Combining ibrutinib and checkpoint blockade improves CD8+ T-cell function and control of chronic lymphocytic leukemia in Em-TCL1 mice.

Haematologica
Bola S HannaMartina Seiffert

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 i...Continue Reading

References

Jan 15, 2000·The Journal of Biological Chemistry·S C BunnellL J Berg
May 16, 2002·Proceedings of the National Academy of Sciences of the United States of America·Roberta BichiCarlo M Croce
Apr 9, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Cheng-Rui Li, Leslie J Berg
Jan 21, 2006·The Journal of Immunology : Official Journal of the American Association of Immunologists·Luana O AtherlyLeslie J Berg
May 25, 2011·The Journal of Experimental Medicine·Amy E MoranKristin A Hogquist
Oct 20, 2012·Nature Reviews. Immunology·Susan M Kaech, Weiguo Cui
Mar 22, 2014·Blood·Holbrook E KohrtJohn C Byrd
Jun 20, 2014·Future Oncology·Matthew S Davids, Jennifer R Brown
Nov 13, 2014·Expert Review of Hematology·Talha BadarSusan O'Brien
Mar 3, 2015·Proceedings of the National Academy of Sciences of the United States of America·Idit Sagiv-BarfiRonald Levy
Jul 15, 2015·Frontiers in Immunology·Silvia A Fuertes MarracoDaniel E Speiser
Dec 15, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Carsten U NiemannAdrian Wiestner
Dec 31, 2015·Cancer Discovery·Andrew J GundersonLisa M Coussens
Feb 6, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Pavan Bachireddy, Catherine J Wu
Jan 13, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Qingsong YinJan A Burger
Jan 20, 2017·Nature Reviews. Disease Primers·Thomas J KippsKanti Rai
Feb 19, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Senta M KapnickPamela L Schwartzberg
Jul 18, 2017·The Journal of Clinical Investigation·Meixiao LongJohn C Byrd
Jul 30, 2017·Science Immunology·Franziska HaderkMartina Seiffert
Sep 9, 2017·The Journal of Pharmacology and Experimental Therapeutics·Tjeerd BarfAllard Kaptein
Jan 4, 2018·Blood Advances·Kamira MaharajJavier Pinilla-Ibarz
May 20, 2018·Nature Reviews. Clinical Oncology·Jan A Burger, Susan O'Brien
Nov 24, 2018·International Journal of Cancer. Journal International Du Cancer·Eriong Lee-VergésDolors Colomer

❮ Previous
Next ❯

Citations

May 28, 2020·Leukemia·Philipp M Roessner, Martina Seiffert
Dec 15, 2020·Frontiers in Immunology·Valentina GriggioMarta Coscia
Jul 3, 2021·Cancers·Elisavet VlachonikolaAnastasia Chatzidimitriou
Apr 23, 2021·Haematologica·Rebecka SvanbergCarsten U Niemann
Sep 18, 2021·Immunology·Charlotte McDonaldEfterpi Kostareli

❮ Previous
Next ❯

Related Concepts

Related Feeds

B-Cell Leukemia (Keystone)

B-cell leukemia includes various types of lymphoid leukemia that affect B cells. Here is the latest research on B-cell leukemia.