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Haematologica 2021 Volume 106(4):968-977
Combining ibrutinib and checkpoint blockade +
improves CD8 T-cell function and control of chronic lymphocytic leukemia in Em-TCL1 mice
Bola S. Hanna,1 Haniyeh Yazdanparast,1 Yasmin Demerdash,1
Philipp M. Roessner,1 Ralph Schulz,1 Peter Lichter,1 Stephan Stilgenbauer2 and Martina Seiffert1
1Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg and 2Internal Medicine III, University of Ulm, Ulm, Germany
Chronic Lymphocytic Leukemia
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 effec- tor 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 antibod- iestargetingPD-1/PD-L1axisinvivoimprovedCD8+ T-celleffectorfunction 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.
Introduction
Within the last decade, a new era of therapeutic opportunities for patients with chronic lymphocytic leukemia (CLL) has begun.1 Treatment responses, also in patients with relapsed and refractory disease or unfavorable genetic profile, have dramatically improved with the development and approval of kinase inhibitors that target B-cell receptor (BCR) signaling, a well-known driver of disease.2,3 Ibrutinib is an orally bioavailable, irreversible inhibitor of Bruton’s tyrosine kinase (BTK). Both in vitro and in patients, ibrutinib has been shown to potently inhibit BCR signaling, prevent lymphocyte adhesion and homing, and inhibit protective effects of the microenvironment, which yields high response rates and durable remissions in patients with CLL if applied continuously.4,5
In addition to pro-survival pathways in malignant cells, like BCR signaling, T cells represent an attractive therapeutic target in CLL. In patients and mouse models of CLL, T cells expand along with the disease course.6,7 Our recent work has demon- strated a non-redundant role of CD8+ T cells in suppressing CLL progression in an IFNγ-dependent manner.8 Yet chronic exposure to tumor-derived antigens in second- ary lymphoid organs leads to their continuous activation, upregulation of inhibitory receptors, such as PD-1, and ultimately exhaustion.8 Therefore, targeting inhibitory receptors, such as PD-1 and Lag3, offered novel opportunities of therapeutic reacti- vation of adaptive anti-tumor immunity by immune checkpoint blockade.9,10 Notably, immune checkpoint blockade showed promising activity in a subgroup of CLL patients with Richter’s transformation, suggesting that unleashing inhibited T cells results in better control of leukemia progression.11 Besides its direct cytotoxic activity against malignant B cells, ibrutinib also exerts immunomodulatory effects (reviewed by Maharaj et al.).12 Ibrutinib-mediated inhibition of STAT3 results in decreased expression of immunosuppressive molecules, such as PD-L1 and IL-10, by
Correspondence:
MARTINA SEIFFERT
m.seiffert@dkfz.de
BOLA S. HANNA
b.hanna@dkfz.de
Received: September 11, 2019. Accepted: March 3, 2020. Pre-published: March 5, 2020.
https://doi.org/10.3324/haematol.2019.238154
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