Therapeutic molecules targeting the malignant B cell microenvironment of chronic lymphocytic leukemia

  • Georgiana Ene SUUB
  • Ana Maria Vladareanu Hematology Clinic, University Emergency Hospital Bucharest
  • Horia Bumbea Hematology Clinic, University Emergency Hospital Bucharest
Keywords: chronic lymphocytic leukemia, microenvironment, malignant B cell, treatment.


Although valuable advances have been made in the hematological field over the past years, most of the B-cell malignancies remain incurable, as malignant B cells retain the ability to respond to a variety of microenvironment signals, providing additional opportunities in the development of therapeutic interactions.
The role that the microenvironment has in the natural history of malignant B cell of chronic lymphocytic leukemia (CLL) appears to favor the development of new treatment modalities aimed at interrupting the interaction between malignant B cells and microenvironment. At this moment, the therapeutic approaches whose target is the CLL microenvironment or the signaling pathways associated with CLL microenvironment are one of the most important therapeutic strategy. Interactions taking place within the tumor microenvironment are targeted by multiple clinical trials, and preliminary results are favorable.
Chronic Lymphocytic Leukemia (CLL) is a size of complexity because leukemic cells are grown and protected by anti-cancer therapies by the components constituting the tumor microenvironment in lymphoid organs (e.g., endothelial cells, dendritic cells (CD), T cells, myeloid-derived suppressor cells (MDSCs), monocyte-derived nurse-like cells (NLC))[1]
Current standard therapy in CLL combines chemotherapy with an anti-CD20 monoclonal antibody. This combination induces substantial toxicity and is not curative, as most patients relapse. Recent advances using kinase inhibitors, such as ibrutinib and idelalisib or BCL2 signaling inhibitors e.g Venetoclax, indicate a major change promising to treat chronic lymphocytic leukemia without chemotherapy. At present, these therapeutic agents do not provide complete responses and should be administered continuously by the patient in order to avoid recurrence/relapse of the disease. Resistance to ibrutinib has already been detected in patients with high genetic risk. [2] This problem requires the identification of therapies that combine agents with distinct mechanisms of action.


A.P. Kater, et al., How does lenalidomide target the chronic lymphocytic leukemia microenvironment? Blood 124 (14) (2014) 2184–2189.

J.A. Jones, J.C. Byrd, How will B-cell-receptor-targeted therapies change future CLL therapy? Blood 123 (10) (2014) 1455–1460.

Elisa ten Hacken and Jan A. Burger Molecular Pathways: Targeting the Microenvironment in Chronic Lymphocytic Leukemia—Focus on the B-Cell Receptor Clinical Cancer Research 20(3) February 1, 2014, 548–56 Published Online First December 9, 2013

Han T-T, Fan L, Li J-Y, Xu W. Role of chemokines and their receptors in chronic lymphocytic leukemia: Function in microenvironment and targeted therapy. Cancer biology & therapy. 2014;15:3-9.

Burger JA. Chemokines and chemokine receptors in chronic lymphocytic leukemia (CLL): from understanding the basics towards therapeutic targeting. Semin Cancer Biol 2010; 20:424-30;

Elisa ten Hacken, Jan A. Burger Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment Biochimica et Biophysica Acta (BBA)- Molecular Cell Research Volume 1863, Issue 3 March 2016, Pages 401-413

J.A. Burger, book S. Malek (ed.), Advances in Chronic Lymphocytic Leukemia, Advances in Experimental Medicine and Biology (2013) 792,Chapter 2 The CLL Cell Microenvironment

Nicole S. Nicholas, Benedetta Apollonio, Alan G. Ramsay, Tumor microenvironment (TME)-driven immune suppression in B cell malignancy, Biochimica et Biophysica Acta 1863 (2016) 471–482.

Michele Dal Bo, Riccardo Bomben, Antonella Zucchetto, Giovanni Del Poeta, Gianluca Gaidano, Silvia Deaglio, Dimitar G. Efremov and Valter Gattei, Microenvironmental Interactions in Chronic Lymphocytic Leukemia: Hints for Pathogenesis and Identification of Targets for Rational Therapy, Current Pharmaceutical Design, 2012, 18, 3323-3334

Caligaris-Cappio F Role of the microenvironment in chronic lymphocytic leukaemia. British Journal of Haematology, 2003, Nov, 123, 380–388.

Jessie-F. Fecteau, Thomas J. Kipps, Structure and function of the hematopoietic cancer niche: focus on chronic lymphocytic leukemia Front Biosci(Schol Ed).(2004); 4: 61–73.

Burger M, Hartmann T, Krome M, Rawluk J, Tamamura H, Fujii N, Kipps TJ, Burger JA. Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells. Blood 2005; 106:182430;

Nicholas Chiorazzi and Manlio Ferrarini B cell chronic lymphocytic leukemia: Lessons Learned from Studies of the B Cell Antigen Receptor Annu. Rev. Immunol. 2003. 21:841–94

Burger JA, Chiorazzi N. B cell receptor signaling in chronic lymphocytic leukemia. Trends Immunol. 2013;34(12):592-601.

Burger JA, Burger M, Kipps TJ. Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. Blood. 1999;94:3658-3667

Alsagaby SA, Brennan P, Pepper C, Key Molecular Drivers of Chronic Lymphocytic Leukaemia (CLL), Clinical Lymphoma, Myeloma and Leukemia (2016), doi:10.1016/ j.clml.2016.08.008.

Hoellenriegel J, Coffey GP, Sinha U, Pandey A, Sivina M, Ferrajoli A, Ravandi F, Wierda WG, O’Brien S, Keating MJ, et al. Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration. Leukemia 2012; 26:1576-83;

Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, Keating MJ, O’Brien S, Chiorazzi N, Burger JA. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 2012; 119:1182-9;

Hoellenriegel J, Meadows SA, Sivina M, Wierda WG, Kantarjian H, Keating MJ, Giese N, O’Brien S, Yu A, Miller LL, et al. The phosphoinositide 3′-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood 2011; 118:360312;

Garcia-Munoz R, Llorente L. Chronic lymphocytic leukemia: could immunological tolerance mechanisms be the origin of lymphoid neoplasms? Immunology 2014;142:536e40.

Tadeusz Robak and Piotr Smolewski, Novel target to kill CLL Blood, January 2015 x Vol. 125, number 2

Gobessi S, Laurenti L, Longo PG, Carsetti L, Berno V, Sica S, Leone G, Efremov DG. Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells. Leukemia 2009; 23:686-97;

Braselmann S, Taylor V, Zhao H, Wang S, Sylvain C, Baluom M, Qu K, Herlaar E, Lau A, Young C, et al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther 2006; 319:998-1008;

Herman SE, Barr PM, McAuley EM, Delong Liu, Friedberg JW, Adrian Wiestner. Fostamatinib Inhibits BCR Signaling, and Reduces Tumor Cell Activation and Proliferation in Patients with Relapsed Refractory Chronic Lymphocytic Leukemia. 54th American society of hematology, 2012, 2882 Abstract

J.A. Burger, A. Peled CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers Leukemia, 23 (2009), pp. 43-52

B. Stamatopoulos, N. Meuleman, C. De Bruyn, K. Pieters, P. Mineur, C. Le Roy, S. Saint-Georges, N. Varin-Blank, F. Cymbalista, D. Bron, L. Lagneaux AMD3100 disrupts the cross-talk between chronic lymphocytic leukemia cells and a mesenchymal stromal or nurse-like cell-based microenvironment: pre-clinical evidence for its association with chronic lymphocytic leukemia treatments Haematologica, 97 (2012), pp. 608-615

Andritsos LA, Byrd JC, Hewes B, Kipps TJ, Johns D, Burger JA., Preliminary results from a phase I/II dose escalation study to determine the maximum tolerated dose of plerixafor in combination with rituximab in patients with relapsed chronic lymphocytic leukemia. Haematologica 2010; 95 Abstract 0772

R. Berger, et al., Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies, Clin. Cancer Res. 14 (10) (2008) 3044–3051.

I. Sagiv-Barfi, et al.,Therapeutic antitumor immunity by check point blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK, Proc. Natl. Acad. Sci. U. S. A. 112 (9) (2015) E966–E972.

J. A. Dubovsky, et al., Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes, Blood 122 (15) (2013) 2539–2549.

B.N. Lee, H. Gao, E.N. Cohen, X. Badoux, W.G. Wierda, Z. Estrov, S.H. Faderl, M.J. Keating, A. Ferrajoli, J.M. Reuben Treatment with lenalidomide modulates T-cell immunophenotype and cytokine production in patients with chronic lymphocytic leukemia Cancer, 117 (2011), pp. 3999-4008

Vallet S, Palumbo A, Raje N, Boccadoro M, Anderson KC. Thalidomide and lenalidomide: Mechanism-based potential drug combinations. Leukemia & Lymphoma (July 2008) 49(7): 1238–45.

G. Aue, N. Njuguna, X. Tian, S. Soto, T. Hughes, B. Vire, K. Keyvanfar, F. Gibellini, J. Valdez, C. Boss, L. Samsel, J.P. McCoy Jr., W.H. Wilson, S. Pittaluga, A. Wiestner Lenalidomide-induced upregulation of CD80 on tumor cells correlates with T-cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia Haematologica, 94 (2009), pp. 1266-1273

A. Acebes-Huerta, L. Huergo-Zapico, A.P. Gonzalez-Rodriguez, A. Fernandez-Guizan, A.R. Payer, A. Lopez-Soto, S. Gonzalez Lenalidomide induces immunomodulation in chronic lymphocytic leukemia and enhances antitumor immune responses mediated by NK and CD4 T cells BioMed. Res. Int., 2014 (2014), p. 265840

A.G. Ramsay, A.J. Johnson, A.M. Lee, G. Gorgun, R. Le Dieu, W. Blum, J.C. Byrd, J.G. Gribben Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug J. Clin. Invest., 118 (2008), pp. 2427-2437

A.G. Ramsay, R. Evans, S. Kiaii, L. Svensson, N. Hogg, J.G. Gribben Chronic lymphocytic leukemia cells induce defective LFA-1-directed T-cell motility by altering Rho GTPase signaling that is reversible with lenalidomide Blood, 121 (2013), pp. 2704-2714

R. Lapalombella, L. Andritsos, Q. Liu, S.E. May, R. Browning, L.V. Pham, K.A. Blum, W. Blum, A. Ramanunni, C.A. Raymond, L.L. Smith, A. Lehman, X. Mo, D. Jarjoura, C.S. Chen, R. Ford Jr., C. Rader, N. Muthusamy, A.J. Johnson, J.C. Byrd Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B cells through a PI3-kinase-dependent pathway Blood, 115 (2010), pp. 2619-2629

C. Galustian, B. Meyer, M.C. Labarthe, K. Dredge, D. Klaschka, J. Henry, S. Todryk, R. Chen, G. Muller, D. Stirling, P. Schafer, J.B. Bartlett, A.G. Dalgleish The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells Cancer Immunol. Immunother., 58 (2009), pp. 1033-1045

Idler I, Giannopoulos K, Zenz T, Bhattacharya N, Nothing M, Dohner H, Stilgenbauer S, Mertens D. Lenalidomide treatment of chronic lymphocytic leukaemia patients reduces regulatory T cells and induces Th17 T helper cells. Br J Haematol. 2010; 148(6):948–50.

R. Maffei, S. Fiorcari, J. Bulgarelli, L. Rizzotto, S. Martinelli, G.M. Rigolin, G. Debbia, I. Castelli, G. Bonacorsi, R. Santachiara, F. Forconi, D. Rossi, L. Laurenti, G.A. Palumbo, D. Vallisa, A. Cuneo, G. Gaidano, M. Luppi, R. Marasca Endothelium-mediated survival of leukemic cells and angiogenesis-related factors are affected by lenalidomide treatment in chronic lymphocytic leukemia Exp. Hematol., 42 (2014), pp. 126-136 (e121)

A.G. Ramsay,et al., Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer, Blood 120 (7) (2012) 1412–1421.

R. Majeti, et al., CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells, Cell 138 (2) (2009) 286–299.

M.P. Chao, et al., Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma, Cell 142 (5) (2010) 699–713.

Tam CS, O’Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112(4): 975-980.

Martijn HA van Attekum, Eric Eldering and Arnon P Kater Chronic lymphocytic leukemia cells are active participants in microenvironmental cross-talk Haematologica 2017 Volume 102(9):1469-1476

Messmer D, Fecteau JF, O’Hayre M, Bharati IS, Handel TM, Kipps TJ. Chronic lymphocytic leukemia cells receive RAF-dependent survival signals in response to CXCL12 that are sensitive to inhibition by sorafenib. Blood 2011; 117:8829;

McCaig AM, Cosimo E, Leach MT, Michie AM. Dasatinib inhibits B cell receptor signalling in chronic lymphocytic leukaemia but novel combination approaches are required to overcome additional prosurvival microenvironmental signals. Br J Haematol 2011; 153:199-211;

Amrein PC, Attar EC, Takvorian T, Hochberg EP, Ballen KK, Leahy KM, Fisher DC, Lacasce AS, Jacobsen ED, Armand P, et al. Phase II study of dasatinib in relapsed or refractory chronic lymphocytic leukemia. Clin Cancer Res 2011; 17:2977-86.

Quiroga MP, Balakrishnan K, Kurtova AV, et al. B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406. Blood 2009; 114: 1029-37.

Suljagic M, Longo PG, Bennardo S, et al. The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Emu- TCL1 transgenic mouse model of CLL by blocking antigen-dependent Bcell receptor signaling. Blood 2010; 116: 4894-905

Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in nonHodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010; 115: 2578-85.

Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood 2010; 116: 2078-88.

Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 2011; 117: 591-4.

Liang X, Moseman EA, Farrar MA, et al. Toll-like receptor 9 signaling by CpG-B oligodeoxynucleotides induces an apoptotic pathway in human chronic lymphocytic leukemia B cells. Blood 2010; 115: 5041-52

Castro JE, Prada CE, Loria O, et al. ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia. Blood 2005; 106: 2506-12.

van de Donk NW, Kamps S, Mutis T, Lokhorst HM. Monoclonal antibody-based therapy as a new treatment strategy in multiple myeloma. Leukemia 2011;

Burger JA, Peled A. CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. Leukemia 2009; 23: 43-52.

Kofler DM, Gawlik B, Elter T, Gianella-Borradori A, Wendtner CM, Hallek M. Final Results of a Phase Ib Trial of Atacicept to Neutralize APRIL and BLyS in Patients with Refractory or Relapsed Chronic Lymphocytic Leukemia (CLL). Blood (ASH Annual Meeting Abstracts). 2009; 114:2373

Campas C, Cosialls AM, Barragan M, Iglesias-Serret D, Santidrian AF, Coll-Mulet L, de Frias M, Domingo A, Pons G, Gil J. Bcl-2 inhibitors induce apoptosis in chronic lymphocytic leukemia cells. Exp Hematol. 2006; 34(12):1663–9.

O’Brien SM, Claxton DF, Crump M, Faderl S, Kipps T, Keating MJ, Viallet J, Cheson BD. Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood. 2009; 113(2):299–305.

Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, Roberts L, Tahir SK, Xiao Y, Yang X, Zhang H, Fesik S, Rosenberg SH, Elmore SW. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008; 68(9): 3421–8.

Vogler M, Furdas SD, Jung M, Kuwana T, Dyer MJ, Cohen GM. Diminished sensitivity of chronic lymphocytic leukemia cells to ABT-737 and ABT-263 due to albumin binding in blood. Clin Cancer Res. 2010; 16(16):4217–25.

Wilson W, O’Connor OO, Roberts AW, Czuczman M, Brown J, Xiong H, Xiong H, Chiu Y, Krivoshik A, Enschede S, Humerickhouse R. ABT-263 activity and safety in patients with relapsed or refractory lymphoid malignancies in particular chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL). J Clin Oncol. 2009; 2009(27):8574.

Zucchetto A, Benedetti D, Tripodo C, Bomben R, Dal Bo M, Marconi D, Bossi F, Lorenzon D, Degan M, Rossi FM. CD38/CD31, the CCL3 and CCL4 chemokines, and CD49d/vascular cell adhesion molecule-1 are interchained by sequential events sustaining chronic lymphocytic leukemia cell survival. Cancer research. 2009;69:4001-4009. .

Burger JA, Quiroga MP, Hartmann E, et al. High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR stimulation. Blood 2009; 113: 3050-8.

Sabroe I, Peck MJ, Van Keulen BJ, et al. A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. J Biol Chem 2000; 275: 25985-92.

Dau B, Holodniy M. Novel targets for antiretroviral therapy: clinical progress to date. Drugs 2009; 69: 31-50.

Chang JT, Lichtenstein GR. Drug insight: antagonists of tumornecrosis factor-alpha in the treatment of inflammatory bowel disease. Nat Clin Pract Gastroenterol Hepatol 2006; 3: 220-8.

Nesbitt A, Fossati G, Bergin M, et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other antitumor necrosis factor alpha agents. Inflamm Bowel Dis 2007; 13: 1323-32.

Melmed GY, Targan SR, Yasothan U, Hanicq D, Kirkpatrick P. Certolizumab pegol. Nat Rev Drug Discov 2008; 7: 641-2.

Schmidt, S.M., Schag, K., Muller, M.R., Weck, M.M., Appel, S., Kanz, L., Grunebach, F. & Brossart, P. Survivin is a shared tumor-associated antigen expressed in a broad variety of malignancies and recognized by specific cytotoxic T cells. Blood, 102,571–576

How to Cite
Ene, G., Vladareanu, A., & Bumbea, H. (2019). Therapeutic molecules targeting the malignant B cell microenvironment of chronic lymphocytic leukemia. Romanian Journal of Clinical Research, 2(1), 17-29.