B-cell receptor pathway inhibitors affect CD20 levels and impair antitumor activity of anti-CD20 monoclonal antibodies

Bojarczuk, Kamil; Siernicka, Marta; Dwojak, Michal; Bobrowicz, Małgorzata; Pyrzyńska, Beata; Gaj, Paweł; Karp, Marta; Giannopoulos, Krzysztof; Efremov, Dimitar G.; Fauriat, Cyril; Gołąb, Jakub; Winiarska, Magdalena

doi:10.1038/leu.2014.12

Cited by 60 publications

(69 citation statements)

References 13 publications

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“…Raji) and CLL samples, and that this leads to inhibition of CDC. 34 The difference with our data may be due to the different cell lines tested, since these authors showed no modulation of CD20 by ibrutinib in MEC-1, in agreement with our findings. In the context of complement, it is worth noting that ibrutinib and other kinase inhibitors acting downstream of the BCR induce early lymphocytosis in vivo due to egress of neoplastic B cells into the peripheral blood.…”

Section: Discussionsupporting

confidence: 74%

“…Our findings are in agreement with and extend recently published data that showed inhibition of antibody-induced NK-cell degranulation, NK-cell-mediated cytokine production and ADCC by 0.1-1 μM ibrutinib. 34,38 A direct role of Btk in NK cell activation and cytotoxicity has emerged from work with Btk knock-out mice as well as in patients with X-linked agammaglobulinemia. 39 In the latter study, however, TLR3 rather than FcγR-mediated signaling was investigated.…”

Section: Discussionmentioning

confidence: 99%

“…22 The efficacy of CDC may, however, be reduced by the potential downmodulation of CD20 and up-regulation of CD55 after prolonged exposure to ibrutinib, at least in some cases. 34 ADCC is thought to be a major effector mechanism of anti-CD20 monoclonal antibodies, 28 especially for glycoengineered obinutuzumab which binds FcγRIIIA more efficiently. 6 We showed here that ibrutinib strongly inhibited NK-cell degranulation and ADCC mediated by all anti-CD20 monoclonal antibodies.…”

Section: Discussionmentioning

confidence: 99%

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Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy

et al. 2014

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy

et al. 2014

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“…[112][113][114][115] These data, and the observation that the sequencing of antibody and kinase inhibitor may matter, 82 suggest that optimizing the benefit of combination therapy could be more complex than initially thought.…”

Section: A Wiestnermentioning

confidence: 99%

The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia

Wiestner

2015

Haematologica

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Chronic lymphocytic leukemia is a malignancy of mature auto-reactive B cells. Genetic and functional studies implicate B-cell receptor signaling as a pivotal pathway in its pathogenesis. Full B-cell receptor activation requires tumor-microenvironment interactions in lymphoid tissues. Spleen tyrosine kinase, Bruton's tyrosine kinase, and the phosphatidylinositol 3-kinase (PI3K) δ isoform are essential for B-cell receptor signal transduction but also mediate the effect of other pathways engaged in chronic lymphocytic leukemia cells in the tissue-microenvironment. Orally bioavailable inhibitors of spleen tyrosine kinase, Bruton's tyrosine kinase, or PI3Kδ, induce high rates of durable responses. Ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, and idelalisib, a selective inhibitor of PI3Kδ, have obtained regulatory approval in chronic lymphocytic leukemia. Ibrutinib and idelalisib are active in patients with high-risk features, achieving superior disease control in difficult-to-treat patients than prior best therapy, making them the preferred agents for chronic lymphocytic leukemia with TP53 aberrations and for patients resistant to chemoimmunotherapy. In randomized trials, both ibrutinib, versus ofatumumab, and idelalisib in combination with rituximab, versus placebo with rituximab improved survival in relapsed/refractory chronic lymphocytic leukemia. Responses to B-cell receptor inhibitors are mostly partial, and within clinical trials treatment is continued until progression or occurrence of intolerable side effects. Ibrutinib and idelalisib are, overall, well tolerated; notable adverse events include increased bruising and incidence of atrial fibrillation on ibrutinib and colitis, pneumonitis and transaminase elevations on idelalisib. Randomized trials investigate the role of B-cell receptor inhibitors in first-line therapy and the benefit of combinations. This review discusses the biological basis for targeted therapy of chronic lymphocytic leukemia with B-cell receptor inhibitors, and summarizes the clinical experience with these agents. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia Adrian WiestnerHematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA ABSTRACT junction genes (J) in order to form a novel, unique sequence that encodes the antigen binding domain of the BCR (Figure 1). In theory, billions of different combinations are possible, generating a vastly diverse repertoire of possible antigen binding sites. However, CLL cells display a highly restricted, non-random repertoire of different immunoglobulin heavy chain variable (IGHV) region genes, suggesting that CLL cells have distinct antigen specificities. 15,18,19 Furthermore, the presence or absence of somatic mutations in the clonal IGHV gene, a mark of antigenic selection, distinguishes two major CLL subtypes; IGHV mutated (M-CLL) and IGHV unmutated (U-CLL); the latter having more than 98% sequence homology of the clonal IGHV g...

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“…In the following studies, we used a co-incubation model 33 that reflected more physiological conditions where both target and effector cells were co-incubated for 4 hr in the presence of ADNT. In the co-incubation model, ADNT potently inhibited NK cell degranulation in spontaneous NK cell cytotoxicity and R-ADCC assays (Fig.…”

Section: Adenanthin Impairs the Functions Of Nk Cells In A Coincubatimentioning

confidence: 99%

Adenanthin, a new inhibitor of thiol‐dependent antioxidant enzymes, impairs the effector functions of human natural killer cells

et al. 2015

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SummaryNatural killer (NK) cells are considered critical components of the innate and adaptive immune responses. Deficiencies in NK cell activity are common, such as those that occur in cancer patients, and they can be responsible for dysfunctional immune surveillance. Persistent oxidative stress is intrinsic to many malignant tumours, and numerous studies have focused on the effects of reactive oxygen species on the anti-tumour activity of NK cells. Indeed, investigations in animal models have suggested that one of the most important thiol-dependent antioxidant enzymes, peroxiredoxin 1 (PRDX1), is essential for NK cell function. In this work, our analysis of the transcriptomic expression pattern of antioxidant enzymes in human NK cells has identified PRDX1 as the most prominently induced transcript out of the 18 transcripts evaluated in activated NK cells. The change in PRDX1 expression was followed by increased expression of two other enzymes from the PRDX-related antioxidant chain: thioredoxin and thioredoxin reductase. To study the role of thiol-dependent antioxidants in more detail, we applied a novel compound, adenanthin, to induce an abrupt dysfunction of the PRDX-related antioxidant chain in NK cells. In human primary NK cells, we observed profound alterations in spontaneous and antibody-dependent NK cell cytotoxicity against cancer cells, impaired degranulation, and a decreased expression of activation markers under these conditions. Collectively, our study pinpoints the unique role for the antioxidant activity of the PRDX-related enzymatic chain in human NK cell functions. Further understanding this phenomenon will prospectively lead to fine-tuning of the novel NK-targeted therapeutic approaches to human disease.

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B-cell receptor pathway inhibitors affect CD20 levels and impair antitumor activity of anti-CD20 monoclonal antibodies

Cited by 60 publications

References 13 publications

Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy

Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy

The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia

Adenanthin, a new inhibitor of thiol‐dependent antioxidant enzymes, impairs the effector functions of human natural killer cells

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