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Comment by rubicon33 | Hacker News Reader

Fascinating, this drug (molecule) somehow “unmasks” the cancer cells, allowing the body’s natural immune system to target and destroy them.

How does a molecule do that!? Enters the blood stream, is absorbed by the cancer cell, and then…? Blocks some enzyme?

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The name of the drug ends in "-mab" [0] indicating that the drug is based on monoclonal antibodies [1,2]. Those antibodies are tweaked to bind to cancer cells which makes the immune system attack the cancer cells.

[0] https://en.wikipedia.org/wiki/Drug_nomenclature#List_of_stem...

[1] https://en.wikipedia.org/wiki/Monoclonal_antibody

[2] https://en.wikipedia.org/wiki/Monoclonal_antibody_therapy

IIRC, in this particular case the antibodies bind to immune cells. Immune Checkpoints are a mechanism that keeps the immune system from attacking the own body but in cancer it can also stop the immune system from destroying the cancer. The checkpoint inhibitor antibodies remove these restrictions and allow the immune cells to attack the cancer. (The price is that they also become free to attack other things they shouldn't; autoimmune inflamations are common side effects.)

https://en.wikipedia.org/wiki/Checkpoint_inhibitor

Who the hell designed this computer?

Several varieties of T cells are very dangerous and like to murder other cells. In order to prevent them from going on a rampage, they have a switch called PD-1 that calms them down. This prevents various auto-immune diseases in healthy people.

Some varieties of cancer cells release a PD-1 ligand that turns off T cells when they get close to the cancer. So the cancer can "hide" from the immune system.

This monoclonal antibody blocks PD-1 on T cells, turning them into unstoppable murderers. The hope is that they preferentially murder the cancer cells. Wikipedia says that ~5% of patients get dangerous side effects from blocking T cell PD-1, probably because the unstoppable T cells attack healthy kidney or liver tissue. But for people with specific types of cancer, the hope is that turning the T cells loose will kill the cancer first.

That is the function of checkpoint inhibitors, according to an explanation I got from a cancer researcher after asking a similar question.

Essential, cancer cells convince the immune system not to attack them, so these inhibitors target the mechanisms by which they do so to get the immune system to take note of these cells. Hope someone more knowledgeable will correct me if I'm wrong.

Cancer cells express proteins that communicate with lymphocytes (white blood cells) to block apoptosis (cell death).

We can't target the cancer cells, so we tweak the lymphocytes to block PD-1 receptors, thus ignoring ALL cells that express a lot of PD-L! protein.

This unfortunately includes healthy cells.

It's an antibody.

https://en.m.wikipedia.org/wiki/Dostarlimab

https://en.wikipedia.org/wiki/Pembrolizumab

There are two types PD1 and PDL1 inhibitors.

Cancer cells (and our own cells) express PDL1. Our immune cells touch PDL1 with their PD1 and if this connection works then the immune cell does not kill.

If the connection does not work (PDL1 or PD1 absent) the immune cell will kill the target cell.

These antibodies either block PDL1 or PD1.

Couldn't read the article but yea, if it's a small molecule, most likely it's inhibiting some protein specific to cancerous cells. In this case, it sounds like it's blocking some protein that blocks human cells' innate ability to produce antigens, which signal to T-cells that they are defective and need to be destroyed.

Sometimes we understand the biology after we discover a treatment.

It’s not a small molecule, it’s a biologic (antibody). It was designed specifically to do what it does, and not discovered by chance.

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