Evaluation of vecabrutinib as a model for noncovalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia.

Abstract

Covalent Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib, have proven to be highly beneficial in the treatment of chronic lymphocytic leukemia (CLL). Interestingly, the off-target inhibition of IL-2-inducible T-cell kinase (ITK) by ibrutinib may also play a role in modulating the tumor microenvironment, potentially enhancing the treatment benefit. However, resistance to covalently binding BTK inhibitors can develop as the result of a mutation in cysteine 481 of BTK (C481S), which prevents irreversible binding of the drugs. In the present study we performed preclinical characterization of vecabrutinib, a next-generation noncovalent BTK inhibitor that has ITK-inhibitory properties similar to those of ibrutinib. Unlike ibrutinib and other covalent BTK inhibitors, vecabrutinib showed retention of the inhibitory effect on C481S BTK mutants in vitro, similar to that of wild-type BTK. In the murine Eμ-TCL1 adoptive transfer model, vecabrutinib reduced tumor burden and significantly improved survival. Vecabrutinib treatment led to a decrease in CD8+ effector and memory T-cell populations, whereas the naive populations were increased. Of importance, vecabrutinib treatment significantly reduced the frequency of regulatory CD4+ T cells in vivo. Unlike ibrutinib, vecabrutinib treatment showed minimal adverse impact on the activation and proliferation of isolated T cells. Lastly, combination treatment with vecabrutinib and venetoclax augmented treatment efficacy, significantly improved survival, and led to favorable reprogramming of the microenvironment in the murine Eμ-TCL1 model. Thus, noncovalent BTK/ITK inhibitors, such as vecabrutinib, may be efficacious in C481S BTK mutant CLL while preserving the T-cell immunomodulatory function of ibrutinib.

• Authors: Billy Michael Chelliah Jebaraj, Annika Müller, Rashmi Priyadharshini Dheenadayalan, Sascha Endres, Philipp M Roessner, Felix Seyfried, Claudia Walliser, Martin Wist, Jialei Qi, Eugen Tausch, Daniel Mertens, Judith A Fox, Klaus-Michael Debatin, Lüder Hinrich Meyer, Pietro Taverna, Martina Seiffert, Peter Gierschik, Stephan Stilgenbauer
• Journal: Blood (Blood) Vol. 139 Issue 6 Pg. 859-875 (02 10 2022) ISSN: 1528-0020 [Electronic] United States
• PMID: 34662393 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 by The American Society of Hematology.

Chemical References

• Agammaglobulinaemia Tyrosine Kinase
• emt protein-tyrosine kinase
• Protein Kinase Inhibitors
• Protein-Tyrosine Kinases
• vecabrutinib

Topics

• Animals
• Female
• Humans
• Agammaglobulinaemia Tyrosine Kinase (antagonists & inhibitors)
• Cell Line, Tumor
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, pathology)
• Mice, Inbred C57BL
• Models, Molecular
• Protein Kinase Inhibitors (therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Tumor Burden (drug effects)
• Mice