This presentation is part of CLL Global Research Foundation’s first-ever Patient-Focused research symposium, featuring CLL Global–funded researchers sharing insights from their latest studies and clinical trials—showcasing how their work is directly improving outcomes for patients with chronic lymphocytic leukemia (CLL).
Expert Presenter:
Deepa Sampath, PhD
Professor, Department of Hematopoietic Biology and Malignancy
The University of Texas MD Anderson Cancer Center
Download the slide deck.
Transcript:
Dr. Deepa Sampath: Hello, everyone. Really happy to be here and give you an example of what we do beyond established trials and how your support helps this in a number of ways. So, I’d like to summarize. Dr. Jain gave us a very detailed description of all the trials that are being run at MD Anderson and the spectacular responses that people are having when they’re on these trials. But this goes beyond that, and I’m just going to use this slide to tell everybody about all the work that we do and the results that come from it.
So, when you look at CLL cells under the microscope, they all look like number 1. They look identical. But, actually, they’re quite different. You can see that all cells are made of DNA, RNA, and protein. And even at the very early stages, there are small differences in the DNA, in the RNA, and in the protein. So, when patients receive their first BTKi, and this happens in a number of institutions and also in the community. They do really well. They get the covalent BTKi, but then their DNA starts acting up, and they get resistant. Then they get non-covalent BTKi, some of the – there are other changes that happen in the DNA, and they get resistant. And in the community, what happens is then they relapse, then they go onto BCL-2 inhibitors, most commonly venetoclax (Venclexta), but again, the DNA and the RNA undergoes changes, and they become resistant.
At MD Anderson, Dr. Jain and Dr. Wierda have come up with this combination of using BTKi and BCL-2 inhibitors together. And those are pretty good because you have a great response, 100 percent response likely, but over time, some of the cells begin to come back. And one of the big, and that’s called the minimal residual disease state. And one of the big focus that we are having as a group is we are trying to see at the single cell level, what is the DNA, the RNA, and the protein of the MRD-positive cells, and how those cells can push the disease to come back as dual-refracted disease resistant to BTK and BCL-2. Once you have MRD, the problem is you have to go – you respond pretty well to either BTKi given again, or BCL-2, but then you’re back in the situation at the top. You can develop resistance mechanisms, and you have dual refractory disease.
So, these BTK and BCL-2 mutations, as well as certain other mutations, they go away when you treat with BTKi and with BCL-2. But they come back as dual refractory disease. So, one way to think about it is like, yeah, they’re there, what did they do? We decided to do – or study the protein at the single cell level to see what do these mutations, although they are not associated with venetoclax or BTK resistance directly, what do they do? One of the things we see is, they increase the amount of BCL-2 and a sister protein called BCLxL. Now these proteins work together to increase the power of the cell to survive. At the RNA level, what we do is we look at the cells at the single-cell level. And you can see that when it becomes dual-resistant, or resistant to both BTKi and BCL-2 inhibitors, they increase the level of BCL-xL and it’s technically called BCL-2.
So, what we are finding is when the cells become resistant to the most standard of care treatments of BTKi and BCL-2i, they not only retain dependence on BCL-2, but they also gain dependence on BCL-xL, a sister protein that blocks cell death. So, to combat it, my lab came up with a small molecule inhibitor that blocks both BCL-2 and BCL-xL. We’ve published this in pre-clinical studies, and it’s now in a Phase I trial. So, this is a long way off from Phase III trials, where you test it and you really understand is it going to work or no? But, initial work, this is a multi-center study, so patients have been entered at MD Anderson and at Ohio State University. And this small molecule that blocks BCL-2 and BCL-xL has done really well for CLL patients. But these are early days yet, and we need to test it some more.
Most times, just one molecule is never the magic bullet. So, my lab is developing another way, which is using a proton degrader to target BCL-2 and BCL-xL, and we are hopeful that at MD Anderson, we’ll be able to conduct trials later to see if this concept works for patients with dual-refractory CLL. Thank you so much.