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嵌合抗原受体疗法
Chimeric Antigen Receptor Therapy


Carl H. June ... 肿瘤 • 2018.07.05
相关阅读
• 悲剧、坚持和机遇——CAR-T疗法的故事 • 慢性淋巴细胞白血病的CAR-T细胞疗法

嵌合抗原受体治疗的成就和展望

 

黄河†,张鸿声‡*

† 浙江大学医学院附属第一医院;‡同济大学医学院

* 通讯作者

 

嵌合抗原受体治疗(chimeric antigen receptor T cell,CAR T)已于2017年被美国FDA批准,针对CD19靶标治疗复发、难治性急性淋巴细胞白血病(ALL)和弥漫性大B细胞淋巴瘤。因其常规治疗无法比拟的疗效和临床前景,CAR T疗法近5年成为目前全球肿瘤治疗研发和转化的热点。2018年7月5日《新英格兰医学杂志》发表了这一领域的最新综述1。该综述罕见地由两名在美国不同研究机构的CAR T治疗研发和临床转化先驱联合撰写。其中纪念斯隆·凯特琳癌症研究中心的Michel Sadelain对CAR T治疗的早期研发做出过重要贡献,是首位发展出携带CD28共刺激信号第二代CAR的科学家2,并一直引导着这一领域的科研前沿。最近,Sadelain实验室又发现了CAR T治疗中发生细胞因子释放综合征(cytokine release syndrome,CRS)的新机制3。虽然Carl June团队发展出携带4-1BB共刺激信号第二代CAR的早期技术来源于另外一个研究机构4,5,但他们针对B细胞白血病的治疗最早在临床上获得成功6,经他们治疗的女孩Emily已成为CAR T治疗白血病成功的里程碑。

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癌症免疫疗法的目标是增强针对肿瘤细胞的免疫应答。作为治疗转移性癌症的第一个广泛成功的策略,免疫肿瘤学疗法的出现需要临床医师将这种新疗法与化疗、手术、放疗和靶向小分子治疗相结合。免疫肿瘤药物包括范围广泛的药物,包含抗体、疫苗、辅助疗法、细胞因子、溶瘤病毒、双特异性分子和细胞疗法1。除非用于预防病毒诱导的肿瘤,疫苗通常被证明无效2。选择性靶向肿瘤特异性突变3产生的新抗原可能证明有效。另外,过继性细胞转移疗法可以绕过对主动免疫的需求,因此对免疫功能受损的癌症患者有潜在疗效。

基因工程改造的T细胞构成了一类强大的新型治疗药物,为治愈癌症患者提供了希望。嵌合抗原受体(CAR)T细胞最近获得了美国食品药品监督管理局(FDA)批准,即将在临床实践中用于治疗白血病和淋巴瘤(见视频)。用于细胞工程的合成生物学方法提供了一系列广泛的工具,用于免疫细胞编程以增强功能。在T细胞工程、基因编辑、功能最强的淋巴细胞的选择以及细胞制造方面的进展,有可能拓展基于T细胞的疗法,并促进肿瘤学以外,在感染性疾病、器官移植和自身免疫领域的新应用。本综述介绍T细胞工程和合成免疫的原理,重点介绍目前CAR疗法的疗效和毒性作用。





作者信息

Carl H. June, M.D., and Michel Sadelain, M.D., Ph.D.
From the Center for Cellular Immunotherapies, Perelman School of Medicine, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia (C.H.J.); and the Center for Cell Engineering, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York (M.S.). Address reprint requests to Dr. June at the Smilow Center for Translational Research, 3400 Civic Center Blvd., Bldg. 421, 8th Fl., Rm. 123, Philadelphia, PA 19104-5156, or at cjune@upenn.edu; or to Dr. Sadelain at the Center for Cell Engineering, 1250 First Ave., Schwartz Bldg., 10th Fl., Rm. S1021, New York, NY 10065, or at m-sadelain@ski.mskcc.org.

 

参考文献

1. Hoos A. Development of immuno-oncology drugs — from CTLA4 to PD1 to the next generations. Nat Rev Drug Discov 2016;15:235-247.

2. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007;356:1928-1943.

3. Ott PA, Hu Z, Keskin DB, et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 2017;547:217-221.

4. Billingham RE, Brent L, Medawar PB. Quantitative studies on tissue transplantation immunity. II. The origin, strength and duration of actively and adoptively acquired immunity. Proc R Soc Lond B Biol Sci 1954;143:58-80.

5. Mitchison NA. Studies on the immunological response to foreign tumor transplants in the mouse. I. The role of lymph node cells in conferring immunity by adoptive transfer. J Exp Med 1955;102:157-177.

6. Rosenberg SA, Packard BS, Aebersold PM, et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma: a preliminary report. N Engl J Med 1988;319:1676-1680.

7. Kolb HJ, Mittermüller J, Clemm C, et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990;76:2462-2465.

8. Sadelain M, Rivière I, Riddell S. Therapeutic T cell engineering. Nature 2017;545:423-431.

9. Sadelain M, Brentjens R, Rivière I. The promise and potential pitfalls of chimeric antigen receptors. Curr Opin Immunol 2009;21:215-223.

10. Davenport AJ, Jenkins MR, Cross RS, et al. CAR-T cells inflict sequential killing of multiple tumor target cells. Cancer Immunol Res 2015;3:483-494.

11. Stephan MT, Ponomarev V, Brentjens RJ, et al. T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat Med 2007;13:1440-1449.

12. Scholler J, Brady T, Binder-Scholl G, et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med 2012;4:132ra53-132ra53.

13. Silverstein AM. Autoimmunity versus horror autotoxicus: the struggle for recognition. Nat Immunol 2001;2:279-281.

14. Finn OJ. Cancer immunology. N Engl J Med 2008;358:2704-2715.

15. June CH, Warshauer JT, Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 2017;23:540-547.

16. Kuwana Y, Asakura Y, Utsunomiya N, et al. Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions. Biochem Biophys Res Commun 1987;149:960-968.

17. Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci U S A 1993;90:720-724.

18. Brocker T, Peter A, Traunecker A, Karjalainen K. New simplified molecular design for functional T cell receptor. Eur J Immunol 1993;23:1435-1439.

19. Brocker T, Karjalainen K. Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes. J Exp Med 1995;181:1653-1659.

20. Gong MC, Latouche JB, Krause A, Heston WD, Bander NH, Sadelain M. Cancer patient T cells genetically targeted to prostate-specific membrane antigen specifically lyse prostate cancer cells and release cytokines in response to prostate-specific membrane antigen. Neoplasia 1999;1:123-127.

21. Krause A, Guo HF, Latouche JB, Tan C, Cheung NK, Sadelain M. Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J Exp Med 1998;188:619-626.

22. Maher J, Brentjens RJ, Gunset G, Rivière I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. Nat Biotechnol 2002;20:70-75.

23. LeBien TW, Tedder TF. B lymphocytes: how they develop and function. Blood 2008;112:1570-1580.

24. Brentjens RJ, Latouche JB, Santos E, et al. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat Med 2003;9:279-286.

25. Levine BL, Cotte J, Small CC, et al. Large-scale production of CD4+ T cells from HIV-1-infected donors after CD3/CD28 costimulation. J Hematother 1998;7:437-448.

26. Hollyman D, Stefanski J, Przybylowski M, et al. Manufacturing validation of biologically functional T cells targeted to CD19 antigen for autologous adoptive cell therapy. J Immunother 2009;32:169-180.

27. Brentjens RJ, Santos E, Nikhamin Y, et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res 2007;13:5426-5435.

28. Milone MC, Fish JD, Carpenito C, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 2009;17:1453-1464.

29. Kochenderfer JN, Wilson WH, Janik JE, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 2010;116:4099-4102.

30. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor–modified T cells in chronic lymphoid leukemia. N Engl J Med 2011;365:725-733.

31. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013;5:177ra38-177ra38.

32. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. N Engl J Med 2013;368:1509-1518.

33. Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol 2018;15:31-46.

34. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 2018;378:439-448.

35. Park JH, Rivière I, Wang X, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med 2018;378:449-459.

36. Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 2014;6:224ra25-224ra25.

37. Turtle CJ, Hanafi L-A, Berger C, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest 2016;126:2123-2138.

38. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014;371:1507-1517.

39. Fry TJ, Shah NN, Orentas RJ, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med 2018;24:20-28.

40. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 2015;385:517-528.

41. Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 2015;7:303ra139-303ra139.

42. Turtle CJ, Hay KA, Hanafi LA, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J Clin Oncol 2017;35:3010-3020.

43. Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med 2016;8:355ra116-355ra116.

44. Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol 2015;33:540-549.

45. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med 2017;377:2545-2554.

46. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017;377:2531-2544.

47. Ali SA, Shi V, Maric I, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 2016;128:1688-1700.

48. Fan F, Zhao WH, Liu J, et al. Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma. J Clin Oncol 2017 June 5 (Epub ahead of print).

49. Berdeja JG, Lin Y, Raje NS, et al. First-in-human multicenter study of bb2121 anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: updated results. J Clin Oncol 2017;35:Suppl:3010-3010.

50. Brown CE, Alizadeh D, Starr R, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med 2016;375:2561-2569.

51. Beatty GL, O’Hara MH, Lacey SF, et al. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology 2018 March 20 (Epub ahead of print).

52. Kochenderfer JN, Dudley ME, Feldman SA, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 2012;119:2709-2720.

53. Kalos M, Levine BL, Porter DL, et al. T cells expressing chimeric receptors establish memory and potent antitumor effects in patients with advanced leukemia. Sci Transl Med 2011;3:95ra73-95ra73.

54. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014;124:188-195.

55. Teachey DT, Lacey SF, Shaw PA, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov 2016;6:664-679.

56. Rubin CB, Elenitsas R, Taylor L, et al. Evaluating the skin in patients undergoing chimeric antigen receptor modified T-cell therapy. J Am Acad Dermatol 2016;75:1054-1057.

57. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 2016;127:3321-3330.

58. Gust J, Hay KA, Hanafi LA, et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov 2017;7:1404-1419.

59. Riches JC, Davies JK, McClanahan F, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood 2013;121:1612-1621.

60. Maus MV, Haas AR, Beatty GL, et al. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res 2013;1:26-31.

61. Lamers CH, Sleijfer S, Vulto AG, et al. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol 2006;24(13):e20-e22.

62. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 2010;18:843-851.

63. Thistlethwaite FC, Gilham DE, Guest RD, et al. The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity. Cancer Immunol Immunother 2017;66:1425-1436.

64. Byun DJ, Wolchok JD, Rosenberg LM, Girotra M. Cancer immunotherapy — immune checkpoint blockade and associated endocrinopathies. Nat Rev Endocrinol 2017;13:195-207.

65. Muller PY, Milton MN. The determination and interpretation of the therapeutic index in drug development. Nat Rev Drug Discov 2012;11:751-761.

66. Paszkiewicz PJ, Fräßle SP, Srivastava S, et al. Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia. J Clin Invest 2016;126:4262-4272.

67. Bhoj VG, Arhontoulis D, Wertheim G, et al. Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy. Blood 2016;128:360-370.

68. Topp MS, Gökbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol 2015;16:57-66.

69. Harris J. Kite reports cerebral edema death in ZUMA-1 CAR T-cell trial. OncLive May 8, 2017 (https://www.onclive.com/web-exclusives/kite-reports-cerebral-edema-death-in-zuma1-car-tcell-trial).

70. Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest 2008;118:3132-3142.

71. Sotillo E, Barrett DM, Black KL, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov 2015;5:1282-1295.

72. Perna F, Berman SH, Soni RK, et al. Integrating proteomics and transcriptomics for systematic combinatorial chimeric antigen receptor therapy of AML. Cancer Cell 2017;32(4):506-519.e5.

73. Lim WA, June CH. The principles of engineering immune cells to treat cancer. Cell 2017;168:724-740.

74. Zhao Z, Condomines M, van der Stegen SJC, et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 2015;28:415-428.

75. Pegram HJ, Lee JC, Hayman EG, et al. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 2012;119:4133-4141.

76. Hu B, Ren J, Luo Y, et al. Augmentation of antitumor immunity by human and mouse CAR T cells secreting IL-18. Cell Rep 2017;20:3025-3033.

77. Zhou X, Dotti G, Krance RA, et al. Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation. Blood 2015;125:4103-4113.

78. Tebas P, Stein D, Tang WW, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med 2014;370:901-910.

79. Gaj T, Gersbach CA, Barbas CF III ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol 2013;31:397-405.

80. Eyquem J, Mansilla-Soto J, Giavridis T, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 2017;543:113-117.

81. Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol 2015;33:1974-1982.

82. Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 2014;344:641-645.

83. Tran E, Robbins PF, Lu Y-C, et al. T-cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med 2016;375:2255-2262.

84. Qasim W, Zhan H, Samarasinghe S, et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci Transl Med 2017;9:9-9.

85. Themeli M, Rivière I, Sadelain M. New cell sources for T cell engineering and adoptive immunotherapy. Cell Stem Cell 2015;16:357-366.

86. Lederman MM, Cannon PM, Currier JS, et al. A cure for HIV infection: “not in my lifetime” or “just around the corner”? Pathog Immun 2016;1:154-164.

87. DuPage M, Bluestone JA. Harnessing the plasticity of CD4(+) T cells to treat immune-mediated disease. Nat Rev Immunol 2016;16:149-163.

88. June CH, O’Connor RS, Kawalekar OU, et al. CAR T cell immunotherapy for human cancer. Science 2018;359(6382):1361-1365.

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