期刊
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
卷 88, 期 2, 页码 836-841出版社
WILEY
DOI: 10.1111/bcp.14962
关键词
chronic lymphocytic leukaemia; MCL1; PD-1; spleen tyrosine kinase
资金
- Gilead Sciences Inc
- Roche/Genentech
- Leukemia & Lymphoma Society Scholar in Clinical Research Award [2319-19]
- American Society of Hematology Bridge Award
A phase 2 clinical trial found that combination therapy of SYK inhibitor entospletinib and anti-CD20 antibody obinutuzumab in CLL patients led to rapid downmodulation of activated proteins and anti-apoptotic proteins in CLL cells, partially restoring T-cell immunity.
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-gamma 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.
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