Proapoptotic and immunomodulatory effects of SYK inhibitor entospletinib in combination with obinutuzumab in patients with chronic lymphocytic leukaemia

Vi Lam, Scott Best, Adam Kittai, Kirsten Orand, Stephen E Spurgeon, Tingting Liu, Alexey V Danilov, Vi Lam, Scott Best, Adam Kittai, Kirsten Orand, Stephen E Spurgeon, Tingting Liu, Alexey V Danilov

Abstract

Spleen tyrosine kinase (SYK) is indispensable in B-cell receptor signalling. SYK inhibitor entospletinib demonstrated clinical efficacy in patients with chronic lymphocytic leukaemia (CLL). However, pharmacodynamic effects of SYK inhibition in CLL cells and immunomodulatory effects of B-cell receptor-signalling inhibitors in patients with CLL are poorly understood. We conducted a phase 2 trial of entospletinib in combination with obinutuzumab, an anti-CD20 antibody, in 17 patients with relapsed/refractory CLL. Pharmacodynamic analysis demonstrated that treatment with entospletinib led to rapid downmodulation of pSTAT3 and the anti-apoptotic protein MCL1 in CLL cells. Meanwhile, 6 months of combination therapy was accompanied by a reduction in interferon-γ secretion in CD4+ T-cells and a reversal of exhausted phenotype, as evidenced by downregulation of PD-1. Thus, SYK inhibition downmodulates MCL-1 and partially restores T-cell immunity in CLL. Trial registration number NCT03010358.

Keywords: MCL1; PD-1; chronic lymphocytic leukaemia; spleen tyrosine kinase.

© 2021 British Pharmacological Society.

References

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Source: PubMed

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