To understand the potential of CCR8 assets, it's important to first highlight the importance of PD-1 drug products.

Think of a tumor as a living fortress. It has plenty of ways to defend itself against invaders, which in this case is your own immune system. The good guys are storming the gates in this analogy.

One mechanism is to block immune cells right before they attack. The surface of tumor cells is dotted with PD-L1 receptors, which intercept T cells by binding to their PD-1 receptors, like a lock and key.

Drug products can block this interaction by binding to either the PD-L1 receptor on tumor cells or the PD-1 receptor on T cells. By doing so, they can play a foundational role in many solid tumor and even several liquid tumor cancers. In 2023, these drug products had combined revenue of nearly $45 billion – by far the most of any drug class in history.

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Despite their value, PD-1 / L1 inhibitors have some drawbacks. They're generally not very effective when used alone (as a "monotherapy") and tumor cells gradually develop resistance. Oopsies. However, both primary drawbacks can be explained by the simple fact that blocking PD-1 / L1 interactions is a last line of defense. It occurs right before T cells attack a tumor cell.

So, why not thwart tumor cell defenses further from the fortress gates?

This is where new immuno-oncology targets come into play. One of the most promising is CCR8, which is expressed on regulatory T cells. These cells, called Tregs for short, have a calming effect on the immune system. There's an inverse relationship between Tregs and T cells. Meaning, a higher number of calming Tregs results in a lower number of attacking T cells.

Tumors cells take advantage by bribing Tregs. The currency here is a molecule called CCL1, which binds to CCR8 receptors on the surface of Tregs.

Tumor cells excrete CCL1 to attract Tregs into the vicinity of the fortress, called the tumor microenvironment (TME). Tregs get rich and, in turn, reduce the number of T cells that have a chance to get close to the fortress gates. That alone makes the PD-1 / L1 mechanism – the last line of defense for tumor cells – more effective. If fewer T cells sneak into the TME, then tumor cells have a higher chance of capturing them through receptor interactions.

This is why drug developers are interested in developing CCR8 inhibitors. If a drug product can block the interaction between CCL1 molecules and CCR8 receptors, then tumor cells won't be able to bribe Tregs as easily. If there are fewer Tregs in the TME, then more T cells will have the chance to storm the fortress gates – increasing the chances to overwhelm tumor cells.

Even better, why not create combination therapies by administering both PD-1 / L1 inhibitors and CCR8 inhibitors? Cancerous fortresses might not be so impenetrable after all.

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