FINALLY, I'm ready to talk about the approaches in immunotherapy with Approach 1: Immune checkpoint blockade therapy.

I feel like I’m just about to embark upon listing off all the characters in Game of Thrones...regardless, we’re going to start with a simplified overview of a few key players in immune checkpoint blockade therapy in order to then try to keep track of the various receptors that either activate or reign in these key players.

OK, here we go!

Receptors are these protrusions made of proteins that are embedded on the cell surface, and they basically function to identify and/or interact with what is beyond the cell membrane. Receptors are specific shapes, and sometimes are made up of separate proteins which combine to form a unique receptor. That which binds to a receptor is called a ligand, and some ligands can bind to more than one type of receptor (see B7.1/2 on the APC cells in image). The same type of receptor can also be found on many different kinds of cells, as we’ll see in the next post.

Once a cell has been triggered by a receptor bound by its ligand, that cell will perform its active duties and continue to do so, forever. So what shuts it down? When we’re hungry, for instance, a signal from our satiety center will tell us to stop eating. What then, is that signal for a cell?

The answer: yet another receptor that is bound by its ligand will tell the cell to STOP. With the APC–T cell complex above, this receptor–ligand is the CTLA-4--B7.1/2 pairing. So, as the APC is presenting the antigen from a tumor via its MHC to the T cell, it is simultaneously binding with the T cell’s CTLA-4 receptor to tell it to “HEAL!” But if it encounters that antigen again, it will cut loose.

The T cell then continues along having not been activated. But it has been primed to recognize that antigen.

Next post, let’s get to the heart of checkpoint blockade immunotherapy.

The last post’s question was: what do you think happens when your immune cells encounter a cancerous, or tumor cell?

Our whole immune system works because of a most important feature, and that is the ability to distinguish a self entity from a non-self entity. That means there is a”loophole” with a cancer cell, because a cancer cell was once a normal cell. So, herein lies the basis of WHY cancer cells might have the ability to evade our immune system: the cancer cells are still regarded as “self,” to a certain extent.

An activated T cell can be likened to the Looney Tunes’ Tasmanian devil: when he gets going, he is out of control, voracious and destructive to everything in his path. But clearly that doesn’t happen in a normal scenario with T cells. Otherwise, the cells invaded by bacteria/viruses/other foreign particles would be under attack ALL the time, as once the T cells are triggered, they will keep attacking. Instead, the T cells themselves have internal systems that stop them from attacking everything in sight, that are triggered by other cells through receptors. These can be analogous to the “breaks” on a car, except that the brake system is activated externally.

So, all these built-in programs of the immune system are targeted in Immunotherapy, and are outlined in the graphic as Approaches 1, 2 and 3.

Next post, which will be September 22, we’ll tackle Approach 1: Checkpoint inhibitors.