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CD20-targeting in B-cell malignancies: novel prospects for antibodies and combination therapies

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Abstract

Expression of CD20 antigen by the most of transformed B cells is believed to be the driving force for targeting this molecule by using anti-CD20 monoclonal antibodies. While it is true that most lymphoma/leukemia patients can be cured, these regimens are limited by the emergence of treatment resistance. Based on these observations, development of anti-CD20 monoclonal antibodies and combination therapies have been recently proposed, in particular with the aim to optimize the cytotoxic activity. Here we outline a range of new experimental agents concerning the CD20 positive B-cell tumors which provide high benefit from conventional therapy.

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References

  1. Loken MR, Shah VO, Dattilio KL, Civin CI (1987) Flow cytometric analysis of human bone marrow. II. Normal B lymphocyte development. Blood 70:1316–1324

    CAS  PubMed  Google Scholar 

  2. Kuijpers TW, Bende RJ, Baars PA, Grummels A, Derks IA, Dolman KM, Beaumont T, Tedder TF, van Noesel CJ, Eldering E, van Lier RA (2010) CD20 deficiency in humans results in impaired T cell-independent antibody responses. J Clin Invest 120:214–222

    Article  CAS  PubMed  Google Scholar 

  3. Tedder TF, Engel P (1994) CD20: a regulator of cell-cycle progression of B lymphocytes. Immunol Today 15:450–454

    Article  CAS  PubMed  Google Scholar 

  4. Winiarska M, Bil J, Nowis D, Golab J (2010) Proteolytic pathways involved in modulation of CD20 levels. Autophagy 6:810–812

    Article  PubMed  Google Scholar 

  5. van Meerten T, Hagenbeek A (2009) CD20-targeted therapy: a breakthrough in the treatment of non-Hodgkin’s lymphoma. Neth J Med 67:251–259

    PubMed  Google Scholar 

  6. Farajnia S, Ahmadzadeh V, Tanomand A, Veisi K, Khosroshahi SA, Rahbarnia L (2014) Development trends for generation of single-chain antibody fragments. Immunopharmacol Immunotoxicol 36:297–308

    Article  CAS  PubMed  Google Scholar 

  7. Cragg MS, Walshe CA, Ivanov AO, Glennie MJ (2005) The biology of CD20 and its potential as a target for mAb therapy. Curr Dir Autoimmun 8:140–174

    Article  CAS  PubMed  Google Scholar 

  8. Polyak MJ, Tailor SH, Deans JP (1998) Identification of a cytoplasmic region of CD20 required for its redistribution to a detergent-insoluble membrane compartment. J Immunol 161:3242–3248

    CAS  PubMed  Google Scholar 

  9. Binder M, Otto F, Mertelsmann R, Veelken H, Trepel M (2006) The epitope recognized by rituximab. Blood 108:1975–1978

    Article  CAS  PubMed  Google Scholar 

  10. Tedder TF, Schlossman SF (1988) Phosphorylation of the B1 (CD20) molecule by normal and malignant human B lymphocytes. J Biol Chem 263:10009–10015

    CAS  PubMed  Google Scholar 

  11. Ivaldi C, Martin BR, Kieffer-Jaquinod S, Chapel A, Levade T, Garin J, Journet A (2012) Proteomic analysis of S-acylated proteins in human B cells reveals palmitoylation of the immune regulators CD20 and CD23. PLoS One 7:e37187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Giles FJ, Vose JM, Do KA, Johnson MM, Manshouri T, Bociek G, Bierman PJ, O’Brien SM, Keating MJ, Kantarjian HM, Armitage JO, Albitar M (2003) Circulating CD20 and CD52 in patients with non-Hodgkin’s lymphoma or Hodgkin’s disease. Br J Haematol 123:850–857

    Article  CAS  PubMed  Google Scholar 

  13. Deans JP, Li H, Polyak MJ (2002) CD20-mediated apoptosis: signalling through lipid rafts. Immunology 107:176–182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Li H, Ayer LM, Lytton J, Deans JP (2003) Store-operated cation entry mediated by CD20 in membrane rafts. J Biol Chem 278:42427–42434

    Article  CAS  PubMed  Google Scholar 

  15. Vugmeyster Y, Howell K, Bakshl A, Flores C, Canova-Davis E (2003) Effect of anti-CD20 monoclonal antibody, Rituxan, on cynomolgus monkey and human B cells in a whole blood matrix. Cytom A 52:101–109

    Article  CAS  Google Scholar 

  16. Al-Zoobi L, Salti S, Colavecchio A, Jundi M, Nadiri A, Hassan GS, El-Gabalawy H, Mourad W (2014) Enhancement of Rituximab-induced cell death by the physical association of CD20 with CD40 molecules on the cell surface. Int Immunol 26:451–465

    Article  CAS  PubMed  Google Scholar 

  17. Rohrbach P, Broders O, Toleikis L, Dubel S (2003) Therapeutic antibodies and antibody fusion proteins. Biotechnol Genet Eng Rev 20:137–163

    Article  CAS  PubMed  Google Scholar 

  18. Rossi EA, Goldenberg DM, Cardillo TM, Stein R, Wang Y, Chang CH (2008) Novel designs of multivalent anti-CD20 humanized antibodies as improved lymphoma therapeutics. Cancer Res 68:8384–8392

    Article  CAS  PubMed  Google Scholar 

  19. Henry C, Deschamps M, Rohrlich PS, Pallandre JR, Remy-Martin JP, Callanan M, Traverse-Glehen A, GrandClement C, Garnache-Ottou F, Gressin R, Deconinck E, Salles G, Robinet E, Tiberghien P, Borg C, Ferrand C (2010) Identification of an alternative CD20 transcript variant in B-cell malignancies coding for a novel protein associated to rituximab resistance. Blood 115:2420–2429

    Article  CAS  PubMed  Google Scholar 

  20. Beers SA, French RR, Chan HT, Lim SH, Jarrett TC, Vidal RM, Wijayaweera SS, Dixon SV, Kim H, Cox KL, Kerr JP, Johnston DA, Johnson PW, Verbeek JS, Glennie MJ, Cragg MS (2010) Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection. Blood 115:5191–5201

    Article  CAS  PubMed  Google Scholar 

  21. Reslan L, Dalle S, Dumontet C (2000) Understanding and circumventing resistance to anticancer monoclonal antibodies. MAbs 1:222–229

    Article  Google Scholar 

  22. Racila E, Link BK, Weng WK, Witzig TE, Ansell S, Maurer MJ, Huang J, Dahle C, Halwani A, Levy R, Weiner GJ (2008) A polymorphism in the complement component C1qA correlates with prolonged response following rituximab therapy of follicular lymphoma. Clin Cancer Res 14:6697–6703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Treon SP, Hansen M, Branagan AR, Verselis S, Emmanouilides C, Kimby E, Frankel SR, Touroutoglou N, Turnbull B, Anderson KC, Maloney DG, Fox EA (2005) Polymorphisms in FcgammaRIIIA (CD16) receptor expression are associated with clinical response to rituximab in Waldenstrom’s macroglobulinemia. J Clin Oncol 23:474–481

    Article  CAS  PubMed  Google Scholar 

  24. Golay J, Zaffaroni L, Vaccari T, Lazzari M, Borleri GM, Bernasconi S, Tedesco F, Rambaldi A, Introna M (2000) Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood 95:3900–3908

    CAS  PubMed  Google Scholar 

  25. Boross P, Leusen JH (2012) Mechanisms of action of CD20 antibodies. Am J Cancer Res 2:676–690

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Teeling JL, Mackus WJ, Wiegman LJ, van den Brakel JH, Beers SA, French RR, van Meerten T, Ebeling S, Vink T, Slootstra JW, Parren PW, Glennie MJ, van de Winkel JG (2006) The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol 177:362–371

    Article  CAS  PubMed  Google Scholar 

  27. Nishida M, Uematsu N, Kobayashi H, Matsunaga Y, Ishida S, Takata M, Niwa O, Padlan EA, Newman R (2011) BM-ca is a newly defined type I/II anti-CD20 monoclonal antibody with unique biological properties. Int J Oncol 38:335–344

    Article  PubMed  Google Scholar 

  28. Alduaij W, Ivanov A, Honeychurch J, Cheadle EJ, Potluri S, Lim SH, Shimada K, Chan CH, Tutt A, Beers SA, Glennie MJ, Cragg MS, Illidge TM (2011) Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies. Blood 117:4519–4529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chan HT, Hughes D, French RR, Tutt AL, Walshe CA, Teeling JL, Glennie MJ, Cragg MS (2003) CD20-induced lymphoma cell death is independent of both caspases and its redistribution into triton X-100 insoluble membrane rafts. Cancer Res 63:5480–5489

    CAS  PubMed  Google Scholar 

  30. Cragg MS, Morgan SM, Chan HT, Morgan BP, Filatov AV, Johnson PW, French RR, Glennie MJ (2003) Complement-mediated lysis by anti-CD20 mAb correlates with segregation into lipid rafts. Blood 101:1045–1052

    Article  CAS  PubMed  Google Scholar 

  31. Cragg MS, Glennie MJ (2004) Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents. Blood 103:2738–2743

    Article  CAS  PubMed  Google Scholar 

  32. Mossner E, Brunker P, Moser S, Puntener U, Schmidt C, Herter S, Grau R, Gerdes C, Nopora A, van Puijenbroek E, Ferrara C, Sondermann P, Jager C, Strein P, Fertig G, Friess T, Schull C, Bauer S, Dal PJ, Del NC, Dabbagh K, Dyer MJ, Poppema S, Klein C, Umana P (2010) Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood 115:4393–4402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Niederfellner G, Lammens A, Mundigl O, Georges GJ, Schaefer W, Schwaiger M, Franke A, Wiechmann K, Jenewein S, Slootstra JW, Timmerman P, Brannstrom A, Lindstrom F, Mossner E, Umana P, Hopfner KP, Klein C (2011) Epitope characterization and crystal structure of GA101 provide insights into the molecular basis for type I/II distinction of CD20 antibodies. Blood 118:358–367

    Article  CAS  PubMed  Google Scholar 

  34. Kensei Tobinai MO, Dai M, Tatsuya S, Yukio K, Toshiki U, Suguru F, Takashi O, Tomoharu F, Yasuhiko K (2013) Phase I study of a novel humanized anti-CD20 antibody, BM-ca, in patients (pts) with relapsed or refractory indolent B cell non-Hodgkin lymphoma (B-NHL) pretreated with rituximab. J Clin Oncol 31:8551

    Google Scholar 

  35. Forero-Torres A, de Vos S, Pohlman BL, Pashkevich M, Cronier DM, Dang NH, Carpenter SP, Allan BW, Nelson JG, Slapak CA, Smith MR, Link BK, Wooldridge JE, Ganjoo KN (2012) Results of a phase 1 study of AME-133v (LY2469298), an Fc-engineered humanized monoclonal anti-CD20 antibody, in FcgammaRIIIa-genotyped patients with previously treated follicular lymphoma. Clin Cancer Res 18:1395–1403

    Article  CAS  PubMed  Google Scholar 

  36. Ganjoo KN, de Vos S, Pohlman BL, Flinn IW, Forero-Torres A, Enas NH, Cronier DM, Dang NH, Foon KA, Carpenter SP, Slapak CA, Link BK, Smith MR, Mapara MY, Wooldridge JE (2015) Phase 1/2 study of ocaratuzumab, an Fc-engineered humanized anti-CD20 monoclonal antibody, in low-affinity FcgammaRIIIa patients with previously treated follicular lymphoma. Leuk Lymphoma 56:42–48

    Article  CAS  PubMed  Google Scholar 

  37. Salles GA, Morschhauser F, Solal-Celigny P, Thieblemont C, Lamy T, Tilly H, Gyan E, Lei G, Wenger M, Wassner-Fritsch E, Cartron G (2013) Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol 31:2920–2926

    Article  CAS  PubMed  Google Scholar 

  38. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner C, Chagorova T, De la Serna J, Dilhuydy M, Opat S, Carolyn J, Owen CJ, Samoylova O, Kreuzer K, Anton W, Langerak AW, Ritgen M, Stilgenbauer S, Döhner HD, Asikanius E, Humphrey K, Michael K, Wenger MK, Hallek M (2013) Head-to-head comparison of obinutuzumab (GA101) plus chlorambucil (Clb) versus rituximab plus Clb in patients with chronic lymphocytic leukemia (CLL) and co-existing medical conditions (comorbidities): final stage two results of the CLL11 trial. Blood 122:6

    Article  Google Scholar 

  39. Morschhauser FA, Cartron G, Thieblemont C, Solal-Celigny P, Haioun C, Bouabdallah R, Feugier P, Bouabdallah K, Asikanius E, Lei G, Wenger M, Wassner-Fritsch E, Salles GA (2013) Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large b-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol 31:2912–2919

    Article  CAS  PubMed  Google Scholar 

  40. Morschhauser F, Leonard JP, Fayad L, Coiffier B, Petillon MO, Coleman M, Schuster SJ, Dyer MJ, Horne H, Teoh N, Wegener WA, Goldenberg DM (2009) Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin’s lymphoma: phase I/II results. J Clin Oncol 27:3346–3353

    Article  CAS  PubMed  Google Scholar 

  41. Brown JR, O’Brien S, Kingsley CD, Eradat H, Pagel JM, Lymp J, Hirata J, Kipps TJ (2015) Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood 125:2779–2785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Morschhauser F, Marlton P, Vitolo U, Linden O, Seymour JF, Crump M, Coiffier B, Foa R, Wassner E, Burger HU, Brennan B, Mendila M (2010) Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma. Ann Oncol 21:1870–1876

    Article  CAS  PubMed  Google Scholar 

  43. Casulo C, Vose JM, Ho WY, Kahl B, Brunvand M, Goy A, Kasamon Y, Cheson B, Friedberg JW (2014) A phase I study of PRO131921, a novel anti-CD20 monoclonal antibody in patients with relapsed/refractory CD20+ indolent NHL: correlation between clinical responses and AUC pharmacokinetics. Clin Immunol 154:37–46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jak M, van Bochove GG, Reits EA, Kallemeijn WW, Tromp JM, Umana P, Klein C, van Lier RA, van Oers MH, Eldering E (2011) CD40 stimulation sensitizes CLL cells to lysosomal cell death induction by type II anti-CD20 mAb GA101. Blood 118:5178–5188

    Article  CAS  PubMed  Google Scholar 

  45. Yin C, Lee S, O’Connell T, Ayello J, van de Ven C, Cairo MS (2014) Obinutuzumab (GA101) Significantly Inhibits Cell Proliferation and Induces Programmed Cell Death in Primary Mediastinal B-Cell Lymphoma (PMBL): Obinutuzumab May be a Future Targeted Agent for the Treatment of PMBL. Blood 124:4492

    Google Scholar 

  46. Byrd JC, Flynn JM, Kipps TJ, Boxer M, Kolibaba KS, Carlile DJ, Fingerle-Rowson G, Tyson N, Hirata J, Sharman JP (2016) Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia. Blood 127:79–86

    Article  PubMed  PubMed Central  Google Scholar 

  47. Rafiq S, Butchar JP, Cheney C, Mo X, Trotta R, Caligiuri M, Jarjoura D, Tridandapani S, Muthusamy N, Byrd JC (2013) Comparative assessment of clinically utilized CD20-directed antibodies in chronic lymphocytic leukemia cells reveals divergent NK cell, monocyte, and macrophage properties. J Immunol 190:2702–2711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Brychtova Y, Panovska A, Sebejova L, Stehlikova O, Chovancova J, Malcikova J, Smardova J, Plevova K, Volfova P, Trbusek M, Mraz M, Bakesova D, Trizuljak J, Hadrabova M, Obrtlikova P, Karban J, Smolej L, Oltova A, Jelinkova E, Pospisilova S, Mayer J (2015) Ofatumumab added to dexamethasone in patients with relapsed or refractory chronic lymphocytic leukemia: results from a phase II study. Am J Hematol 90:417–421

    Article  PubMed  CAS  Google Scholar 

  49. Goldenberg DM, Rossi EA, Stein R, Cardillo TM, Czuczman MS, Hernandez-Ilizaliturri FJ, Hansen HJ, Chang CH (2009) Properties and structure-function relationships of veltuzumab (hA20), a humanized anti-CD20 monoclonal antibody. Blood 113:1062–1107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Negrea GO, Elstrom R, Allen SL, Rai KR, Abbasi RM, Farber CM, Teoh N, Horne H, Wegener WA, Goldenberg DM (2011) Subcutaneous injections of low-dose veltuzumab (humanized anti-CD20 antibody) are safe and active in patients with indolent non-Hodgkin’s lymphoma. Haematologica 96:567–573

    Article  CAS  PubMed  Google Scholar 

  51. Christian BA, Poi M, Jones JA, Porcu P, Maddocks K, Flynn JM, Benson DM Jr, Phelps MA, Wei L, Byrd JC, Wegener WA, Goldenberg DM, Baiocchi RA, Blum KA (2015) The combination of milatuzumab, a humanized anti-CD74 antibody, and veltuzumab, a humanized anti-CD20 antibody, demonstrates activity in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Br J Haematol 169:701–710

    Article  CAS  PubMed  Google Scholar 

  52. Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H (2002) Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 99:754–758

    Article  CAS  PubMed  Google Scholar 

  53. Kobayashi H, Matsunaga Y, Uchiyama Y, Nagura K, Komatsu Y (2013) Novel humanized anti-CD20 antibody BM-ca binds to a unique epitope and exerts stronger cellular activity than others. Cancer Med 2:130–143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tuscano JM, Ma Y, Martin SM, Kato J, O’Donnell RT (2011) The Bs20x22 anti-CD20-CD22 bispecific antibody has more lymphomacidal activity than do the parent antibodies alone. Cancer Immunol Immunother 60:771–780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhao L, Tong Q, Qian W, Li B, Zhang D, Fu T, Duan S, Zhang X, Zhao J, Dai J, Wang H, Hou S, Guo Y (2013) Eradication of non-Hodgkin lymphoma through the induction of tumor-specific T-cell immunity by CD20-Flex BiFP. Blood 122:4230–4236

    Article  CAS  PubMed  Google Scholar 

  56. Piccione EC, Juarez S, Liu J, Tseng S, Ryan C, Narayanan C, Wang L, Weiskopf K, Majeti R (2015) A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells. MAbs. doi:10.1080/19420862.2015.1062192

    PubMed  PubMed Central  Google Scholar 

  57. Ruf P, Lindhofer H (2001) Induction of a long-lasting antitumor immunity by a trifunctional bispecific antibody. Blood 98:2526–2534

    Article  CAS  PubMed  Google Scholar 

  58. Stanglmaier M, Faltin M, Ruf P, Bodenhausen A, Schroder P, Lindhofer H (2008) Bi20 (fBTA05), a novel trifunctional bispecific antibody (anti-CD20 x anti-CD3), mediates efficient killing of B-cell lymphoma cells even with very low CD20 expression levels. Int J Cancer 123:1181–1189

    Article  CAS  PubMed  Google Scholar 

  59. Damm JK, Gordon S, Ehinger M, Jerkeman M, Gullberg U, Hultquist A, Drott K (2015) Pharmacologically relevant doses of valproate upregulate CD20 expression in three diffuse large B-cell lymphoma patients in vivo. Exp Hematol Oncol 4:4

    Article  PubMed  PubMed Central  Google Scholar 

  60. Sun LL, Ellerman D, Mathieu M, Hristopoulos M, Chen X, Li Y, Yan X, Clark R, Reyes A, Stefanich E, Mai E, Young J, Johnson C, Huseni M, Wang X, Chen Y, Wang P, Wang H, Dybdal N, Chu YW, Chiorazzi N, Scheer JM, Junttila T, Totpal K, Dennis MS, Ebens AJ (2015) Anti-CD20/CD3 T cell-dependent bispecific antibody for the treatment of B cell malignancies. Sci Transl Med 7:287ra70

    Article  PubMed  Google Scholar 

  61. Jakob CG, Edalji R, Judge RA, DiGiammarino E, Li Y, Gu J, Ghayur T (2013) Structure reveals function of the dual variable domain immunoglobulin (DVD-Ig) molecule. MAbs 5:358–363

    Article  PubMed  PubMed Central  Google Scholar 

  62. Zeng J, Liu R, Wang J, Fang Y (2015) A bispecific antibody directly induces lymphoma cell death by simultaneously targeting CD20 and HLA-DR. J Cancer Res Clin Oncol. doi:10.1007/s00432-015-1949-7

    Google Scholar 

  63. Gupta P, Goldenberg DM, Rossi EA, Cardillo TM, Byrd JC, Muthusamy N, Furman RR, Chang CH (2012) Dual-targeting immunotherapy of lymphoma: potent cytotoxicity of anti-CD20/CD74 bispecific antibodies in mantle cell and other lymphomas. Blood 119:3767–3778

    Article  CAS  PubMed  Google Scholar 

  64. Fisher RI, Kaminski MS, Wahl RL, Knox SJ, Zelenetz AD, Vose JM, Leonard JP, Kroll S, Goldsmith SJ, Coleman M (2005) Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin’s lymphomas. J Clin Oncol 23:7565–7573

    Article  CAS  PubMed  Google Scholar 

  65. Jacobs SA (2007) Yttrium ibritumomab tiuxetan in the treatment of non-Hodgkin’s lymphoma: current status and future prospects. Biologics 1:215–227

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Pandey U, Kameswaran M, Dev SH, Samuel G (2014) 99mTc carbonyl DTPA-rituximab: preparation and preliminary bioevaluation. Appl Radiat Isot 86:52–56

    Article  CAS  PubMed  Google Scholar 

  67. Sharkey RM, Karacay H, Litwin S, Rossi EA, McBride WJ, Chang CH, Goldenberg DM (2008) Improved therapeutic results by pretargeted radioimmunotherapy of non-Hodgkin’s lymphoma with a new recombinant, trivalent, anti-CD20, bispecific antibody. Cancer Res 68:5282–5290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Law CL, Cerveny CG, Gordon KA, Klussman K, Mixan BJ, Chace DF, Meyer DL, Doronina SO, Siegall CB, Francisco JA, Senter PD, Wahl AF (2004) Efficient elimination of B-lineage lymphomas by anti-CD20-auristatin conjugates. Clin Cancer Res 10:7842–7851

    Article  CAS  PubMed  Google Scholar 

  69. Li ZH, Zhang Q, Wang HB, Zhang YN, Ding D, Pan LQ, Miao D, Xu S, Zhang C, Luo PH, Naranmandura H, Chen SQ (2014) Preclinical studies of targeted therapies for CD20-positive B lymphoid malignancies by Ofatumumab conjugated with auristatin. Invest New Drugs 32:75–86

    Article  PubMed  CAS  Google Scholar 

  70. Polito L, Bolognesi A, Tazzari PL, Farini V, Lubelli C, Zinzani PL, Ricci F, Stirpe F (2004) The conjugate Rituximab/saporin-S6 completely inhibits clonogenic growth of CD20-expressing cells and produces a synergistic toxic effect with Fludarabine. Leukemia 18:1215–1222

    Article  CAS  PubMed  Google Scholar 

  71. Vincent M, Teppaz G, Lajoie L, Sole V, Bessard A, Maillasson M, Loisel S, Bechard D, Clemenceau B, Thibault G, Garrigue-Antar L, Jacques Y, Quemener A (2014) Highly potent anti-CD20-RLI immunocytokine targeting established human B lymphoma in SCID mouse. MAbs 6:1026–1037

    Article  PubMed  PubMed Central  Google Scholar 

  72. Rossi EA, Goldenberg DM, Cardillo TM, Stein R, Chang CH (2009) CD20-targeted tetrameric interferon-alpha, a novel and potent immunocytokine for the therapy of B-cell lymphomas. Blood 114:3864–3871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Rossi EA, Rossi DL, Stein R, Goldenberg DM, Chang CH (2010) A bispecific antibody-IFNalpha2b immunocytokine targeting CD20 and HLA-DR is highly toxic to human lymphoma and multiple myeloma cells. Cancer Res 70:7600–7609

    Article  CAS  PubMed  Google Scholar 

  74. Marusic C, Novelli F, Salzano AM, Scaloni A, Benvenuto E, Pioli C, Donini M (2015) Production of an active anti-CD20-hIL-2 immunocytokine in Nicotiana benthamiana. Plant Biotechnol J. doi:10.1111/pbi.12378

    PubMed  Google Scholar 

  75. Ocampo García BE, Miranda Olvera RM, Santos Cuevas CL, García Becerra R, Azorín Vega EP, Ordaz Rosado D (2014) In vitro decrease of the BCL-2 protein levels in lymphoma cells induced by gold nanoparticles and gold nanoparticles-anti-CD20. Nanosci Technol 1:1–6

    Google Scholar 

  76. Minai L, Yeheskely-Hayon D, Yelin D (2013) High levels of reactive oxygen species in gold nanoparticle-targeted cancer cells following femtosecond pulse irradiation. Sci Rep 3:2146

    Article  PubMed  PubMed Central  Google Scholar 

  77. Voltan R, Secchiero P, Ruozi B, Forni F, Agostinis C, Caruso L, Vandelli MA, Zauli G (2013) Nanoparticles engineered with rituximab and loaded with Nutlin-3 show promising therapeutic activity in B-leukemic xenografts. Clin Cancer Res 19:3871–3880

    Article  CAS  PubMed  Google Scholar 

  78. Sapra P, Allen TM (2004) Improved outcome when B-cell lymphoma is treated with combinations of immunoliposomal anticancer drugs targeted to both the CD19 and CD20 epitopes. Clin Cancer Res 10:2530–2537

    Article  CAS  PubMed  Google Scholar 

  79. Davidson N, Camburn T, Keary I, Houghton D (2014) Substituting Doxorubicin with nonpegylated liposomal Doxorubicin for the treatment of early breast cancer: results of a retrospective study. Int J Breast Cancer 2014:984067

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Iannitto E, Luminari S, Tripodo C, Mancuso S, Cesaretti M, Marcheselli L, Merli F, Stelitano C, Carella AM, Fragasso A, Montechiarello E, Ricciuti G, Pulsoni A, Paulli M, Franco V, Federico M (2015) Rituximab with cyclophosphamide, vincristine, non-pegylated liposomal doxorubicin and prednisone as first-line treatment for splenic marginal zone lymphoma: a Fondazione Italiana Linfomi phase II study. Leuk Lymphoma. doi:10.3109/10428194.2015.1029925

    PubMed  Google Scholar 

  81. Yu B, Mao Y, Bai LY, Herman SE, Wang X, Ramanunni A, Jin Y, Mo X, Cheney C, Chan KK, Jarjoura D, Marcucci G, Lee RJ, Byrd JC, Lee LJ, Muthusamy N (2013) Targeted nanoparticle delivery overcomes off-target immunostimulatory effects of oligonucleotides and improves therapeutic efficacy in chronic lymphocytic leukemia. Blood 121:136–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chu TW, Yang J, Kopecek J (2012) Anti-CD20 multivalent HPMA copolymer-Fab’ conjugates for the direct induction of apoptosis. Biomaterials 33:7174–7181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, Forman SJ (2010) Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transplant 16:1245–1256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, Qian X, James SE, Raubitschek A, Forman SJ, Gopal AK, Pagel JM, Lindgren CG, Greenberg PD, Riddell SR, Press OW (2008) Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 112:2261–2271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Till BG, Jensen MC, Wang J, Qian X, Gopal AK, Maloney DG, Lindgren CG, Lin Y, Pagel JM, Budde LE, Raubitschek A, Forman SJ, Greenberg PD, Riddell SR, Press OW (2012) CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood 119:3940–3950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Jensen M, Tan G, Forman S, Wu AM, Raubitschek A (1998) CD20 is a molecular target for scFvFc:zeta receptor redirected T cells: implications for cellular immunotherapy of CD20+ malignancy. Biol Blood Marrow Transplant 4:75–83

    Article  CAS  PubMed  Google Scholar 

  87. Jensen MC, Cooper LJ, Wu AM, Forman SJ, Raubitschek A (2003) Engineered CD20-specific primary human cytotoxic T lymphocytes for targeting B-cell malignancy. Cytotherapy 5:131–138

    Article  CAS  PubMed  Google Scholar 

  88. Wang J, Jensen M, Lin Y, Sui X, Chen E, Lindgren CG, Till B, Raubitschek A, Forman SJ, Qian X, James S, Greenberg P, Riddell S, Press OW (2007) Optimizing adoptive polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains. Hum Gene Ther 18:712–725

    Article  CAS  PubMed  Google Scholar 

  89. Budde LE, Berger C, Lin Y, Wang J, Lin X, Frayo SE, Brouns SA, Spencer DM, Till BG, Jensen MC, Riddell SR, Press OW (2013) Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma. PLoS One 8, e82742

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Muller T, Uherek C, Maki G, Chow KU, Schimpf A, Klingemann HG, Tonn T, Wels WS (2008) Expression of a CD20-specific chimeric antigen receptor enhances cytotoxic activity of NK cells and overcomes NK-resistance of lymphoma and leukemia cells. Cancer Immunol Immunother 57:411–423

    Article  PubMed  CAS  Google Scholar 

  91. Boissel L, Betancur-Boissel M, Lu W, Krause DS, Van Etten RA, Wels WS, Klingemann H (2013) Retargeting NK-92 cells by means of. Oncoimmunology 2, e26527

    Article  PubMed  PubMed Central  Google Scholar 

  92. Chu Y, Hochberg J, Yahr A, Ayello J, van de Ven C, Barth M, Czuczman M, Cairo MS (2015) Targeting CD20+ aggressive B-cell non-hodgkin lymphoma by anti-CD20 CAR mRNA-modified expanded natural killer cells in vitro and in NSG mice. Cancer Immunol Res 3:333–344

    Article  CAS  PubMed  Google Scholar 

  93. Reagan MR, Seib FP, McMillin DW, Sage EK, Mitsiades CS, Janes SM, Ghobrial IM, Kaplan DL (2012) Stem cell implants for cancer therapy: TRAIL-expressing Mesenchymal stem cells target cancer cells in situ. J Breast Cancer 15:273–282

    Article  PubMed  PubMed Central  Google Scholar 

  94. Yan C, Li S, Li Z, Peng H, Yuan X, Jiang L, Zhang Y, Fan D, Hu X, Yang M, Xiong D (2013) Human umbilical cord mesenchymal stem cells as vehicles of CD20-specific TRAIL fusion protein delivery: a double-target therapy against non-Hodgkin’s lymphoma. Mol Pharm 10:142–151

    Article  CAS  PubMed  Google Scholar 

  95. Bremer E, Ten CB, Samplonius DF, Mueller N, Wajant H, Stel AJ, Chamuleau M, van de Loosdrecht AA, Stieglmaier J, Fey GH, Helfrich W (2008) Superior activity of fusion protein scFvRit:sFasL over cotreatment with rituximab and Fas agonists. Cancer Res 68:597–604

    Article  CAS  PubMed  Google Scholar 

  96. Brunekreeft KL, Strohm C, Gooden MJ, Rybczynska AA, Nijman HW, Grigoleit GU, Helfrich W, Bremer E, Siegmund D, Wajant H, de Bruyn M (2014) Targeted delivery of CD40L promotes restricted activation of antigen-presenting cells and induction of cancer cell death. Mol Cancer 13:85

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Gisselbrecht C, Schmitz N, Mounier N, Singh GD, Linch DC, Trneny M, Bosly A, Milpied NJ, Radford J, Ketterer N, Shpilberg O, Duhrsen U, Hagberg H, Ma DD, Viardot A, Lowenthal R, Briere J, Salles G, Moskowitz CH, Glass B (2012) Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol 30:4462–4469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Abou-Nassar KE, Stevenson KE, Antin JH, McDermott K, Ho VT, Cutler CS, Lacasce AS, Jacobsen ED, Fisher DC, Soiffer RJ, Alyea EP, Koreth J, Freedman AS (2011) (90)Y-ibritumomab tiuxetan followed by reduced-intensity conditioning and allo-SCT in patients with advanced follicular lymphoma. Bone Marrow Transplant 46:1503–1509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Chang JE, Seo S, Kim KM, Werndli JE, Bottner WA, Rodrigues GA, Sanchez FA, Saphner TJ, Longo WL, Kahl BS (2010) Rituximab and CHOP chemotherapy plus GM-CSF for previously untreated diffuse large B-cell lymphoma in the elderly: a Wisconsin oncology network study. Clin Lymphoma Myeloma Leuk 10:379–384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Schliemann C, Palumbo A, Zuberbuhler K, Villa A, Kaspar M, Trachsel E, Klapper W, Menssen HD, Neri D (2009) Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL2. Blood 113:2275–2283

    Article  CAS  PubMed  Google Scholar 

  101. Rosario M, Liu B, Kong L, Schneider SE, Jeng EK, Rhode PR, Wong H, Fehniger TA (2014) The IL-15 superagonist ALT-803 enhances NK cell ADCC and in vivo clearance of B cell lymphomas directed by an anti-CD20 monoclonal antibody. Blood 124:807

    Google Scholar 

  102. Timmerman JM, Byrd JC, Andorsky DJ, Yamada RE, Kramer J, Muthusamy N, Hunder N, Pagel JM (2012) A phase I dose-finding trial of recombinant interleukin-21 and rituximab in relapsed and refractory low grade B-cell lymphoproliferative disorders. Clin Cancer Res 18:5752–5760

    Article  CAS  PubMed  Google Scholar 

  103. Abes R, Gelize E, Fridman WH, Teillaud JL (2010) Long-lasting antitumor protection by anti-CD20 antibody through cellular immune response. Blood 116:926–934

    Article  CAS  PubMed  Google Scholar 

  104. Manzur S, Cohen S, Haimovich J, Hollander N (2012) Enhanced therapeutic effect of B cell-depleting anti-CD20 antibodies upon combination with in-situ dendritic cell vaccination in advanced lymphoma. Clin Exp Immunol 170:291–299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Oksvold MP, Kullmann A, Forfang L, Kierulf B, Li M, Brech A, Vlassov AV, Smeland EB, Neurauter A, Pedersen KW (2014) Expression of B-cell surface antigens in subpopulations of exosomes released from B-cell lymphoma cells. Clin Ther 36:847–862

    Article  CAS  PubMed  Google Scholar 

  106. Rialland P, Lankar D, Raposo G, Bonnerot C, Hubert P (2006) BCR-bound antigen is targeted to exosomes in human follicular lymphoma B-cells. Biol Cell 98:491–501

    Article  CAS  PubMed  Google Scholar 

  107. Bennit HRF, Valenzuela MMA, Jutzy JS, Wall NP (2014) B-cell lymphoma-derived exosomes are reservoirs of inhibitors of apoptosis. Cancer Res 74:1108

    Article  Google Scholar 

  108. Aung T, Chapuy B, Vogel D, Wenzel D, Oppermann M, Lahmann M, Weinhage T, Menck K, Hupfeld T, Koch R, Trumper L, Wulf GG (2011) Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3. Proc Natl Acad Sci U S A 108:15336–15341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Stuhmer T, Zollinger A, Siegmund D, Chatterjee M, Grella E, Knop S, Kortum M, Unzicker C, Jensen MR, Quadt C, Chene P, Schoepfer J, Garcia-Echeverria C, Einsele H, Wajant H, Bargou RC (2008) Signalling profile and antitumour activity of the novel Hsp90 inhibitor NVP-AUY922 in multiple myeloma. Leukemia 22:1604–1612

    Article  CAS  PubMed  Google Scholar 

  110. Richter K, Muschler P, Hainzl O, Reinstein J, Buchner J (2003) Sti1 is a non-competitive inhibitor of the Hsp90 ATPase. Binding prevents the N-terminal dimerization reaction during the atpase cycle. J Biol Chem 278:10328–10333

    Article  CAS  PubMed  Google Scholar 

  111. Czuczman MS, Olejniczak S, Gowda A, Kotowski A, Binder A, Kaur H, Knight J, Starostik P, Deans J, Hernandez-Ilizaliturri FJ (2008) Acquirement of rituximab resistance in lymphoma cell lines is associated with both global CD20 gene and protein down-regulation regulated at the pretranscriptional and posttranscriptional levels. Clin Cancer Res 14:1561–1570

    Article  CAS  PubMed  Google Scholar 

  112. Ottosson-Wadlund A, Ceder R, Preta G, Pokrovskaja K, Grafstrom RC, Heyman M, Soderhall S, Grander D, Hedenfalk I, Robertson JD, Fadeel B (2013) Requirement of apoptotic protease-activating factor-1 for bortezomib-induced apoptosis but not for Fas-mediated apoptosis in human leukemic cells. Mol Pharmacol 83:245–255

    Article  PubMed  CAS  Google Scholar 

  113. Gressin R, Houot R, Uribe MO, Mounier C, Bouabdallah K, Alexis M, Senecal D, Molles MP, Tournilhac O, Park S, Rodon P, Yamani AEI, Sutton L, Lioure B, Assouline D, Harousseau J, Maisonneuve H, Caulet S, Gouill SL (2010) Final results of the RiPAD+C regimen including Velcade in front line therapy for elderly patients with mantle cell lymphoma. A phase II prospective study of the GOELAMS group. Blood 116:2791

    Google Scholar 

  114. Ruan J, Martin P, Furman RR, Lee SM, Cheung K, Vose JM, Lacasce A, Morrison J, Elstrom R, Ely S, Chadburn A, Cesarman E, Coleman M, Leonard JP (2011) Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J Clin Oncol 29:690–697

    Article  CAS  PubMed  Google Scholar 

  115. Liu H, Westergard TD, Cashen A, Piwnica-Worms DR, Kunkle L, Vij R, Pham CG, DiPersio J, Cheng EH, Hsieh JJ (2014) Proteasome inhibitors evoke latent tumor suppression programs in pro-B MLL leukemias through MLL-AF4. Cancer Cell 25:530–542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Riaz W, Hernandez-Ilizaliturri FJ, Mavis C, Tsai P, Czuczman MS (2010) Efficacy of combination of rituximab (R), obatoclax (O), and bortezomib (B) against rituximab-sensitive (RSCL) and rituximab-resistant B-cell lymphoma cell lines (RRCL). J Clin Oncol 28:8094

    Article  CAS  Google Scholar 

  117. Johnson AJ, Wagner AJ, Cheney CM, Smith LL, Lucas DM, Guster SK, Grever MR, Lin TS, Byrd JC (2007) Rituximab and 17-allylamino-17-demethoxygeldanamycin induce synergistic apoptosis in B-cell chronic lymphocytic leukaemia. Br J Haematol 139:837–844

    Article  CAS  PubMed  Google Scholar 

  118. Reddy N, Hicks D, Jagasia M, Amiri K (2009) SNX 2112, an oral Hsp-90 inhibitor exerts antiproliferative effects in combination with bortezomib and rituximab in rituximab resistant non-Hodgkin’s lymphoma. Blood 114:3733

    Google Scholar 

  119. Ashkenazi A, Holland P, Eckhardt SG (2008) Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/Tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL). J Clin Oncol 26:3621–3630

    Article  CAS  PubMed  Google Scholar 

  120. Maddipatla S, Hernandez-Ilizaliturri FJ, Knight J, Czuczman MS (2007) Augmented antitumor activity against B-cell lymphoma by a combination of monoclonal antibodies targeting TRAIL-R1 and CD20. Clin Cancer Res 13:4556–4564

    Article  CAS  PubMed  Google Scholar 

  121. Yee L, Fanale M, Dimick K, Calvert S, Robins C, Ing J, Novotny W, Ashkenazi A, Burris IH (2007) A phase IB safety and pharmacokinetic (PK) study of recombinant human Apo2L/TRAIL in combination with rituximab in patients with low-grade non-Hodgkin lymphoma. J Clin Oncol 25:8078

    Google Scholar 

  122. Cheah CY, Belada D, Fanale MA, Janikova A, Czucman MS, Flinn IW, Kapp AV, Ashkenazi A, Kelley S, Bray GL, Holden S, Seymour JF (2015) Dulanermin with rituximab in patients with relapsed indolent B-cell lymphoma: an open-label phase 1b/2 randomised study. Lancet Haematol 2:166–174

    Article  Google Scholar 

  123. Stephens DM, Ruppert AS, Maddocks K, Andritsos L, Baiocchi R, Jones J, Johnson AJ, Smith LL, Zhao Y, Ling Y, Li J, Phelps MA, Grever MR, Byrd JC, Flynn JM (2013) Cyclophosphamide, alvocidib (flavopiridol), and rituximab, a novel feasible chemoimmunotherapy regimen for patients with high-risk chronic lymphocytic leukemia. Leuk Res 37:1195–1199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Fabre C, Gobbi M, Ezzili C, Zoubir M, Sablin MP, Small K, Im E, Shinwari N, Zhang D, Zhou H, Le TC (2014) Clinical study of the novel cyclin-dependent kinase inhibitor dinaciclib in combination with rituximab in relapsed/refractory chronic lymphocytic leukemia patients. Cancer Chemother Pharmacol 74:1057–1064

    Article  CAS  PubMed  Google Scholar 

  125. Seki R, Ohshima K, Fujisaki T, Uike N, Kawano F, Gondo H, Makino S, Eto T, Moriuchi Y, Taguchi F, Kamimura T, Tsuda H, Shimoda K, Okamura T (2010) Prognostic significance of S-phase kinase-associated protein 2 and p27kip1 in patients with diffuse large B-cell lymphoma: effects of rituximab. Ann Oncol 21:833–841

    Article  CAS  PubMed  Google Scholar 

  126. Mahadevan D, Stejskal A, Cooke LS, Manziello A, Morales C, Persky DO, Fisher RI, Miller TP, Qi W (2012) Aurora A inhibitor (MLN8237) plus vincristine plus rituximab is synthetic lethal and a potential curative therapy in aggressive B-cell non-Hodgkin lymphoma. Clin Cancer Res 18:2210–2219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Xu ZZ, Wang WF, Fu WB, Wang AH, Liu ZY, Chen LY, Guo P, Li JM (2014) Combination of rituximab and mammalian target of rapamycin inhibitor everolimus (RAD001) in diffuse large B-cell lymphoma. Leuk Lymphoma 55:1151–1157

    Article  CAS  PubMed  Google Scholar 

  128. Prasad A, Shrivastava A, Papadopoulos E, Kuzontkoski PM, Reddy MV, Gillum AM, Kumar R, Reddy EP, Groopman JE (2013) Combined administration of rituximab and on 013105 induces apoptosis in mantle cell lymphoma cells and reduces tumor burden in a mouse model of mantle cell lymphoma. Clin Cancer Res 19:85–95

    Article  CAS  PubMed  Google Scholar 

  129. Wang ML, Lee H, Chuang H, Wagner-Bartak N, Hagemeister F, Westin J, Fayad L, Samaniego F, Turturro F, Oki Y, Chen W, Badillo M, Nomie K, Rosa MD, Zhao D, Lam L, Addison A, Zhang H, Young KH, Li S, Santos D, Medeiros LJ, Champlin R, Romaguera J, Zhang L (2016) Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial. Lancet Oncol 17:48–56

    Article  CAS  PubMed  Google Scholar 

  130. O’Brien SM, Lamanna N, Kipps TJ, Flinn I, Zelenetz AD, Burger JA, Keating M, Mitra S, Holes L, Yu AS, Johnson DM, Miller LL, Kim Y, Dansey RD, Dubowy RL, Coutre SE (2015) A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia. Blood 17(126):2686–2694

    Article  CAS  Google Scholar 

  131. Zhang LH, Kosek J, Wang M, Heise C, Schafer PH, Chopra R (2013) Lenalidomide efficacy in activated B-cell-like subtype diffuse large B-cell lymphoma is dependent upon IRF4 and cereblon expression. Br J Haematol 160:487–502

    Article  CAS  PubMed  Google Scholar 

  132. Fecteau JF, Corral LG, Ghia EM, Gaidarova S, Futalan D, Bharati IS, Cathers B, Schwaederle M, Cui B, Lopez-Girona A, Messmer D, Kipps TJ (2014) Lenalidomide inhibits the proliferation of CLL cells via a cereblon/p21(WAF1/Cip1)-dependent mechanism independent of functional p53. Blood 124:1637–1644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, Ottman E, Czuczman MS (2005) Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res 11:5984–5992

    Article  CAS  PubMed  Google Scholar 

  134. Reddy N, Hernandez-Ilizaliturri FJ, Deeb G, Roth M, Vaughn M, Knight J, Wallace P, Czuczman MS (2008) Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo. Br J Haematol 140:36–45

    CAS  PubMed  Google Scholar 

  135. Wu L, Adams M, Carter T, Chen R, Muller G, Stirling D, Schafer P, Bartlett JB (2008) lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res 14:4650–4657

    Article  CAS  PubMed  Google Scholar 

  136. Gaidarova S, Corral L, Glezer E, Schafer P, Lopez-Girona A (2009) Treatment of MCL cells with combined rituximab and lenalidomide enhances NK-mediated synapse formation and cell killing. ASH Ann Meet 114:1687

    Google Scholar 

  137. Gaidarova S, Mendy D, Heise C, Aukerman S, Daniel T, Chopra R, Lopez-Girona A (2010) Lenalidomide induces capping of CD20 and cytoskeleton proteins to enhance rituximab immune recognition of malignant B-cells. ASH Annual Meeting 116:2845

    Google Scholar 

  138. Fowler NH, Davis RE, Rawal S, Nastoupil L, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE, Fanale MA, Fayad LE, Westin JR, Shah J, Orlowski RZ, Wang M, Turturro F, Oki Y, Claret LC, Feng L, Baladandayuthapani V, Muzzafar T, Tsai KY, Samaniego F, Neelapu SS (2014) Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol 15:1311–1318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Chong EA, Ahmadi T, Aqui NA, Svoboda J, Nasta SD, Mato AR, Walsh KM, Schuster SJ (2015) Combination of Lenalidomide and rituximab overcomes rituximab resistance in patients with indolent B-cell and mantle cell lymphomas. Clin Cancer Res 21:1835–1842

    Article  CAS  PubMed  Google Scholar 

  140. Ruan J, Martin P, Shah BD, Schuster SJ, Smith SM, Furman RR, Christos P, Rodriguez A, Wolstencroft P, Svoboda J, Bender A, Lewis J, Coleman M, Leonard JP (2014) Sustained remission with the combination biologic doublet of lenalidomide plus rituximab as initial treatment for mantle cell lymphoma: a multi-center phase II study report. Blood 124:625

    Google Scholar 

  141. Flinn I, Mainwaring M, Peacock N, Shipley D, Arrowsmith E, Savona M, Hainsworth JD, Berdeja JG (2012) Rituximab, lenalidomide, and bortezomib in the first-line or second-line treatment of patients with mantle cell lymphoma a phase I/II trial. ASH Annual Meeting 120:2748

    Google Scholar 

  142. Hagner PR, Man HW, Fontanillo C, Wang M, Couto S, Breider M, Bjorklund C, Havens CG, Lu G, Rychak E, Raymon H, Narla RK, Barnes L, Khambatta G, Chiu H, Kosek J, Kang J, Amantangelo MD, Waldman M, Lopez-Girona A, Cai T, Pourdehnad M, Trotter M, Daniel TO, Schafer PH, Klippel A, Thakurta A, Chopra R, Gandhi AK (2015) CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. Blood. doi:10.1182/blood-2015-02-628669

    PubMed  PubMed Central  Google Scholar 

  143. Hasanali Z, Sharma K, Spurgeon S, Okada C, Stuart A, Shimko S, Leshchenko V, Parekh S, Chen Y, Kirschbaum M, Epner EM (2013) Combined epigenetic and immunotherapy produces dramatic responses in 100% of newly diagnosed mantle cell lymphoma patients. Cancer Res 73:LB-140

    Article  Google Scholar 

  144. Sharma K, Leshchenko VV, Hasanali Z, Stuart A, Shimko S, Spurgeon SE, Parekh S, Epner EM (2013) Combined epigenetic and immunotherapy for newly diagnosed mantle cell lymphoma: correlative studies suggest the importance of enhanced ADCC, mechanisms of resistance and cyclin D1 nuclear localization genotype. Blood 122:3063

    Article  Google Scholar 

  145. Spurgeon S, Sharma K, Claxton DF, Ehmann C, Shimko S, Stewart A, Parekh S, Leshchenko VV, Chen Y, Mori M, Pu JJ, Epner EM (2014) Final results of a phase 1–2 study of vorinostat (SAHA), cladribine, and rituximab (SCR) relapsed B-Cell non-Hodgkin’s lymphoma and previously untreated mantle cell lymphoma. Blood 124:1714

    Google Scholar 

  146. Spurgeon S, Chen AI, Okada C, Parekh S, Leshchenko VV, Palmbach G, Ratterree B, Subbiah N, Capper C, Epner EM (2011) A Phase I/II Study ofvorinostat (SAHA), cladribine (2-CdA), and rituximab shows significant activity inpreviously untreated mantle cell lymphoma. Blood 118:203

    Google Scholar 

  147. Chen R, Frankel P, Popplewell L, Siddiqi T, Ruel N, Rotter A, Thomas SH, Mott M, Nathwani N, Htut M, Nademanee A, Forman SJ, Kirschbaum M (2015) A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma. Haematologica 100:357–362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Gopal AK, Pagel JM, Hedin N, Press OW (2004) Fenretinide enhances rituximab-induced cytotoxicity against B-cell lymphoma xenografts through a caspase-dependent mechanism. Blood 103:3516–3520

    Article  CAS  PubMed  Google Scholar 

  149. Adams S, Miller GT, Jesson MI, Watanabe T, Jones B, Wallner BP (2004) PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res 64:5471–5480

    Article  CAS  PubMed  Google Scholar 

  150. Pagel JM, Laugen C, Bonham L, Hackman RC, Hockenbery DM, Bhatt R, Hollenback D, Carew H, Singer JW, Press OW (2005) Induction of apoptosis using inhibitors of lysophosphatidic acid acyltransferase-beta and anti-CD20 monoclonal antibodies for treatment of human non-Hodgkin's lymphomas. Clin Cancer Res 11:4857–4866

    Article  CAS  PubMed  Google Scholar 

  151. Winiarska M, Nowis D, Bil J, Glodkowska-Mrowka E, Muchowicz A, Wanczyk M, Bojarczuk K, Dwojak M, Firczuk M, Wilczek E, Wachowska M, Roszczenko K, Miaczynska M, Chlebowska J, Basak GW, Golab J (2012) Prenyltransferases regulate CD20 protein levels and influence anti-CD20 monoclonal antibody-mediated activation of complement-dependent cytotoxicity. J Biol Chem 287:31983–31993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Cellular and Molecular Research Center, Taleghani Children Hospital, Gorgan University of Medical Sciences, Gorgan, Iran

    Yaghoub Safdari

  2. Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Vahideh Ahmadzadeh & Safar Farajnia

  3. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Safar Farajnia

  4. Department of Biotechnology, Faculty of Advanced Medical Technologies, Golestan University of Medical Sciences, Gorgan, Iran

    Yaghoub Safdari

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Safdari, Y., Ahmadzadeh, V. & Farajnia, S. CD20-targeting in B-cell malignancies: novel prospects for antibodies and combination therapies. Invest New Drugs 34, 497–512 (2016). https://doi.org/10.1007/s10637-016-0349-4

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