How Do BTK Degraders Affect the Tumor Cell Microenvironment in CLL?

Our recent CLL Global Research Foundation Town Hall featured CLL Global President, Dr. William Wierda, and Dr. Constantine Tam from Monash University in Melbourne. CLL patient advocate Jeff Folloder moderated the event. Watch the full webinar.

Transcript

Jeff Folloder:                          

We have a question – actually, a couple of questions that came in about the BTK degraders. So, Dr. Tam, a patient from Uruguay asked do BTK degraders affect the tumor cell microenvironment?

Prof. Constantine Tam:          

Excellent question. So, the BTK degraders block the BTK pathway in much the same way as a traditional BTK inhibitors do. So, everything that the traditional drugs do, the BTK degraders do exactly the same. Obviously, expected they do the same. And we do know that traditional BTK degraders – the traditional BTK drugs block the nice sort of nourishing signal that the tumor microenvironment gives to the CLL cells.

So, the CLL cells like living the lymph nodes, in the bone marrow, in the spleen because that’s where they get all the nourishment, and care, and protection from treatment. And the BTK degraders cut that link, and basically stops the CLL cells of survival. So, they do exactly the same as BTK degraders.

Jeff Folloder:                          

So, good information. Let’s stick with the BTK degraders for just a moment. Deb has what I consider to be an awesome question. What happens to healthy cells that are off target cells with the BTK degraders? And if something does happen, is that a permanent negative effect?

Prof. Constantine Tam:          

That’s a wonderful question. So, firstly, it is not permanent. So, the BTK degraders, while they are still in the body, will get your body to destroy the BTK protein. But once you stop taking the medication, it washes out. Now, what happens to normal cells? And that’s always a big question, right? As a patient, you go on to medication that damage your normal cells. And that’s what causes side effects.

So, the BTK degraders, much to our comfort, didn’t have any new side effects compared to the traditional BTK drugs, which is fantastic. And that’s partly backed up by what we know about BTK. So, there’s actually a human disease where children are born without BTK. Okay? It’s called Bruton’s agammaglobulinemia. These are kids who are born without BTK. And what do we know about these kids? We know they have no B cells. So, the B cells are where CLL comes from.

The B cells also make immunoglobulins, which defend against the infection. And that explains why BTK-deficient patients require immunoglobulin replacement. But those kids live normal lives otherwise. They do eventually succumb to infection in the 40s, because they have lifelong lowered immune system. But the heart, the lungs, everything else is normal. So, we do know that in a human, that you can actually be missing BTK for most of your life, and it doesn’t do anything bad to you, except that you will not have any B cells.