Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

CAP-100 is a novel therapeutic antibody directed against the ligand binding site of human CCR7. This chemokine receptor is overexpressed in chronic lymphocytic leukemia (CLL) and orchestrates the homing of CLL cells into the lymph node. Previous studies, on a very limited number of samples, hypothesized that the Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib might induce loss of surface CCR7 levels in CLL cells. CAP-100 will be evaluated in clinical trials as a therapy for relapse/refractory CLL patients, who have received at least two systemic therapies (NCT04704323). As nowadays many relapse/refractory CLL patients will have received ibrutinib as a prior therapy, we aimed to investigate in a large cohort of CLL patients the impact of this BTKi on CCR7 expression and functionality as well as on the therapeutic activity of CAP-100. Our data confirm that ibrutinib moderately down-regulates the very high expression of CCR7 in CLL cells but has no apparent effect on CCR7-induced chemotaxis. Moreover, CLL cells are perfectly targetable by CAP-100 which led to a complete inhibition of CCR7-mediated migration and induced strong target cell killing through antibody-dependent cell-mediated cytotoxicity, irrespective of previous or contemporary ibrutinib administration. Together, these results validate the therapeutic utility of CAP-100 as a next-line single-agent therapy for CLL patients who failed to ibrutinib and confirm that CAP-100 and ibrutinib have complementary non-overlapping mechanisms of action, potentially allowing for combination therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. HauserLegler MADF (2016) Common and biased signaling pathways of the chemokine receptor CCR7 elicited by its ligands CCL19 and CCL21 in leukocytes. J Leukoc Biol 99:869–882

    Article  Google Scholar 

  2. ComerfordHarata-LeeBuntingGregorKaraMcColl IYMDCEESR (2013) A myriad of functions and complex regulation of the CCR7/CCL19/CCL21 chemokine axis in the adaptive immune system. Cytokine Growth Factor Rev 24:269–283

    Article  Google Scholar 

  3. ForsterDavalos-MisslitzRot RACA (2008) CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol 8:362–371

    Article  Google Scholar 

  4. TillLinZuzelCawley KJKMJC (2002) The chemokine receptor CCR7 and alpha4 integrin are important for migration of chronic lymphocytic leukemia cells into lymph nodes. Blood 99:2977–2984

    Article  Google Scholar 

  5. De Lopez-GiralQuintanaCabrerizoAlfonso-PerezSala-ValdesSoriaFernandez-RanadaFernandez-RuizMunoz SNEMMMVGJMEC (2004) Chemokine receptors that mediate B cell homing to secondary lymphoid tissues are highly expressed in B cell chronic lymphocytic leukemia and non-Hodgkin lymphomas with widespread nodular dissemination. J Leukoc Biol 76:462–471. https://doi.org/10.1189/jlb.1203652

    Article  CAS  Google Scholar 

  6. RichardsonMatthewsCatherwood SJCMA et al (2006) ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B-cell chronic lymphocytic leukemia (B-CLL). Blood 107:3584–3592

    Article  Google Scholar 

  7. YanDozmorovLi XJIW et al (2011) Identification of outcome-correlated cytokine clusters in chronic lymphocytic leukemia. Blood 118:5201–5210. https://doi.org/10.1182/blood-2011-03-342436

    Article  CAS  Google Scholar 

  8. Cuesta-MateosLoscertalesKreutzmanColom-FernandezPortero-SainzPerez-VillarTerronMunoz-Calleja CJABIJJFC (2015) Preclinical activity of anti-CCR7 immunotherapy in patients with high-risk chronic lymphocytic leukemia. Cancer Immunol Immunother 64:665–676

    Article  Google Scholar 

  9. PatrussiCapitaniMartini LNV et al (2015) Enhanced chemokine receptor recycling and impaired S1P1 expression promote leukemic cell infiltration of lymph nodes in chronic lymphocytic leukemia. Cancer Res 75:4153–4163

    Article  Google Scholar 

  10. Redondo-MunozJose TerolGarcia-MarcoGarcia-Pardo JMJAA (2008) Matrix metalloproteinase-9 is up-regulated by CCL21/CCR7 interaction via extracellular signal-regulated kinase-1/2 signaling and is involved in CCL21-driven B-cell chronic lymphocytic leukemia cell invasion and migration. Blood 111:383–386

    Article  Google Scholar 

  11. RehmMensenSchradi AAK et al (2011) Cooperative function of CCR7 and lymphotoxin in the formation of a lymphoma-permissive niche within murine secondary lymphoid organs. Blood 118:1020–1033

    Google Scholar 

  12. GirblHinterseerGrossinger TEEM et al (2013) CD40-mediated activation of chronic lymphocytic leukemia cells promotes their CD44-dependent adhesion to hyaluronan and restricts CCL21-induced motility. Cancer Res 73:561–570. https://doi.org/10.1158/0008-5472.CAN-12-2749

    Article  CAS  Google Scholar 

  13. GanghammerHuttererHinterseer SEE et al (2015) CXCL12-induced VLA-4 activation is impaired in trisomy 12 chronic lymphocytic leukemia cells: a role for CCL21. Oncotarget 6:12048–12060. https://doi.org/10.18632/oncotarget.3660

    Article  Google Scholar 

  14. LauferLyckLegler JMRDF (2018) ZAP70 expression enhances chemokine-driven chronic lymphocytic leukemia cell migration and arrest by valency regulation of integrins. FASEB J 32:4824–4835. https://doi.org/10.1096/fj.201701452RR

    Article  Google Scholar 

  15. TicchioniEssafiJeandelDaviCassutoDeckertBernard MMPYFJPMA (2007) Homeostatic chemokines increase survival of B-chronic lymphocytic leukemia cells through inactivation of transcription factor FOXO3a. Oncogene 26:7081–7091

    Article  Google Scholar 

  16. de Cuesta-MateosLopez-GiralAlfonso-PerezSoriaLoscertalesGuasch-VidalBeltranZapataMunoz-Calleja CSMVGJSAEJMC (2010) Analysis of migratory and prosurvival pathways induced by the homeostatic chemokines CCL19 and CCL21 in B-cell chronic lymphocytic leukemia. Exp Hematol 38:756–764, 64 e1–4. https://doi.org/10.1016/j.exphem.2010.05.003

    Article  CAS  Google Scholar 

  17. CuestaMunoz-CallegaLoscertalesTerronMol CCJFW (2019) CAP-100: First-in-class antibody for CCR7+ hematological malignancies. J Clinic Oncol 37:e19008-e. https://doi.org/10.1200/JCO.2019.37.15_suppl.e19008

    Article  Google Scholar 

  18. Cuesta-MateosMuñoz-CallejaLoscertalesTerronMol CCJFW (2019) Abstract 4849: CAP-100: first-in-class anti-CCR7 antibody for CLL. Cancer Res 79:4849. https://doi.org/10.1158/1538-7445.AM2019-4849

    Article  Google Scholar 

  19. KaurSwami VA (2017) Ibrutinib in CLL: a focus on adverse events, resistance, and novel approaches beyond ibrutinib. Ann Hematol 96:1175–1184. https://doi.org/10.1007/s00277-017-2973-2

    Article  CAS  Google Scholar 

  20. CameronSanford FM (2014) Ibrutinib: first global approval. Drugs 74:263–271. https://doi.org/10.1007/s40265-014-0178-8

    Article  CAS  Google Scholar 

  21. Brown JR (2018) Relapsed CLL: sequencing, combinations, and novel agents. Hematology Am Soc Hematol Educ Program 2018:248–255. https://doi.org/10.1182/asheducation-2018.1.248

    Article  PubMed  PubMed Central  Google Scholar 

  22. Jain N (2018) Selecting Frontline Therapy for CLL in 2018. Hematology Am Soc Hematol Educ Program 2018:242–247. https://doi.org/10.1182/asheducation-2018.1.242

    Article  PubMed  PubMed Central  Google Scholar 

  23. HallekChesonCatovsky MBDD et al (2018) iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 131:2745–2760. https://doi.org/10.1182/blood-2017-09-806398

    Article  CAS  Google Scholar 

  24. MaddocksRuppertLozanski KJASG et al (2015) Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia. JAMA Oncol 1:80–87. https://doi.org/10.1001/jamaoncol.2014.218

    Article  Google Scholar 

  25. MatoRoekerAllan ARLEJN et al (2018) Outcomes of front-line ibrutinib treated CLL patients excluded from landmark clinical trial. Am J Hematol 93:1394–1401. https://doi.org/10.1002/ajh.25261

    Article  CAS  Google Scholar 

  26. de RooijKuilGeestElderingChangBuggyPalsSpaargaren MFACREBYJJSTM (2012) The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood 119:2590–2594. https://doi.org/10.1182/blood-2011-11-390989

    Article  CAS  Google Scholar 

  27. Alfonso-PerezLopez-GiralQuintanaLoscertalesMartin-JimenezMunoz MSNEJPC (2006) Anti-CCR7 monoclonal antibodies as a novel tool for the treatment of chronic lymphocyte leukemia. J Leukoc Biol 79:1157–1165. https://doi.org/10.1189/jlb.1105623

    Article  CAS  Google Scholar 

  28. PavlasovaBorskySeda GMV et al (2016) Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis. Blood 128:1609–1613. https://doi.org/10.1182/blood-2016-04-709519

    Article  CAS  Google Scholar 

  29. SkarzynskiNiemannLee MCUYS et al (2016) Interactions between Ibrutinib and Anti-CD20 Antibodies: Competing Effects on the Outcome of Combination Therapy. Clinical Cancer Res Official J Am Assoc Cancer Res 22:86–95. https://doi.org/10.1158/1078-0432.CCR-15-1304

    Article  CAS  Google Scholar 

  30. ScottWolchokOld AMJDLJ (2012) Antibody therapy of cancer. Nat Rev Cancer 12:278–287

    Article  Google Scholar 

  31. PatrussiCapitaniCattaneo LNF et al (2018) p66Shc deficiency enhances CXCR4 and CCR7 recycling in CLL B cells by facilitating their dephosphorylation-dependent release from beta-arrestin at early endosomes. Oncogene 37:1534–1550. https://doi.org/10.1038/s41388-017-0066-2

    Article  CAS  Google Scholar 

  32. HermanMustafaJonesWongFarooquiWiestner SEMRZJDHMA (2015) Treatment with Ibrutinib Inhibits BTK- and VLA-4-Dependent Adhesion of Chronic Lymphocytic Leukemia Cells In Vivo. Clinical Cancer Res Official J Am Assoc Cancer Res 21:4642–4651. https://doi.org/10.1158/1078-0432.CCR-15-0781

    Article  CAS  Google Scholar 

  33. CapitaniPatrussiTrentin NLL et al (2012) S1P1 expression is controlled by the pro-oxidant activity of p66Shc and is impaired in B-CLL patients with unfavorable prognosis. Blood 120:4391–4399

    Google Scholar 

  34. CalpeCodonyBaptistaAbrisquetaCarpioPurroyBoschCrespo ECMJPCNFM (2011) ZAP-70 enhances migration of malignant B lymphocytes toward CCL21 by inducing CCR7 expression via IgM-ERK1/2 activation. Blood 118:4401–4410

    Google Scholar 

  35. HinmanBushanamNicholsSatterthwaite RMJNWAAB (2007) B cell receptor signaling down-regulates forkhead box transcription factor class O 1 mRNA expression via phosphatidylinositol 3-kinase and Bruton’s tyrosine kinase. J Immunol 178:740–747

    Article  Google Scholar 

  36. WolfGardingFilarsky CAK et al (2017) NFATC1 activation by DNA hypomethylation in chronic lymphocytic leukemia correlates with clinical staging and can be inhibited by ibrutinib. Int J Cancer 2017:31057

    Google Scholar 

  37. RodriguezMartinezCamacho ANFI et al (2004) Variability in the degree of expression of phosphorylated IkappaBalpha in chronic lymphocytic leukemia cases with nodal involvement. Clin Cancer Res 10:6796–6806

    Article  Google Scholar 

  38. PingDingShi LNY et al (2017) The Bruton’s tyrosine kinase inhibitor ibrutinib exerts immunomodulatory effects through regulation of tumor-infiltrating macrophages. Oncotarget 8:39218–39229. https://doi.org/10.18632/oncotarget.16836

    Article  Google Scholar 

  39. ChenChangChangTongHamSherryBurgerRaiChiorazzi SSBYSTSBJAKRN (2016) BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia. Leukemia 30:833–843. https://doi.org/10.1038/leu.2015.316

    Article  CAS  Google Scholar 

  40. ZaitsevaMurrayShafatLawesMacEwanBowlesRushworth LMYMSMJDJKMSA (2014) Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML. Oncotarget 5:9930–9938. https://doi.org/10.18632/oncotarget.2479

    Article  Google Scholar 

  41. OteroGroettrupLegler CMDF (2006) Opposite fate of endocytosed CCR7 and its ligands: recycling versus degradation. J Immunol 177:2314–2323

    Article  Google Scholar 

  42. MarcheseBenovic AJL (2001) Agonist-promoted ubiquitination of the G protein-coupled receptor CXCR4 mediates lysosomal sorting. J Biol Chem 276:45509–45512

    Article  Google Scholar 

  43. devan GorterBeulingKersseboomMiddendorpGilsHendriksPalsSpaargaren DJEARSJMRWSTM (2007) Bruton’s tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing. Immunity 26:93–104. https://doi.org/10.1016/j.immuni.2006.11.012

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Marty Wulferink and Dr. Wiebe Olive for advice. The authors are also grateful to Dr. Francisco Sánchez-Madrid for reagents and advices and Lawrence Baron for proofreading and editing of the manuscript.

Funding

None of the authors received grants for this work.

Author information

Authors and Affiliations

  1. Immunology Department, Hospital Universitario de La Princesa, IIS-IP, Diego de León 62, 28006, Madrid, Spain

    Tamara Mateu-Albero, Raquel Juárez-Sánchez, Cecilia Muñoz-Calleja & Carlos Cuesta-Mateos

  2. IMMED S.L., Immunological and Medicinal Products, C/ Velázquez 57, 6º derecha, 28001, Madrid, Spain

    Raquel Juárez-Sánchez, Fernando Terrón & Carlos Cuesta-Mateos

  3. Hematology Department, Hospital Universitario de La Princesa, IIS-IP, Diego de León 62, 28006, Madrid, Spain

    Javier Loscertales

  4. Catapult Therapeutics, Lelystad, The Netherlands

    Wim Mol, Fernando Terrón & Carlos Cuesta-Mateos

  5. Medicine Faculty, Universidad Autónoma de Madrid, Madrid, Spain

    Cecilia Muñoz-Calleja

Authors
  1. Tamara Mateu-Albero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raquel Juárez-Sánchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Javier Loscertales
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wim Mol
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fernando Terrón
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cecilia Muñoz-Calleja
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carlos Cuesta-Mateos
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TMA, RJS, JL, WM, and CCM carried out in vitro and ex vivo assays and analyzed data. FT, WM, CMC, and CCM designed the study, developed experimental procedures, analyzed data, carried out the statistical design and analysis, discussed results, and wrote the manuscript. All the authors reviewed the manuscript. All the authors approved the submission of the manuscript.

Corresponding author

Correspondence to Carlos Cuesta-Mateos.

Ethics declarations

Conflict of interest

CCM is an employee of Catapult Therapeutics and of Immunological and Medical Products (IMMED S.L.) and a shareholder in IMMED. JL has received honoraria from Abbvie, Janssen, BeiGene, and Astra-Zeneca. FT and WM are managing directors of Catapult Therapeutics, and FT is CEO of IMMED.S.L. and a shareholder in the same company and Catapult Therapeutics. CMC is a consultant for IMMED S.L., held a patent for the use of therapeutic antibodies targeting CCR7 in cancer and has received research funds from IMMED.S.L. and Catapult Therapeutics. She also holds shares in IMMED S.L. RJS is an employee of IMMED S.L. The other authors declare that they have no competing interests.

Ethics approval

The clinical study was performed in accordance with the principles of the Declaration of Helsinki and was approved and supervised by the Ethics Committee of Hospital Universitario de la Princesa (PI-352). Written informed consent was obtained from each patient before they entered the study.

Consent to participate

Written informed consent was obtained from each patient before they entered the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 427 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mateu-Albero, T., Juárez-Sánchez, R., Loscertales, J. et al. 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. Cancer Immunol Immunother 71, 627–636 (2022). https://doi.org/10.1007/s00262-021-03014-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-021-03014-2

Keywords

Search

Navigation