Effect of ibrutinib on CCR7 expression and functionality in chronic lymphocytic leukemia and its implication for the activity of CAP-100, a novel therapeutic anti-CCR7 antibody

Mateu‐Albero, Tamara; Juárez-Sánchez, Raquel; Loscertales, Javier; Mol, Wim; Terrón, Fernando; Muñoz‐Calleja, Cecilia; Cuesta-Mateos, Carlos

doi:10.1007/s00262-021-03014-2

Cited by 5 publications

(15 citation statements)

References 39 publications

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“…Three types of patient samples (n = 215) were analyzed: treatment-naïve patients (n = 144), patients on treatment (OT) with ibrutinib (n = 52), and ibrutinib relapsed/refractory patients (n = 19). The characteristics of samples used in this study have been disclosed before [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

“…Analysis of CCR7 expression was conducted, according to published protocols [ 22 ], in whole PB samples with a four-color panel of fluorochrome-labelled monoclonal antibody (mAb): CD19-APC/H7 (SJ25C1), CD3-FITC (SK7) and CD5-APC (L17F12) from BD Biosciences (San Jose, CA, USA), and CCR7-PE (clone 150503) from R&D Systems (Minneapolis, MN). A corresponding PE-conjugated isotype control (IC) was included (R&D Systems).…”

Section: Methodsmentioning

confidence: 99%

“…To gain insight into this topic, we focused on the homeostatic chemokine receptor CCR7 which, upon binding to its cognate ligands CCL19 and CCL21, controls the homing of certain immune cell subsets into T-cell specific regions within SLO and favors T-cell responses [ 20 , 21 ]. By means of in vivo and in vitro migration models, and by analyzing CCR7 expression in pan-T-cells from a large cohort of ibrutinib-treated CLL patients [ 22 ], herein we document the effect of ibrutinib on CCR7 expression and functionality in CLL T-cells.…”

Section: Introductionmentioning

confidence: 99%

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Ibrutinib Does Not Impact CCR7-Mediated Homeostatic Migration in T-Cells from Chronic Lymphocytic Leukemia Patients

Mateu‐Albero

Jiménez

Wissmann

et al. 2022

Cancers

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Bruton’s tyrosine kinase inhibitor ibrutinib has significantly changed treatment landscape in chronic lymphocytic leukemia (CLL). Growing evidence supports ibrutinib to work beyond the effect on tumor cells by means of, for example, restoring functionality of the T-cell compartment and increasing circulating T-cell numbers. Recent evidence suggests T-cell enhanced expansion, rather than increased egress from secondary lymphoid organs (SLO), as a root cause for ibrutinib-induced lymphocytosis. However, whether the latter physiological change is also a consequence of a forced retention in blood remains undisclosed. Since CCR7 is the main chemokine receptor taking over the homing of T-cells from peripheral compartments to lymph nodes and other SLO, we aimed to investigate the impact of ibrutinib on CCR7 functionality in T-cells. To this end, we documented receptor expression in T-cells from a large cohort of ibrutinib-treated CLL patients, and performed different in vivo and in vitro migration models. Overall, our data confirm that CCR7 expression or receptor-mediated migration in CLL T-cells is not affected by ibrutinib. Furthermore, it does not modulate CCR7-driven homing nor nodal interstitial migration. Together, our results support that ibrutinib-induced CLL T-cell accumulation in the blood stream is not derived from an impairment of CCR7-driven recirculation between the SLO and bloodstream, and therefore T-cell expansion is the most plausible cause.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ibrutinib Does Not Impact CCR7-Mediated Homeostatic Migration in T-Cells from Chronic Lymphocytic Leukemia Patients

Mateu‐Albero

Jiménez

Wissmann

et al. 2022

Cancers

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“…Moreover, Catapult Therapeutics presented first pre-clinical results of an antagonist mAb called CAP-100 that will be evaluated in first-inhuman clinical trials in 2021 (NCT04704323) (244). In preclinical settings, both compounds have shown to be highly effective as a single agent and at least CAP-100 revealed the potential for combinations with current standard-of-care drugs (245). Owing to their particular MOA, antagonisticanti-CCR7 mAbs may be likely combined with other standard-of-care drugs to obtain additive or synergistic effects while reducing the likelihood of treatment resistances.…”

Section: Ccr7 As a Therapeutic Target In Blood Cancersmentioning

confidence: 99%

“…Along with the BTK inhibitor ibrutinib or with the PI3Kd inhibitor idelalisib, anti-CCR7 mAbs would additively or synergistically target CCR7-mediated adhesion to lymphoid stroma or endothelium, thus favoring an enhanced cell egress from lymphoid tissues into circulation (44,46,48,246). In fact, we have recently demonstrated that CCR7 expression and functionality is not impaired during ibrutinib treatment in CLL patients and that the anti-CCR7 CAP-100 and ibrutinib show complementary activities (245). Moreover, while the antibody would block recirculation and loops of LN homing, ibrutinib would also interfere with CXCR4-and CXCR5mediated signaling and with the production of chemokines (CXCL12, CXCL13, CCL19) by myeloid stroma cells (44,247), thus acting against potential redundant chemotactic pathways.…”

Section: Ccr7 As a Therapeutic Target In Blood Cancersmentioning

confidence: 99%

CCR7 in Blood Cancers – Review of Its Pathophysiological Roles and the Potential as a Therapeutic Target

Cuesta-Mateos

Terrón²,

Herling³

2021

Front. Oncol.

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According to the classical paradigm, CCR7 is a homing chemokine receptor that grants normal lymphocytes access to secondary lymphoid tissues such as lymph nodes or spleen. As such, in most lymphoproliferative disorders, CCR7 expression correlates with nodal or spleen involvement. Nonetheless, recent evidence suggests that CCR7 is more than a facilitator of lymphatic spread of tumor cells. Here, we review published data to catalogue CCR7 expression across blood cancers and appraise which classical and novel roles are attributed to this receptor in the pathogenesis of specific hematologic neoplasms. We outline why novel therapeutic strategies targeting CCR7 might provide clinical benefits to patients with CCR7-positive hematopoietic tumors.

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Evaluation of the novel therapeutic anti‐CCR7 antibody CAP‐100 as an add‐on therapy in chronic lymphocytic leukemia patients receiving venetoclax

Mateu‐Albero,

Marcos‐Jimenez,

Delgado‐Wicke

et al. 2023

Hematological Oncology

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The Bruton's tyrosine kinase inhibitor ibrutinib and the B‐cell lymphoma 2 anti‐apoptotic protein inhibitor venetoclax provide high response rates in chronic lymphocytic leukemia (CLL). However, there is a growing number of patients that relapse after treatment or show refractory disease, thus new targets and agents are still needed. We have previously reported the chemokine receptor CCR7 as a relevant deregulated target in CLL and have developed CAP‐100, a novel therapeutic anti‐CCR7 antibody that is under evaluation for relapse/refractory CLL (NCT04704323). While CCR7 expression has been shown to be down‐modulated in CLL patients treated with ibrutinib, whether venetoclax acts in a similar manner remains unaddressed. Here, we aimed to document the impact of venetoclax on CCR7 expression in CLL cells, as well as on the pre‐clinical activity of CAP‐100. To this end, we addressed CCR7 expression by flow cytometry and the antibody efficacy by means of in vitro chemotactic and antibody‐dependent cell‐mediated cytotoxicity (ADCC) assays. Our data indicate that venetoclax treatment did not significantly modify CCR7 expression pattern nor CAP‐100 mechanisms of action. Together, these findings support CAP‐100 as an adjuvant therapy to venetoclax that may introduce additional modes of action in CLL therapy.

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Effect of ibrutinib on CCR7 expression and functionality in chronic lymphocytic leukemia and its implication for the activity of CAP-100, a novel therapeutic anti-CCR7 antibody

Cited by 5 publications

References 39 publications

Ibrutinib Does Not Impact CCR7-Mediated Homeostatic Migration in T-Cells from Chronic Lymphocytic Leukemia Patients

Ibrutinib Does Not Impact CCR7-Mediated Homeostatic Migration in T-Cells from Chronic Lymphocytic Leukemia Patients

CCR7 in Blood Cancers – Review of Its Pathophysiological Roles and the Potential as a Therapeutic Target

Evaluation of the novel therapeutic anti‐CCR7 antibody CAP‐100 as an add‐on therapy in chronic lymphocytic leukemia patients receiving venetoclax

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