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Comment by Kalanos | Hacker News Reader

It's a checkpoint inhibitor. Those have been used for ~ every cancer type for over a decade. Keytruda has been a top-selling drug for years.

It looks like this trial was neoadjuvant (before treatment/ alternative to chemo and surgery), but that's not new either.

immunotherapy typically has much lower response rates though, so maybe it's the mismatch repair selection strategy that's novel

at a sample size of 12... they could have gotten lucky

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The targeting here is definitely the point, its the core hypothesis in the abstract. In general this increased targeting ability has been enormously powerful in solving the response rate problem you mentioned. Fundamentally the problem isnt that the response rate is low accross the board, it's that it's incredibly high in a small subset and incredibly low in the rest. Figuring out that subset is basically wins all around - you can identify the actual subpopulation You're treating so your study is better powered (less noise from people who wouldn't be responsive), you can codevelop a diagnostic to identify chance of response, you don't treat and give side effects to patients who won't respond, also saving costs.

This is a bit of a weird post and comment thread because this is an older paper about a technology that is genuinely very successful, but it's being responded to as if it's one of those random mouse trials of a brand new therapeutic strategy. This drug already had accelerated approval and was on the market when this trial was run! In case the rest of the world missed the memo - some of those mouse trials y'all read about in the early 2000s or so? Yeah they worked in humans too. This is one of them.

Using mismatch repair has been a concept for almost a decade now, the initial pd-l1 papers were very much focused on it.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576142/

thanks. yeah i dunno then

First-line nivolumab metastatic colorectal w MMR: https://pubmed.ncbi.nlm.nih.gov/34637336/

first-line keytruda metastatic colorectal w MMR: https://www.nejm.org/doi/full/10.1056/NEJMoa2017699

I'm no expert, but it says it's Dostarlimab, which is billed as a monoclonal antibody. Some googling suggests that monoclonal antibodies and checkpoint inhibitors are both immunotherapy approaches, but that they aren't the same.

They are https://en.m.wikipedia.org/wiki/PD-1_and_PD-L1_inhibitors

The hint is the -mab naming.

-ab means it's an antibody. There are many kinds of antibodies, not just to those two proteins.

And -mab means monoclonal antibody. But your point still stands, there is a huge number of -mab drugs out there today.

It's a really great technology, and not just for drugs. It deservedly won the Nobel Prize in Medicine in 1984.

checkpoint inhibitors are antibodies

For reference, dostarlimab (JEMPERLI) is essentially GSK's answer to Merck's pembrolizumab and BMS's nivolumab. Or KEYTRUDA and OPDIVO, respectively, if you're in the USA and bombarded with pharma ads. All three are monoclonal antibodies that block PD-1 on T cells, thereby stimulating the body's immune system.

i wouldn't refer to it an an immunostimulant. it prevents tumors from hiding.

Immunostimulant is a reasonable way to put it: it takes the brakes off one part of the immune system. (Similarly, we call caffeine a central nervous system stimulant and it works by blocking adenosine, which is one of the brakes on brain activity.)

And it's not always specific to tumours. My wife's thyroid got wiped out. The endocrinologist said it was like bombing a paint factory: first a massive spike in thyroid hormones, then a crash as no more were produced.

More info on the potential side effects of immune checkpoint inhibitors: https://www.cancer.gov/about-cancer/treatment/types/immunoth...

sorry about your wife. an immunostimulant is more about enraging/activating the immune system, not intervening with its capabilities

If you're trying to say that immunostimulant is a term of art distinct from immune checkpoint inhibitor, then fair point.

But what it seems like you're saying is checkpoint inhibitors don't "enrage/activate" the immune system, and they only target tumours, and both points are misleading if not outright wrong.

Yes, it's a different term and entirely separate category of drugs.

Checkpoint inhibitors cut the brakes. This reduces their ability to detect "self," and attack blindly.

What they don't do is poke immune cells with a stick to anger them like chemoattractants and cytokines. This approach can be used to signal, "hey, the tumor is over here." Causing them to attack more intelligently.

If you would like to learn more, I would recommend the books: (a) molecular biology of cancer; mechanisms, targets, and therapeutics, and (b) handbook of therapeutic biomarkers in cancer.

Checkpoint inhibitors are immunotherapies. The checkpoints they're inhibiting are immune checkpoints.

> at a sample size of 12... they could have gotten lucky

right?? this seems like Simpson's Paradox

https://robertheaton.com/2019/02/24/making-peace-with-simpso...

Just like with other tools, good selection matters.

When working with screws, you don't want just any screwdriver, you want the right size.

It is my impression that in this trial, the main idea was to improve the fit between patient and therapy.

The bigger question I have, if these PD-1 blockers all have the same method-of-action, why are they showing different results for different tumors?

even within the same type of tissue, different patients are going to have different mutations/subclones in their tumors.

Depends on if that mechanism of action works for the particular exact set of mutations that the given tumor has (every cancer is essentially unique). Part of the success of the work in that paper is identifying specific markers that indicate that the drug is going to work in that tumor

Both dostarlimab and pembro are PD-1 blockers, yet they are labeled for two different cancers. If all tumors have different characteristics, why are these not labeled for all cancers, in general, that display these expressions? Is this part of the game that the FDA plays?

They are:

https://www.fda.gov/news-events/press-announcements/fda-appr...

https://en.wikipedia.org/wiki/Tissue-agnostic_cancer_drug

If by "game" you mean rigorous regulatory process to ensure safety and efficacy, then yeah. Different monoclonal antibodies even with the same target can behave differently. You'd have to specifically design a trial and seek approval for an indication like the one you described. Which people have done and are doing. It's an exciting field of research!

different cell types express different genes at different amounts at different times

each tumor cell/ subclone has different mutations at different times

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