Journal Article

DKFZ-2020-00515

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Combining ibrutinib and checkpoint blockade improves CD8+ T-cell function and control of chronic lymphocytic leukemia in Em-TCL1 mice.

Hanna, B. (First author)DKFZ* ; Yazdanparast, H.DKFZ* ; Demerdash, Y.DKFZ* ; Roessner, P. M.DKFZ* ; Schulz, R.DKFZ* ; Lichter, P.DKFZ* ; Stilgenbauer, S. ; Seiffert, M. (Last author)DKFZ*

2021
Ferrata Storti Foundation64433 Pavia

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Please use a persistent id in citations: doi:10.3324/haematol.2019.238154

Abstract: 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 Eµ-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 sum, these data emphasize the strong immunomodulatory effects of ibrutinib and the therapeutic potential of its combination with immune checkpoint blockade in CLL.

Note: #EA:B060#LA:B060#2021 Apr 1;106(4):968-977 / #DKFZ-MOST-Ca177#

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Contributing Institute(s):

1. B060 Molekulare Genetik (B060)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2021

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Database coverage:
; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DOAJ Seal ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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