PB1877 DISSECTION OF THE EFFECTS OF JAK AND BTK INHIBITORS ON THE FUNCTIONALITY OF HEALTHY AND MALIGNANT LYMPHOCYTES

Background: Despite the emergence of small molecule inhibitors, current treatment modalities for chronic lymphocytic leukemia (CLL) are not curative, and the search for new therapeutic strategies continues. Pro‐survival signaling derived from the micro‐environment is often mediated via JAK signaling. However, whether JAK inhibitors are useful in CLL therapy has not been studied extensively. JAK inhibitors are valuable therapeutic agents in myelofibrosis and show promising results in graft‐versus‐host‐disease, but are associated with an increased infection risk, presumably due to their effect on other immune cells. Other kinase inhibitors used for CLL treatment, like the BTK inhibitor ibrutinib and PI3Kδ inhibitor idelalisib, have similar off‐tumor effects. Aims: We compared functional effects of the JAK inhibitors momelotinib and ruxolitinib, BTK inhibitors ibrutinib and tirabrutinib and PI3Kδ inhibitor idelalisib on malignant CLL cells, but also healthy T, B and NK lymphocytes. Methods: Immune modulation of CLL cells and healthy lymphocytes by kinase inhibitors was studied using in vitro stimulation assays that activate either B cells, NK cells or T cells. Results: We found several interesting differences among the inhibitors, apart from expected and well–known effects. Momelotinib but not ruxolitinib blocked cytokine‐induced proliferation of CLL cells. Momelotinib also reduced B cell receptor (BCR) signaling in contrast to ruxolitinib, indicating that these JAK inhibitors in fact have a distinct target spectrum. In contrast to tirabrutinib, ibrutinib had inhibitory effects on T cell activation, probably due to ITK inhibition. Remarkably, both BTK inhibitors stimulated IFN‐γ production in a mixed lymphocyte reaction. Summary/Conclusion: Collectively, our results demonstrate that kinase inhibitors directed at identical targets may have differential effects on lymphocyte function, and their unique profile could be strategically employed to balance desired versus unwanted lymphocyte inhibition in cancer‐ or autoimmune therapies.