Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
BTK degrader NX-2127 enhanced T cell function in the lab, suggesting that it may mitigate CLL-associated immunosuppression.
Who Performed the Research and Where Was it Presented:
Dr. Alexey Danilov from City of Hope National Medical Center and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2024.
Background:
Bruton tyrosine kinase (BTK) is a protein that is integral to the survival and proliferation of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) cells. BTK inhibitors work by binding to the BTK protein and inhibiting its function. They have also been shown to improve T cell function, essential for immunocompromised CLL / SLL patients. T cells in CLL / SLL patients are said to be “exhausted,” so they don’t respond to infections, as well as in individuals with fully functional immune systems. Unfortunately, over time, CLL / SLL cells can develop resistance mutations that prevent BTK inhibitors from binding.
BTK degraders are relatively new drugs that destroy the BTK protein rather than just inhibiting its function. They bind to BTK and shuttle it to the cell’s garbage disposal, where it is chopped up and destroyed. Researchers wanted to know whether BTK degraders also affect T cell function.
Methods and Participants:
This lab bench study compared the effects of BTK degraders NX-2127 and NX-5948 with ibrutinib and lenalidomide (another drug with immunomodulatory effects). Blood cells were collected from CLL patients, and the isolated cells were studied in the lab under different treatment conditions.
Results:
- Treatment with both NX-2127 and NX-5948 caused degradation of BTK in CLL cells.
- The BTK degraders did not interfere with T cell activation or survival.
- NX-2127 and lenalidomide enhanced T-cell mediated killing of B-cell non-Hodgkin lymphoma cells in a dish.
- NX-2127 can rebalance a patient’s T cells towards a more proinflammatory, antitumor phenotype, which helps T cells see and kill cancer cells.
- NX-5948 had none of the immunomodulating effects seen with either NX-2127 or lenalidomide.
Conclusions:
NX-2127 enhanced T cell function in the lab, which suggests it may mitigate CLL-associated immunosuppression. Further studies in people are needed to confirm this finding. Lenalidomide is active in CLL and is still used off-label, but its development was stopped due to side effects. If NX-2127 is better tolerated, it is hoped that its dual activity as a BTK degrader and its similar immunomodulatory effects might lead to a potent therapy.
Links and Resources:
Watch the interview on the abstract here:
You can read the ASH abstract here: Nx-2127 and Nx-5948, Two Clinical Stage Cereblon-Recruiting BTK Degraders, Facilitate T Cell Functionality in Chronic Lymphocytic Leukemia
