Comment by OrthoMetaPara | Hacker News Reader

Comment by OrthoMetaPara | Hacker News Reader

Apparently, these tumors proliferate because they are able to trick killer T cells into not attacking them. The antibody, nivolumab, inhibits this signaling pathway so that the T-cells are capable of attacking the tumor.

From: Gettinger SN, Horn L, Gandhi L, et al. Overall Survival and Long-Term Safety of Nivolumab (Anti–Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer. Journal of Clinical Oncology. 2015;33(18):2004-2012. doi:10.1200/JCO.2014.58.3708.

Programmed death 1 (PD-1) is an immune checkpoint receptor expressed on activated T cells, which normally serves to dampen the immune response to protect against excessive inflammation and the development of autoimmunity. However, in the setting of malignancy, PD-1 signaling, driven primarily by adaptive expression of programmed death ligand 1 (PD-L1) within the tumor, inactivates primed T cells that recognize tumor-specific antigens, allowing tumor growth and metastasis. PD-1 pathway blockade with monoclonal antibodies offers a novel approach to restoring T cell–mediated antitumor immunity, with the potential for application across a broad population of patients with NSCLC.

From the article:

In a trial of more than 350 patients, published in the New England Journal of Medicine, 36% treated with the immunotherapy drug nivolumab were alive after one year compared with 17% who received chemotherapy.

That seems like a small improvement rather than a "game changer."

It's a very big improvement, relative to most cancer treatment advances, assuming it holds up and produces at least temporary remissions for these patients. "Previously treated advanced cancer" means widespread metastatic cancer that has already shown resistance against current therapies. Basically, this is end-stage cancer, with next to no options for the patients. If a treatment approach has been found, it will be extended to more patients and improved. Of course, they won't just rest on their laurels.

Most advances in cancer treatment (which have together added many years to the lives of cancer patients) are actually much smaller than this: a few weeks added to life expectancy here and a small improvement to the survival rate there. But they steadily add up.

> That seems like a small improvement rather than a "game changer."

It shows you are not really aware of the state of Cancer drugs these days. Drugs that can make 20~30% patients live 3 months longer are usually considered pretty good, doubling the percentage of survival in ADVANCED cancer is certainly unheard of.

That's a pretty pathetic standard for "good"

Chimeric Antigen Receptor therapy seems like more of a "game changer," given that it's a new therapeutic direction. This is just another monoclonal antibody.

Spoken like someone who hasn't been following the Kite trials...

Also of note: just like good ol' mAbs, you need a target for CAR-T cells. And BiTEs, and BiKEs, and what have you.

Also also of note: the approaches that took pediatric ALL and adult APL (among others) from 5-10% survival to 90-95% survival weren't single pronged. (Good thing, too; I've seen patients who seemed ideal for CAR-T die when their malignancy outran the engineered cells) The majority of progress in real-world outcomes has arisen from combination or sequential therapies, incrementally improved to decrease toxicity and maximize efficacy.

Which is to say, incrementally advanced.

Last: per the above, you can use the two together. If a tumor is actively suppressing T cells, it isn't going to dissolve from CAR-T cells without a fight. There are additional tactics useful for "priming" the immune system, but in the end I don't see a lot of solid tumors melting away in trials of CAR-T cells (feel free to correct me).

Do take a look at the Kite trials and how they're structured. When you have to condition a patient with fludarabine to hit outcomes (at all) that's not a wonder drug. It's another tool in the toolbox. A necessary and useful tool, but a tool, not a magic wand.

Hey, just so I'm not a total hypocrite, it turns out that you can "turn off" PD-1 and PD-L1 response in CAR-T cells (at least in mouse models, https://www.jci.org/articles/view/83092 ). In the end I stand by my contention that it's a tool and it needs to be used for the right jobs, but it's a very versatile tool.

I work on immunosenescence and immune stimulation (the real thing) in oncology, and I happen to believe that we do many patients a disservice by nuking their immune systems with chemo and then relying on things like TKIs or BiTEs to pick up the mess. But it's also important to keep in mind that Gleevec alone didn't get rid of CML, and the way ALL and APL were managed up to 95% cure rates is by adding a little poison (As2O3, methotrexate, etc.) to the brew (asterisk) to finish things off. It's a delicate balance. I think it always will be.

(asterisk: ok more like a metric fuckload of poisons for ALL. But the real trick is "resurrecting" the patient with leukovorin after folate starvation essentially kills them.)

http://blogs.sciencemag.org/pipeline/archives/2016/07/08/car...

Look up the SuperMAB saga for more cautionary tales. Plenty of people have died from chemo and immunosuppression too (nobody benefits from lungs full of aspergillus and a gut full of C. diff). If it were easy, somebody would have figured it out already :-)

>> This is just another monoclonal antibody.

That is like saying "this is just another GPS guided smart weapon". Just because mAbs aren't new, doesn't mean they don't have enormous therapeutic potential.

>That's a pretty pathetic standard for "good"

The standards are set by reality, not wishes.

> That's a pretty pathetic standard for "good"

Thats because there is almost no low hanging fruit for cancer treatment and therefore you only get incremental progress most of the time.

Doubling survival rates while having far less severe side effects along with proven effectiveness on multiple different types of cancer is definitely a major breakthrough. This is also based on human trails and not rats in a lab.

That sentence is such a pleasure to read.

I wish most cancers treatments were tested in rats in the lab - most of the time they only get tested in inbred mice which are a terrible model for human cancer.

Twice the number surviving one year without the side effects of chemotherapy seems like a pretty big improvement to me, although there are a lot of news articles prematurely hyping "cures for cancer" that will probably never see the light of day.

Well, that's the problem with relative numbers. If my absolute chance of survival increases from 0.1% to 0.2%, I'll take a pass.

Would you choose nothing? If not nothing, why wouldn't you choose the option with a slightly higher chance of success and fewer side effects?

It depends on how well studied the treatment is. If it's been on the market for 70 years, I'd take the chance. Otherwise, why risk waking up one morning with a tail, or having my arm fall off ;)

Because you are going to die pretty quickly either way if you have terminal cancer. At least if you try a new treatment you could theoretically help other people in the future live for longer, and other people who will get very, very rich. lol

If news like this brings people hope, I suppose I shouldn't complain too loudly.

Just be happy you and I are not one of them (yet).

In order for a medication to even begin human testing, you need to show that you've done a ton of lab work to show that a medication works, and that the side effect profile is probably minimal. So, by the time it's offered to you, the risks of the drug having disarming side effects, or of causing you to join the caudal class, are pretty damn minimal.

> pretty damn minimal

Let's revisit which medications have harmful side effects a century from now. It's impractical to run studies with thousands of patients, and we haven't had more than half a century of data on most drugs. Not that there's much interest in replicating studies anyways.

I'm not keen to pop a bunch of pills unless there is significant (absolute, not relative) benefit. Drugs are overprescribed in my part of the world, partly because people assume "cuts risk by 50%" must mean "a lot." It might... it might not.

On a long enough timeline, the survival rate for everyone turns to zero.

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