~
dajohnson89
Making the choice between being indebted for your entire life and just dying
is surprisingly hard for me.

------
known
Isn't this how vaccines work?

~~~
jfarlow
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.

