• 解放軍第452醫(yī)院血液腫瘤中心（成都，610021）;

【摘要】　 多發(fā)性骨髓瘤（multiple myeloma， MM）是嚴(yán)重威脅健康的惡性漿細(xì)胞疾病，主要的治療方法是傳統(tǒng)化學(xué)療法，但其療效有限，患者生活質(zhì)量低，預(yù)后差。免疫治療是一種新興的有望在未來徹底消滅腫瘤細(xì)胞的治療手段，過繼細(xì)胞免疫治療（adoptive cellular immunotherapy， ACI）更是經(jīng)體內(nèi)及體外都證實(shí)了具有強(qiáng)大的抗瘤作用。ACI與其他治療手段的有機(jī)結(jié)合和合理安排將對MM的治療帶來新的曙光?，F(xiàn)就目前開展的ACI治療MM的前沿研究予以綜述。

引用本文： 鐘國成,孫薏. 多發(fā)性骨髓瘤過繼細(xì)胞免疫治療的研究進(jìn)展. 華西醫(yī)學(xué), 2011, 26(12): 1805-1809. doi: 復(fù)制

1. 　Dib A, Barlogie B, Shaugllnessy JD, et al. Methylation and expression of the p16INK4A tumor suppressor gene in multiple myeloma[J]. Blood, 2007, 109(3): 1337-1338.
2. 　Anderson KC. From the guest editor: the evolving treatment paradigm in multiple myeloma[J]. Cancer J, 2009, 15(6): 456.
3. 　Rosenblatt J, Avigan D. Cellular immunotherapy for multiple myeloma[J].Best Pract Res Clin Haematol, 2008, 21(3): 559-577.
4. 　Condomines M, Veyrune JL, Larroque M, et al. Increased plasma-immune cytokines throughout the high-dose melphalan-induced lymphodepletion in patients with multiple myeloma: a window for adoptive immunotherapy[J]. J Immunol, 2010, 184(2): 1079-1084.
5. 　Yi Q. Novel immunotherapies[J]. Cancer J, 2009, 15(6): 502-510.
6. 　Lokhorst HM, Liebowitz D. Adoptive T-cell therapy[J]. Semin Hematol, 1999, 36(1): 26-29.
7. 　Lokhorst HM, Schattenberg A, Cornelissen JJ, et al. Dornor leukocyte infusions are effective in multiple myeloma after allogeneic bone marrow transplantation[J]. Blood, 1997, 90(10): 4206-4211.
8. 　Deol A, Lum LG. Role of donor lymphocyte infusions in relapsed hematological malignancies after stem cell transplantation revisited[J]. Cancer Treat Rev, 2010, 36(7): 528-538.
9. 　Klingemann H, Boissel L. Targeted cellular therapy with natural killer cells[J]. Horm Metab Res, 2008, 40(2): 122-125.
10. 　Harnack U, Johnen H, Pecher G. natural killer cell line yt exerts cytotoxicity against CD86+ myeloma cells[J]. Anticancer Res, 2011, 31(2): 475-479.
11. 　Alici E, Konstantinidis KV, Sutlu T, et al. Anti-myeloma activity of endogenous and adoptively transferred activated natural killer cells in experimental multiple myeloma model[J]. Exp Hematol, 2007, 35(12): 1839-1846.
12. 　Zhong G,Wang J,Xu M,et al. Enhanced maturation and functional capacity of dendritic cells induced by mannosylated L2 domain of ErbB2 receptor[J]. Scand J Immunol, 2005, 62(2):108-116.
13. 　Linn YC, Hui KM. Cytokine-induced killer cells: NK-like T cells with cytotolytic-specificity against leukemia[J]. Leukemia Lymphoma, 2003, 44(9): 1457-1462.
14. 　Eubel J, Enk AH. Dendritic cell vaccination as a treatment modality for melanoma[J]. Expert Rev Anticancer Ther, 2009, 9(11):1631-1642.
15. 　Berntsen A, Trepiakas R, Wenandy L, et al. Therapeutic dendritic cell vaccination of patients with metastatic renal cell carcinoma: a clinical phase 1/2 trial[J]. J Immunother, 2008, 31(8): 771-780.
16. 　Rozkova D, Tiserova H, Fucíkova J, et al. FOCUS on FOCIS: combined chemo-immunotherapy for the treatment of hormone-refractory metastatic prostate cancer[J]. Clin Immunol, 2009, 131(1): 1-10.
17. 　李純團(tuán), 朱雄鵬, 許文前, 等. 抗原致敏、GM-CSF基因修飾的樹突狀細(xì)胞誘導(dǎo)免疫殺傷多發(fā)性骨髓瘤細(xì)胞U266的研究[J]. 中國實(shí)驗(yàn)血液學(xué)雜志, 2009, 17(4): 929-932.
18. 　Lee JJ, Choi BH, Kang HK, et al. Induction of multiple myeloma-specific cytotoxic T lymphocyte stimulation by dendritic cell pulsing with purified and optimized myeloma cell lysates[J]. Leuk Lymphoma, 2007, 48(10): 2022-2031.
19. 　Cohen S, Haimovich J, Hollander N. Dendritic cell-based therapeutic vaccination against myeloma: vaccine formulation determines efficacy against light chain myeloma[J]. J Immunol, 2009, 182(3): 1667-1673.
20. 　Pievani A, Belussi C, Klein C, et al. Enhanced killing of human B-cell lymphoma targets by combined use of cytokine-induced killer cell(CIK)cultures and anti-CD20 antibodies[J]. Blood, 2011, 117(2): 510-518.
21. 　Zhao Q, Zhang H, Li Y, et al. Anti-tumor effects of CIK combined with oxaliplatin in human oxaliplatin-resistant gastric cancer cells in vivo and in vitro[J]. J Exp Clin Cancer Res, 2010, 29:118-130.
22. 　Gorschlüter M, Ziske C, Glasmacher A, et al. Current clinical and laboratory strategies to augment the efficacy of immunotherapy in multiple myeloma[J]. Clin Cancer Res, 2001, 7(8): 2195-2204.
23. 　Lin J, Zhu H, Lu X, et al. Autologous cytokine-induced killer cells in the treatment of multiple myeloma concomitant with lung cancer and paraneoplastic dermatoses[J]. Intern Med, 2010, 49(21): 2341-2346.
24. 　Mrten A, Renoth S, von Lilienfeld-Toal M, et al. Enhanced lytic activity of cytokine-induced killer cells against multiple myeloma cells after co-culture with idiotype-pulsed dendritic cells[J]. Haematologica, 2001, 86(10): 1029-1037.
25. 　Su X, Zhang L, Jin L, et al. Coculturing dendritic cells with zoledronate acid efficiently enhance the anti-tumor effects of cytokine-induced killer cells[J]. J Clin Immunol, 2010, 30(5): 766-774.
26. 　鐘國成, 張小玉, 孫薏, 等. 自體腫瘤抗原致敏的樹突狀細(xì)胞聯(lián)合細(xì)胞因子誘導(dǎo)殺傷細(xì)胞應(yīng)用于肺腺癌治療的臨床研究[J]. 腫瘤, 2010, 30(5): 395-400.
27. 　Li H, Wang C, Yu J, et al. Dendritic cell-activated cytokine-induced killer cells enhance the anti-tumor effect of chemotherapy on non-small cell lung cancer in patients after surgery[J]. Cytotherapy, 2009, 11(8): 1076-1083.
28. 　Rajkumar SV, Rosiol L, Hussein M, et al. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma[J]. J Clin Oncol, 2008, 26(13): 2171-2177.
29. 　Thomas SK, Richards TA, Weber DM. Novel agents for relapsed and/or refractory multiple myeloma[J]. Cancer J, 2009, 15(6): 485-493.
30. 　Quach H, Ritchie D, Stewart AK, et al. Mechanism of action of immunomodulatory drugs(IMiDS)in multiple myeloma[J]. Leukemia, 2010, 24(1): 22-32.
31. 　Ritchie DS, Quach H, Fielding K, et al. Drug-mediated and cellular immunotherapy in multiple myeloma[J]. Immunotherapy, 2010, 2(2): 243-255.
32. 　Sharabi A, Laronne-Bar-On A, Meshorer A, et al. Chemoimmunotherapy reduces the progression of multiple myeloma in a mouse model[J]. Cancer Prev Res(Phila), 2010, 3(10): 1265-1276.
33. 　Sharabi A, Ghera NH. Breaking tolerance in a mouse model of multiple myeloma by chemoimmunotherapy[J]. Adv Cancer Res, 2010, 107: 1-37.
34. 　黃香, 陳龍邦. 化療藥物的免疫調(diào)節(jié)作用[J]. 醫(yī)學(xué)研究生學(xué)報(bào), 2010, 23(1): 76-81.
35. 　Frazier JL, Han JE, Lim M, et al. Immunotherapy combined with chemotherapy in the treatment of tumors[J]. Neurosurg Clin N Am, 2010, 21(1): 187-194.
36. 　Harrison SJ, Cook G, Nibbs RJ, et al. Immunotherapy of multiple myeloma: the start of a long and tortuous journey[J]. Expert Rev Anticancer Ther, 2006, 6(12): 1769-1785.
37. 　Vauleon E, Avril T, Collet B, et al. Overview of cellular immunotherapy for patients with glioblastoma[J]. Clin Dev Immunol, 2010, 2010: 1-18.
38. 　Younes A. Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma[J]. Hematology Am Soc Hematol Educ Program, 2009: 507-519.
  1. 1. 　Dib A, Barlogie B, Shaugllnessy JD, et al. Methylation and expression of the p16INK4A tumor suppressor gene in multiple myeloma[J]. Blood, 2007, 109(3): 1337-1338.
  2. 2. 　Anderson KC. From the guest editor: the evolving treatment paradigm in multiple myeloma[J]. Cancer J, 2009, 15(6): 456.
  3. 3. 　Rosenblatt J, Avigan D. Cellular immunotherapy for multiple myeloma[J].Best Pract Res Clin Haematol, 2008, 21(3): 559-577.
  4. 4. 　Condomines M, Veyrune JL, Larroque M, et al. Increased plasma-immune cytokines throughout the high-dose melphalan-induced lymphodepletion in patients with multiple myeloma: a window for adoptive immunotherapy[J]. J Immunol, 2010, 184(2): 1079-1084.
  5. 5. 　Yi Q. Novel immunotherapies[J]. Cancer J, 2009, 15(6): 502-510.
  6. 6. 　Lokhorst HM, Liebowitz D. Adoptive T-cell therapy[J]. Semin Hematol, 1999, 36(1): 26-29.
  7. 7. 　Lokhorst HM, Schattenberg A, Cornelissen JJ, et al. Dornor leukocyte infusions are effective in multiple myeloma after allogeneic bone marrow transplantation[J]. Blood, 1997, 90(10): 4206-4211.
  8. 8. 　Deol A, Lum LG. Role of donor lymphocyte infusions in relapsed hematological malignancies after stem cell transplantation revisited[J]. Cancer Treat Rev, 2010, 36(7): 528-538.
  9. 9. 　Klingemann H, Boissel L. Targeted cellular therapy with natural killer cells[J]. Horm Metab Res, 2008, 40(2): 122-125.
  10. 10. 　Harnack U, Johnen H, Pecher G. natural killer cell line yt exerts cytotoxicity against CD86+ myeloma cells[J]. Anticancer Res, 2011, 31(2): 475-479.
  11. 11. 　Alici E, Konstantinidis KV, Sutlu T, et al. Anti-myeloma activity of endogenous and adoptively transferred activated natural killer cells in experimental multiple myeloma model[J]. Exp Hematol, 2007, 35(12): 1839-1846.
  12. 12. 　Zhong G,Wang J,Xu M,et al. Enhanced maturation and functional capacity of dendritic cells induced by mannosylated L2 domain of ErbB2 receptor[J]. Scand J Immunol, 2005, 62(2):108-116.
  13. 13. 　Linn YC, Hui KM. Cytokine-induced killer cells: NK-like T cells with cytotolytic-specificity against leukemia[J]. Leukemia Lymphoma, 2003, 44(9): 1457-1462.
  14. 14. 　Eubel J, Enk AH. Dendritic cell vaccination as a treatment modality for melanoma[J]. Expert Rev Anticancer Ther, 2009, 9(11):1631-1642.
  15. 15. 　Berntsen A, Trepiakas R, Wenandy L, et al. Therapeutic dendritic cell vaccination of patients with metastatic renal cell carcinoma: a clinical phase 1/2 trial[J]. J Immunother, 2008, 31(8): 771-780.
  16. 16. 　Rozkova D, Tiserova H, Fucíkova J, et al. FOCUS on FOCIS: combined chemo-immunotherapy for the treatment of hormone-refractory metastatic prostate cancer[J]. Clin Immunol, 2009, 131(1): 1-10.
  17. 17. 　李純團(tuán), 朱雄鵬, 許文前, 等. 抗原致敏、GM-CSF基因修飾的樹突狀細(xì)胞誘導(dǎo)免疫殺傷多發(fā)性骨髓瘤細(xì)胞U266的研究[J]. 中國實(shí)驗(yàn)血液學(xué)雜志, 2009, 17(4): 929-932.
  18. 18. 　Lee JJ, Choi BH, Kang HK, et al. Induction of multiple myeloma-specific cytotoxic T lymphocyte stimulation by dendritic cell pulsing with purified and optimized myeloma cell lysates[J]. Leuk Lymphoma, 2007, 48(10): 2022-2031.
  19. 19. 　Cohen S, Haimovich J, Hollander N. Dendritic cell-based therapeutic vaccination against myeloma: vaccine formulation determines efficacy against light chain myeloma[J]. J Immunol, 2009, 182(3): 1667-1673.
  20. 20. 　Pievani A, Belussi C, Klein C, et al. Enhanced killing of human B-cell lymphoma targets by combined use of cytokine-induced killer cell(CIK)cultures and anti-CD20 antibodies[J]. Blood, 2011, 117(2): 510-518.
  21. 21. 　Zhao Q, Zhang H, Li Y, et al. Anti-tumor effects of CIK combined with oxaliplatin in human oxaliplatin-resistant gastric cancer cells in vivo and in vitro[J]. J Exp Clin Cancer Res, 2010, 29:118-130.
  22. 22. 　Gorschlüter M, Ziske C, Glasmacher A, et al. Current clinical and laboratory strategies to augment the efficacy of immunotherapy in multiple myeloma[J]. Clin Cancer Res, 2001, 7(8): 2195-2204.
  23. 23. 　Lin J, Zhu H, Lu X, et al. Autologous cytokine-induced killer cells in the treatment of multiple myeloma concomitant with lung cancer and paraneoplastic dermatoses[J]. Intern Med, 2010, 49(21): 2341-2346.
  24. 24. 　Mrten A, Renoth S, von Lilienfeld-Toal M, et al. Enhanced lytic activity of cytokine-induced killer cells against multiple myeloma cells after co-culture with idiotype-pulsed dendritic cells[J]. Haematologica, 2001, 86(10): 1029-1037.
  25. 25. 　Su X, Zhang L, Jin L, et al. Coculturing dendritic cells with zoledronate acid efficiently enhance the anti-tumor effects of cytokine-induced killer cells[J]. J Clin Immunol, 2010, 30(5): 766-774.
  26. 26. 　鐘國成, 張小玉, 孫薏, 等. 自體腫瘤抗原致敏的樹突狀細(xì)胞聯(lián)合細(xì)胞因子誘導(dǎo)殺傷細(xì)胞應(yīng)用于肺腺癌治療的臨床研究[J]. 腫瘤, 2010, 30(5): 395-400.
  27. 27. 　Li H, Wang C, Yu J, et al. Dendritic cell-activated cytokine-induced killer cells enhance the anti-tumor effect of chemotherapy on non-small cell lung cancer in patients after surgery[J]. Cytotherapy, 2009, 11(8): 1076-1083.
  28. 28. 　Rajkumar SV, Rosiol L, Hussein M, et al. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma[J]. J Clin Oncol, 2008, 26(13): 2171-2177.
  29. 29. 　Thomas SK, Richards TA, Weber DM. Novel agents for relapsed and/or refractory multiple myeloma[J]. Cancer J, 2009, 15(6): 485-493.
  30. 30. 　Quach H, Ritchie D, Stewart AK, et al. Mechanism of action of immunomodulatory drugs(IMiDS)in multiple myeloma[J]. Leukemia, 2010, 24(1): 22-32.
  31. 31. 　Ritchie DS, Quach H, Fielding K, et al. Drug-mediated and cellular immunotherapy in multiple myeloma[J]. Immunotherapy, 2010, 2(2): 243-255.
  32. 32. 　Sharabi A, Laronne-Bar-On A, Meshorer A, et al. Chemoimmunotherapy reduces the progression of multiple myeloma in a mouse model[J]. Cancer Prev Res(Phila), 2010, 3(10): 1265-1276.
  33. 33. 　Sharabi A, Ghera NH. Breaking tolerance in a mouse model of multiple myeloma by chemoimmunotherapy[J]. Adv Cancer Res, 2010, 107: 1-37.
  34. 34. 　黃香, 陳龍邦. 化療藥物的免疫調(diào)節(jié)作用[J]. 醫(yī)學(xué)研究生學(xué)報(bào), 2010, 23(1): 76-81.
  35. 35. 　Frazier JL, Han JE, Lim M, et al. Immunotherapy combined with chemotherapy in the treatment of tumors[J]. Neurosurg Clin N Am, 2010, 21(1): 187-194.
  36. 36. 　Harrison SJ, Cook G, Nibbs RJ, et al. Immunotherapy of multiple myeloma: the start of a long and tortuous journey[J]. Expert Rev Anticancer Ther, 2006, 6(12): 1769-1785.
  37. 37. 　Vauleon E, Avril T, Collet B, et al. Overview of cellular immunotherapy for patients with glioblastoma[J]. Clin Dev Immunol, 2010, 2010: 1-18.
  38. 38. 　Younes A. Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma[J]. Hematology Am Soc Hematol Educ Program, 2009: 507-519.