Journal
HAEMATOLOGICA
Volume 106, Issue 4, Pages 968-977Publisher
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2019.238154
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Funding
- German Jose Carreras Foundation [13R/2018]
- German Cancer Aid [112069]
- BMBF-Network PRECiSe [031L0076A]
- ERA-NET TRANSCAN-2 program JTC 2014-project FIRECLL
- Cooperation Program in Cancer Research of the DKFZ
- Israel's Ministry of Science, Technology and Space
- DFG [SFB1074]
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Ibrutinib, as a BTK inhibitor, not only affects CLL cells by blocking B-cell receptor signaling, but also impacts the microenvironment and CD8(+) T cells. Direct effects on TCR activity and the potential for co-stimulation via CD28 to overcome these effects have been demonstrated in studies. Additionally, combination therapy with PD-1/PD-L1 blockade shows promise in improving CD8(+) T-cell function in CLL.
Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of multiple B-cell malignancies, including chronic lymphocytic leukemia (CLL). In addition to blocking B-cell receptor signaling and chemokine receptor-mediated pathways in CLL cells, that are known drivers of disease, ibrutinib also affects the microenvironment in CLL via targeting BTK in myeloid cells and IL-2-inducible T-cell kinase (ITK) in T cells. These non-BTK effects were suggested to contribute to the success of ibrutinib in CLL. By using the E mu-TCL1 adoptive transfer mouse model of CLL, we observed that ibrutinib effectively controls leukemia development, but also results in significantly lower numbers of CD8(+) effector T cells, with lower expression of activation markers, as well as impaired proliferation and effector function. Using CD8(+) T cells from a T-cell receptor (TCR) reporter mouse, we verified that this is due to a direct effect of ibrutinib on TCR activity, and demonstrate that co-stimulation via CD28 overcomes these effects. Most interestingly, combination of ibrutinib with blocking antibodies targeting PD-1/PD-L1 axis in vivo improved CD8(+) T-cell effector function and control of CLL. In summary, these data emphasize the strong immunomodulatory effects of ibrutinib and the therapeutic potential of its combination with immune checkpoint blockade in CLL.
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