Targeting cancer homing into the lymph node with a novel anti-CCR7 therapeutic antibody: the paradigm of CLL

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

doi:10.1080/19420862.2021.1917484

Cited by 9 publications

(14 citation statements)

References 62 publications

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“…Until then, clinical results with the therapeutic antibody mogamulizumab (which removes CCR4 + T-cell subsets, including T REG ) (283) allow us to speculate that anti-CCR7 can be safe and welltolerated. In line with this, anti-CCR7 therapy in pre-clinical syngeneic mouse models of cancer, autoimmunity, GVHD, or inflammation did not uncover treatment-associated side effects (225,273,275) and CAP-100 toxicology studies in NHP did not reveal overt toxicities or autoimmune disease, all indicating superior tolerability of this novel therapy (244). In the coming months, first data in patients receiving a chronic administration of an anti-CCR7 mAb will be available and, hopefully, results from clinical studies will shed light into the safety and utility of targeting CCR7, and more importantly, will validate anti-CCR7 approaches in hematologic diseases with an urgent need for more rationally based and efficient therapies.…”

Section: Safety Of Novel Therapies Targeting Ccrin Blood Cancersmentioning

confidence: 52%

“…Novartis is enrolling patients into a phase-I trial with JBH492 an antibody-drug conjugate (ADC) targeting CCR7 (NCT042140704). 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).…”

Section: Ccr7 As a Therapeutic Target In Blood Cancersmentioning

confidence: 99%

“…Therefore, anti-CCR7 therapy may reduce priming of antigen-specific T-cells and the production of Abs in a virus-dependent manner. From pre-clinical models, we know that the use of anti-CCR7 mAbs selectively inhibited and/or depleted tumor cells while sparing healthy counterparts (37,45,244,273,274). Notably, CD4 + T N and T CM cells were preferentially impacted while other CCR7expressing subsets such as DC or B-cells were not.…”

Section: Safety Of Novel Therapies Targeting Ccrin Blood Cancersmentioning

confidence: 99%

“…In this regard, CCR7-negative T EFF and T EM rather than CCR7expressing T N or T CM are necessary for effective anti-tumour responses (276). Moreover, naïve tumor-specific CD8 + T-cells, which seem less susceptible to anti-CCR7 therapy (244,273,274), can also become activated and gain effector-cell phenotypes directly at the tumor site, suggesting that crosspresenting DC are also able to prime CD8 + T-cells within the tumor (277). These results indicate that DC migration into LN may not even be completely necessary for DC-mediated antitumor responses.…”

Section: Safety Of Novel Therapies Targeting Ccrin Blood Cancersmentioning

confidence: 99%

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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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Section: Safety Of Novel Therapies Targeting Ccrin Blood Cancersmentioning

confidence: 52%

Section: Ccr7 As a Therapeutic Target In Blood Cancersmentioning

confidence: 99%

Section: Safety Of Novel Therapies Targeting Ccrin Blood Cancersmentioning

confidence: 99%

Section: Safety Of Novel Therapies Targeting Ccrin Blood Cancersmentioning

confidence: 99%

See 2 more Smart Citations

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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“…Chemotaxis towards CCL19 or CCL21 (1 µg/mL, PeproTech, Rocky Hills, NJ, USA) was assayed with Transwell inserts (5-µm diameter pore size, Corning-Costar, Tewksbury, MA, USA) following reported protocols [ 23 , 24 ]. If needed, cells were pre-exposed for 30 min to anti-CCR7 mAb CAP-100 (10 µg/mL, Catapult Therapeutics B.V, The Netherlands), or for three (or 24) hours to ibrutinib [0, 0.01, 0.1, 1, 10 µM] (obtained from La Princesa Pharmacy Service) within published dose ranges [ 10 , 11 ].…”

Section: Methodsmentioning

confidence: 99%

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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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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Targeting cancer homing into the lymph node with a novel anti-CCR7 therapeutic antibody: the paradigm of CLL

Cited by 9 publications

References 62 publications

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

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

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

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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