
Doctors hail world first as woman’s advanced breast cancer is eradicated - okket
https://www.theguardian.com/science/2018/jun/04/doctors-hail-world-first-as-womans-advanced-breast-cancer-is-eradicated
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andyjohnson0
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].

[1] [https://www.cancer.gov/news-events/press-
releases/2018/immun...](https://www.cancer.gov/news-events/press-
releases/2018/immunotherapy-targets-breast-cancer-case-report)

[2]
[https://clinicaltrials.gov/ct2/show/NCT01174121](https://clinicaltrials.gov/ct2/show/NCT01174121)

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justinjlynn
cheers! DOIs really should be a required part the title here (if available)...

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agumonkey
sci-hub support title searches

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justinjlynn
yes, but that's not really the point -- is it? The usage of an applicable DOI
is unambiguous and places much less load on scihub.

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agumonkey
just passing the information, sometimes you don't even have a doi, and sci-hub
might find the paper

that said I don't want to crash sci-hub so use with care

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ronzensci
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.

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chrisprobert
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.

There is a great review on progress in cell based immunotherapies here:
[https://www.cell.com/cell/abstract/S0092-8674(17)30064-8](https://www.cell.com/cell/abstract/S0092-8674\(17\)30064-8)

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kurthr
Thanks! That is an excellent and relatively modern review article.

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asdfman123
Wow, imagine going from "You have 3 years to live" to "You have no more
cancer." What a miracle.

~~~
munificent
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.

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ergothus
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".

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da_chicken
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.

~~~
civilitty
Even then, don't oncologists highly recommend an annual screening for the rest
of your life?

~~~
da_chicken
Periodically, I think. I don't know how often. Unfortunately, everybody I know
who has had cancer is no longer around.

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epmaybe
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.

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aaavl2821
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

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SubiculumCode
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.

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osrec
This sounds amazing. I know this is just one case, but can someone with more
knowledge confirm that this is as game-changing as it seems?

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TheAdamAndChe
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.

~~~
ForHackernews
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.

[https://www.genome.gov/images/content/costpermb_2017.jpg](https://www.genome.gov/images/content/costpermb_2017.jpg)

~~~
aaavl2821
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

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jtchang
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?

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aaavl2821
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.

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ashelmire
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?

~~~
aaavl2821
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

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agumonkey
One thought for all those who couldn't live long enough to get there.

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mmmBacon
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.

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calewis
Well done to all the smart people involved in making this happen, you're all
making such a positive impact on human society, go you!

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gigatexal
Awesome! This is great news for women everywhere.

~~~
klipt
Good news for everyone really. Men can also get breast cancer, and
immunotherapy treatment is applicable to many other cancer types.

~~~
ralusek
And also it's good news for everybody even if men were not at all subject to
the advancement personally.

~~~
klipt
> 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.

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macintux
I thought that was the point of the parent’s comment.

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AKifer
now comes the time for the pricing

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epmaybe
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.

~~~
klipt
Considering that surgery can cost close to that and isn't a full cure, CAR-T
is not that expensive relatively speaking.

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new_guy
>“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.

