The Amazing that is PD-1 Blockade

The office is clearly closing up shop for the holiday; this’ll be my last task before heading out myself for a few days. I actually really like these quiet days at work; I can often pick up a few of the long-running side projects that are so hard to squeeze in when everybody’s here. This week it’s been some integration work with Illumina’s BaseSpace service, which is honesty pretty sweet.

cover_nature_V515_Number7528_0End of the year holiday time is also always good for a bit of reflection, and I’ve been appreciating the opportunity I’ve had to start working here with the folks at Adaptive. In particular, a paper was just published by a customer that just has me shaking my head at how incredible this space is.

PD-1 Blockade drugs like Nivolumab are the current face of immunology — these incredible therapies seem to be showing more success against cancers than anything we’ve tried in years. Rather than just trying to knock out tumor cells with radiation or toxic chemicals, PD-1 blockades unleash our own immune systems to do the job. Here’s the deal:

Our T- and B-Cells express a particular protein called “programmed cell death 1.” Like other receptors, PD-1 is anchored in the cell kind of like a blade of grass sits in the ground, with part of it inside the cell wall, and the rest dangling outside.

PD-1’s job is to slow down our immune response. It waits for special proteins (PD Ligands) to float by and bind to its receptor end, which can result in one of two behaviors. Normal immune cells just commit suicide; regulatory T-Cells do the opposite and get busy. The net effect is that when PD-1 is activated, your immune system starts to go quiet.

This is normally a good thing — for example, PD-1 keeps our immune system from attacking itself. But many types of cancer have “figured out” the game; they artificially accelerate the production of PD ligands themselves! This is amazing to think about — the cancers have actually evolved to suppress our own immune system so that we can’t fight back.

Once you see how this works, PD-1 blockade therapies seem pretty obvious — create a drug that stops PD-1 from binding with its ligands, and the immune system is freed up to go nuts. And, holy crap, this actually works!

But it’s also expensive, and it doesn’t always work. That’s where Adaptive comes in: we’ve now shown that the clonality* of a person’s immune repertoire can predict their response to PD-1 blockade. This makes sense if you think about it — all the drug is doing is opening the gates; there has to be an immune response ready to fight in the first place.

Well, it turns out that we basically invented the technology that can measure immune system clonality (amongst other things) using next-generation sequencing. Anybody else see value in a quick lab test that predicts the effectiveness of a miracle drug costing hundreds of thousands of dollars?


* When your immune system is gearing up to fight a particular bad guy, it creates millions of copies or “clones” of the specific sequences that recognize just that antigen. This is quite different when you’re healthy — your immune system then is much more diverse, and has smaller amounts of lots of different sequences, all hunting for invaders to show up.

One thought on “The Amazing that is PD-1 Blockade

  1. Pingback: pairSEQ breaks down another barrier to fixing, well, everything. | import immunity;

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