弥漫性大B细胞淋巴瘤的靶向免疫治疗
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摘要
弥漫性大B细胞淋巴瘤是一种具有高度异质性及侵袭性的B细胞淋巴瘤,虽然利妥昔单抗单抗广泛应用于临床治疗患者预后有了明显改善,且利妥昔单抗联合环磷酰胺+多柔比星+长春新碱+泼尼松已成为公认的治疗弥漫性大B细胞淋巴瘤的金标准,但经过一线治疗后仍会出现复发或难治的情况。随着研究的深入,各种弥漫性大B细胞淋巴瘤的治疗靶点不断被发现,如Obinutuzumab(GA101)、Epratuzumab、来那度胺、硼替佐米等靶向药物及程序性死亡受体-1/程序性死亡受体配体1抗体、细胞因子诱导的杀伤细胞治疗和嵌合抗原受体T细胞治疗等免疫疗法对弥漫性大B细胞淋巴瘤的治疗取得了一定的疗效。未来,靶向药物与免疫治疗将为复发/难治性弥漫性大B细胞淋巴瘤的治疗提供新方向。
Diffuse large B-cell lymphoma is a highly heterogeneous and aggressive B-cell lymphoma. Although rituximab has been widely used in clinical treatment,its prognosis has improved significantly,and rituximab combined with cyclophosphamide + doxorubicin + vincristine + prednisone has become a recognized gold standard for the treatment of diffuse large B-cell lymphoma,there are still recurrence or refractory cases after first-line treatment. With the deepening of research,various therapeutic targets for diffuse large B-cell lymphoma have been found,such as obinutuzumab( GA101),epratuzumab,lenadomide,bortezomib,and immunotherapies such as programmed cell death-1/programmed cell death-ligand 1 antibodies,cytokine-induced killer cell therapy and chimeric antigen receptor T cell therapy,have achieved certain therapeutic effect for diffuse large B-cell lymphoma. In the future,targeted drugs and immunotherapy will provide a new direction for the treatment of relapsed/refractory diffuse large B-cell lymphoma.
Diffuse large B-cell lymphoma is a highly heterogeneous and aggressive B-cell lymphoma. Although rituximab has been widely used in clinical treatment,its prognosis has improved significantly,and rituximab combined with cyclophosphamide + doxorubicin + vincristine + prednisone has become a recognized gold standard for the treatment of diffuse large B-cell lymphoma,there are still recurrence or refractory cases after first-line treatment. With the deepening of research,various therapeutic targets for diffuse large B-cell lymphoma have been found,such as obinutuzumab( GA101),epratuzumab,lenadomide,bortezomib,and immunotherapies such as programmed cell death-1/programmed cell death-ligand 1 antibodies,cytokine-induced killer cell therapy and chimeric antigen receptor T cell therapy,have achieved certain therapeutic effect for diffuse large B-cell lymphoma. In the future,targeted drugs and immunotherapy will provide a new direction for the treatment of relapsed/refractory diffuse large B-cell lymphoma.
引文
[1]Nowakowski GS,Chiappella A,Witzig TE,et al.ROBUST:Lenalidomide-R-CHOP versus placebo-R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma[J].Future Oncol,2016,12(13):1553-1563.
[2]Lenz G,Wright G,Dave SS,et al.Stromal gene signatures in large-B-cell lymphomas[J].N Engl J Med,2008,359(22):2313-2323.
[3]邹丹丹,郭博,尹澎,等.153例难治/复发性弥漫大B淋巴瘤的临床分析[J].中国实验血液学杂志,2017,25(1):120-125.
[4]Maloney DG.Anti-CD20 antibody therapy for B-cell lymphomas[J].N Engl J Med,2012,366(21):2008-2016.
[5]Subramanian J,Cavenagh J,Desai B,et al.Rituximab in the treatment of follicular lymphoma:The future of biosimilars in the evolving therapeutic landscape[J].Cancer Manag Res,2017,9:131-140.
[6]Sehn LH,Chua N,Mayer J,et al.Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximabrefractory indolent non-Hodgkin lymphoma(GADOLIN):A randomised,controlled,open-label,multicentre,phase 3 trial[J].Lancet Oncol,2016,17(8):1081-1093.
[7]Czuczman MS,Gregory SA.The future of CD20 monoclonal antibody therapy in B-cell malignancies[J].Leuk Lymphoma,2010,51(6):983-994.
[8]Ogura M,Tobinai K,Hatake K,et al.Phase I study of obinutuzumab(GA101)in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma[J].Cancer Sci,2013,104(1):105-110.
[9]Salles G,Morschhauser F,Lamy T,et al.Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab(GA101)in B-cell lymphoma patients[J].Blood,2012,119(22):5126-5132.
[10]Morschhauser FA,Cartron G,Thieblemont C,et al.Obinutuzumab(GA101)monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma:Results from the phaseⅡGAUGUIN study[J].J Clin Oncol,2013,31(23):2912-2919.
[11]Strauss SJ,Morschhauser F,Rech J,et al.Multicenter phase IItrial of immunotherapy with the humanized anti-CD22 antibody,epratuzumab,in combination with rituximab,in refractory or recurrent non-Hodgkin's lymphoma[J].J Clin Oncol,2006,24(24):3880-3886.
[12]Micallef IN,Maurer MJ,Wiseman GA,et al.Epratuzumab with rituximab,cyclophosphamide,doxorubicin,vincristine,and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma[J].Blood,2011,118(15):4053-4061.
[13]Gribben JG,Fowler N,Morschhauser F.Mechanisms of action of lenalidomide in B-cell non-Hodgkin lymphoma[J].Clin Oncol,2015,33(25):2803-2811.
[14]Wierink PH,Lossos IS,Tuscano JM,et al.Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma[J].J Clin Oncol,2008,26(30):4952-4957.
[15]Wang M,Fowler N,Wagner-Bartak N,et al.Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell,follicular and transformed lymphoma:A phaseⅡclinical trial[J].Leukemia,2013,27(9):1902-1909.
[16]Hernandez-Ilizaliturri FJ,Deeb G,Zinzani PL,et al.Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype[J].Cancer,2011,117(22):5058-5066.
[17]Nowakowski GS,Laplant B,Macon WR,et al.Lenalidomide combined with R-CHOP overcomes negative prognostic impact of nongerminal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma;A phaseⅡstudy[J].J Clin Oncol,2015,33(3):251-257.
[18]Nowakowski GS,Reeder CB,Laplant B,et al.Combination of lenalidomide with R-CHOP(R2CHOP)is safe and effective as initial therapy for aggressive B-Cell lymphomas a phaseⅠ/Ⅱstudy[J].J Clin Oncol,2011,29(15 suppl):8015.
[19]Ruan J,Martin P,Furman RR,et al.Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma[J].Clin Oncol,2011,29(6):690-697.
[20]Goy A,Younes A,Mclaughlin P,et al.Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell nonHodgkin's lymphoma[J].J Clin Oncol,2005,23(4):667-675.
[21]Dunleavy K,Pittaluga S,Czuczman MS,et al.Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma[J].Blood,2009,113(24):6069-6076.
[22]Wilson WH,Young RM,Schmitz R,et al.Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma[J].Nat Med,2015,21(8):922-926.
[23]Winter AM,Landsburg DJ,Mato AR,et al.A Multi-institutional outcomes analysis of patients with relapsed or refractory DLBCLtreated with ibrutinib[J].Blood,2017,130(14):1676-1679.
[24]Hainsworth JD,Arrowsmith ER,Mc Cleod M,et al.A randomized,phase 2 study of R-CHOP plus enzastaurin vs R-CHOP in patients with intermediate-or high-risk diffuse large B-cell lymphoma[J].Leuk Lymphoma,2016,57(1):216-218.
[25]Van Parijs L,Abbas AK.Homeostasis and selftolerance in the immune system:Turning lymphocytes off[J].Science,1998,280(5361):243-248.
[26]Stuart C,Wade W.Practical guide for allergy and immunology in Canada[J].Allergy Asthma Clin Immunol,2011,7(Suppl1):S8.
[27]Berger R,Rotem Yehudar R,Slama G,et al.PhaseⅠsafety and pharmacokinetic study of CT-011,a humanized antibody interacting with PD-1,in patients with advanced hematologic malignancies[J].Clin Cancer Res,2008,14(10):3044-3051.
[28]Armand P,Nagler A,Weller EA,et al.Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma:Results of an international phase II trial[J].J Clin Oncol,2013,31(33):4199-4206.
[29]沈小东,王喜,钱申贤.18F-FDG PET-CT在自体高效CIK细胞联合化疗治疗初诊弥漫大B细胞淋巴瘤中的应用[J].中华全科医学,2018,16(6):892-893.
[30]Lu XC,Yang B,Yu RL,et al.Clinical study of autologous cytokine-induced killer cells for the treatment of elderly patients with diffuse large B-cell lymphoma[J].Cell Biochem Biophys,2012,62(1):257-265.
[31]Schuster SJ,Svoboda J,Dwivedy Nasta S,et al.Sustained remissions following chimeric antigen receptor modified T cells directed against CD19(CTL019)in patients with relapsed or refractory CD19+lymphomas[J].Blood,2015,126(23):183.
[32]Schuster SJ,Svoboda J,Nasta SD,et al.Treatment with chimeric antigen receptor modified T cells directed against CD19(CTL019)results in durable remissions in patients with relapsed or refractory diffuse large B-cell lymphomas of germinal center and non-germinal center origin,"Double Hit"diffuse large B cell lymphomas,and transformed follicular to diffuse large B cell lymphomas[J].Blood,2016,128(22):3026.
[33]Schuster S,Bishop MR,Tam C,et al.Global pivotal phase 2 trial of the CD19-targeted therapy CTL019 in adult patients with relapsed or refractory(R/R)diffuse large B-cell lymphoma(DLBCL)an interim analysis[J].Clin Lymphoma Myeloma Leuk,2017,17(2):S373-374.
[2]Lenz G,Wright G,Dave SS,et al.Stromal gene signatures in large-B-cell lymphomas[J].N Engl J Med,2008,359(22):2313-2323.
[3]邹丹丹,郭博,尹澎,等.153例难治/复发性弥漫大B淋巴瘤的临床分析[J].中国实验血液学杂志,2017,25(1):120-125.
[4]Maloney DG.Anti-CD20 antibody therapy for B-cell lymphomas[J].N Engl J Med,2012,366(21):2008-2016.
[5]Subramanian J,Cavenagh J,Desai B,et al.Rituximab in the treatment of follicular lymphoma:The future of biosimilars in the evolving therapeutic landscape[J].Cancer Manag Res,2017,9:131-140.
[6]Sehn LH,Chua N,Mayer J,et al.Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximabrefractory indolent non-Hodgkin lymphoma(GADOLIN):A randomised,controlled,open-label,multicentre,phase 3 trial[J].Lancet Oncol,2016,17(8):1081-1093.
[7]Czuczman MS,Gregory SA.The future of CD20 monoclonal antibody therapy in B-cell malignancies[J].Leuk Lymphoma,2010,51(6):983-994.
[8]Ogura M,Tobinai K,Hatake K,et al.Phase I study of obinutuzumab(GA101)in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma[J].Cancer Sci,2013,104(1):105-110.
[9]Salles G,Morschhauser F,Lamy T,et al.Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab(GA101)in B-cell lymphoma patients[J].Blood,2012,119(22):5126-5132.
[10]Morschhauser FA,Cartron G,Thieblemont C,et al.Obinutuzumab(GA101)monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma:Results from the phaseⅡGAUGUIN study[J].J Clin Oncol,2013,31(23):2912-2919.
[11]Strauss SJ,Morschhauser F,Rech J,et al.Multicenter phase IItrial of immunotherapy with the humanized anti-CD22 antibody,epratuzumab,in combination with rituximab,in refractory or recurrent non-Hodgkin's lymphoma[J].J Clin Oncol,2006,24(24):3880-3886.
[12]Micallef IN,Maurer MJ,Wiseman GA,et al.Epratuzumab with rituximab,cyclophosphamide,doxorubicin,vincristine,and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma[J].Blood,2011,118(15):4053-4061.
[13]Gribben JG,Fowler N,Morschhauser F.Mechanisms of action of lenalidomide in B-cell non-Hodgkin lymphoma[J].Clin Oncol,2015,33(25):2803-2811.
[14]Wierink PH,Lossos IS,Tuscano JM,et al.Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma[J].J Clin Oncol,2008,26(30):4952-4957.
[15]Wang M,Fowler N,Wagner-Bartak N,et al.Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell,follicular and transformed lymphoma:A phaseⅡclinical trial[J].Leukemia,2013,27(9):1902-1909.
[16]Hernandez-Ilizaliturri FJ,Deeb G,Zinzani PL,et al.Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype[J].Cancer,2011,117(22):5058-5066.
[17]Nowakowski GS,Laplant B,Macon WR,et al.Lenalidomide combined with R-CHOP overcomes negative prognostic impact of nongerminal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma;A phaseⅡstudy[J].J Clin Oncol,2015,33(3):251-257.
[18]Nowakowski GS,Reeder CB,Laplant B,et al.Combination of lenalidomide with R-CHOP(R2CHOP)is safe and effective as initial therapy for aggressive B-Cell lymphomas a phaseⅠ/Ⅱstudy[J].J Clin Oncol,2011,29(15 suppl):8015.
[19]Ruan J,Martin P,Furman RR,et al.Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma[J].Clin Oncol,2011,29(6):690-697.
[20]Goy A,Younes A,Mclaughlin P,et al.Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell nonHodgkin's lymphoma[J].J Clin Oncol,2005,23(4):667-675.
[21]Dunleavy K,Pittaluga S,Czuczman MS,et al.Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma[J].Blood,2009,113(24):6069-6076.
[22]Wilson WH,Young RM,Schmitz R,et al.Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma[J].Nat Med,2015,21(8):922-926.
[23]Winter AM,Landsburg DJ,Mato AR,et al.A Multi-institutional outcomes analysis of patients with relapsed or refractory DLBCLtreated with ibrutinib[J].Blood,2017,130(14):1676-1679.
[24]Hainsworth JD,Arrowsmith ER,Mc Cleod M,et al.A randomized,phase 2 study of R-CHOP plus enzastaurin vs R-CHOP in patients with intermediate-or high-risk diffuse large B-cell lymphoma[J].Leuk Lymphoma,2016,57(1):216-218.
[25]Van Parijs L,Abbas AK.Homeostasis and selftolerance in the immune system:Turning lymphocytes off[J].Science,1998,280(5361):243-248.
[26]Stuart C,Wade W.Practical guide for allergy and immunology in Canada[J].Allergy Asthma Clin Immunol,2011,7(Suppl1):S8.
[27]Berger R,Rotem Yehudar R,Slama G,et al.PhaseⅠsafety and pharmacokinetic study of CT-011,a humanized antibody interacting with PD-1,in patients with advanced hematologic malignancies[J].Clin Cancer Res,2008,14(10):3044-3051.
[28]Armand P,Nagler A,Weller EA,et al.Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma:Results of an international phase II trial[J].J Clin Oncol,2013,31(33):4199-4206.
[29]沈小东,王喜,钱申贤.18F-FDG PET-CT在自体高效CIK细胞联合化疗治疗初诊弥漫大B细胞淋巴瘤中的应用[J].中华全科医学,2018,16(6):892-893.
[30]Lu XC,Yang B,Yu RL,et al.Clinical study of autologous cytokine-induced killer cells for the treatment of elderly patients with diffuse large B-cell lymphoma[J].Cell Biochem Biophys,2012,62(1):257-265.
[31]Schuster SJ,Svoboda J,Dwivedy Nasta S,et al.Sustained remissions following chimeric antigen receptor modified T cells directed against CD19(CTL019)in patients with relapsed or refractory CD19+lymphomas[J].Blood,2015,126(23):183.
[32]Schuster SJ,Svoboda J,Nasta SD,et al.Treatment with chimeric antigen receptor modified T cells directed against CD19(CTL019)results in durable remissions in patients with relapsed or refractory diffuse large B-cell lymphomas of germinal center and non-germinal center origin,"Double Hit"diffuse large B cell lymphomas,and transformed follicular to diffuse large B cell lymphomas[J].Blood,2016,128(22):3026.
[33]Schuster S,Bishop MR,Tam C,et al.Global pivotal phase 2 trial of the CD19-targeted therapy CTL019 in adult patients with relapsed or refractory(R/R)diffuse large B-cell lymphoma(DLBCL)an interim analysis[J].Clin Lymphoma Myeloma Leuk,2017,17(2):S373-374.