{"id":55,"date":"2021-11-10T11:31:30","date_gmt":"2021-11-10T03:31:30","guid":{"rendered":"http:\/\/lw.gdpmaa.com\/?p=55"},"modified":"2021-11-10T11:31:30","modified_gmt":"2021-11-10T03:31:30","slug":"%e8%83%9e%e5%86%85%e4%bf%a1%e5%8f%b7%e9%80%9a%e8%b7%af%e8%b0%83%e6%8e%a7car-t%e7%bb%86%e8%83%9e%e5%8a%9f%e8%83%bd%e7%9a%84%e7%a0%94%e7%a9%b6%e8%bf%9b%e5%b1%95","status":"publish","type":"post","link":"http:\/\/lw.gdpmaa.com\/?p=55","title":{"rendered":"\u80de\u5185\u4fe1\u53f7\u901a\u8def\u8c03\u63a7CAR T\u7ec6\u80de\u529f\u80fd\u7684\u7814\u7a76\u8fdb\u5c55"},"content":{"rendered":"\n

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\u6458\u8981\uff1a\u5d4c\u5408\u6297\u539f\u53d7\u4f53\uff08Chimeric antigen receptor\uff0cCAR\uff09T\u7ec6\u80de\u662f\u80bf\u7624\u514d\u75ab\u6cbb\u7597\u9886\u57df\u7684\u65b0\u5174\u7597\u6cd5\uff0c\u901a\u8fc7\u57fa\u56e0\u5de5\u7a0b\u6280\u672f\u6539\u9020T\u7ec6\u80de\uff0c\u4f7f\u5f97CAR T\u7ec6\u80de\u80fd\u591f\u7ed3\u5408\u80bf\u7624\u7ec6\u80de\u8868\u9762\u7684\u7279\u5f02\u6027\u6297\u539f\uff0c\u4fc3\u4f7fT\u7ec6\u80de\u6d3b\u5316\uff0c\u53d1\u6325\u7279\u5f02\u6027\u6297\u80bf\u7624\u4f5c\u7528\u3002\u5d4c\u5408\u6297\u539f\u53d7\u4f53\u7ed3\u6784\u4e2d\u7684\u80de\u5185\u4fe1\u53f7\u533a\u6bb5\u6fc0\u6d3b\u51b3\u5b9a\u4e86CAR T\u7ec6\u80de\u7684\u589e\u6b96\u5206\u5316\u80fd\u529b\uff0c\u8c03\u63a7\u5176\u7ec6\u80de\u4ee3\u8c22\u7279\u5f81\u548c\u514d\u75ab\u6301\u4e45\u6027\uff0c\u8fdb\u800c\u5f71\u54cdCAR T\u7ec6\u80de\u7684\u4e34\u5e8a\u7597\u6548\u3002\u672c\u6587\u4ece\u4e0d\u540c\u80de\u5185\u5171\u523a\u6fc0\u4fe1\u53f7\u901a\u8def\u5bf9CAR T\u7ec6\u80de\u7684\u5f71\u54cd\u548c\u5728\u4e34\u5e8a\u6cbb\u7597\u4e2d\u7684\u5dee\u5f02\uff0c\u5206\u6790\u4e0d\u540c\u5171\u523a\u6fc0\u4fe1\u53f7\u901a\u8def\u5728CAR T\u7ec6\u80de\u7684\u53d7\u4f53\u8bbe\u8ba1\u548c\u4e34\u5e8a\u6cbb\u7597\u7b56\u7565\u9009\u62e9\u65b9\u9762\u7684\u5e94\u7528\u6f5c\u529b\uff0c\u4e3aCAR T\u7ec6\u80de\u5728\u80bf\u7624\u514d\u75ab\u6cbb\u7597\u4e2d\u7684\u7cbe\u51c6\u5e94\u7528\u63d0\u4f9b\u7406\u8bba\u4f9d\u636e\u3002<\/p>\n\n\n\n

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Abstract: Chimeric Antigen Receptor (CAR) T cells is an emerging therapy in tumor immunotherapy. CAR T cells are modified through genetic engineering technology. CAR T cells can bind to the specific antigen on tumor cells to promote T cell full activation and exert anti-tumor activity. The activation of the CAR intracellular signal domain determines the proliferation and differentiation of CAR T cells and then affects the clinical efficacy of CAR T cells. This article will discuss the potential application value of each costimulator from the impact of different costimulatory intracellular signals on CAR T cells and provide a theoretical basis for the precise application of CAR T cells in tumor immunotherapy.<\/p>\n\n\n\n

Keywords\uff1aCAR T, tumor, costimulator<\/p>\n\n\n\n

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CD28 CAR<\/p>\n\n\n\n

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ICOS CAR<\/p>\n\n\n\n

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4-1BB CAR<\/p>\n\n\n\n

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CD27 CAR<\/p>\n\n\n\n

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OX40 CAR<\/p>\n\n\n\n

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\u603b\u7ed3<\/p>\n\n\n\n

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CD28\u548cICOS\u4e3aCD28\u8d85\u5bb6\u65cf\u6210\u5458\uff0c\u4fc3\u8fdbT\u7ec6\u80de\u7684\u5feb\u901f\u589e\u6b96\uff0c\u5176\u80de\u5185\u4fe1\u53f7\u4e3b\u8981\u4ecb\u5bfcCAR T\u7ec6\u80de\u7684\u6548\u5e94\u529f\u80fd\uff0c\u5176\u4e2dCD28\u548cICOS\u4fc3\u8fdb\u6709\u6c27\u7cd6\u9175\u89e3\uff0c\u5e76\u4e14CD28\u80de\u5185\u4fe1\u53f7\u5feb\u901f\u8bf1\u5bfcCAR T\u7684\u589e\u6b96\uff0c\u5bf9\u9700\u8981\u5927\u5242\u91cf\u7684CAR T\u7ec6\u80de\u7684\u5b9e\u4f53\u7624\u6cbb\u7597\u6216\u8bb8\u6709\u76ca\u3002\u800cTNFR\u8d85\u5bb6\u65cf\u7684\u6210\u54584-1BB\u3001CD27\u3001OX40\u4e3b\u8981\u53c2\u4e0e\u8bb0\u5fc6T\u7ec6\u80de\u7684\u8c03\u63a7\uff0c4-1BB\u80de\u5185\u4fe1\u53f7\u4e3b\u8981\u4ecb\u5bfcCAR T\u7ec6\u80de\u7684\u8102\u8d28\u4ee3\u8c22\u548c\u7ebf\u7c92\u4f53\u529f\u80fd\uff0c\u8bf1\u5bfc\u6297\u51cb\u4ea1\u5206\u5b50\u7684\u8868\u8fbe\u3002\u4e0d\u540c\u5171\u523a\u6fc0\u5206\u5b50\u8c03\u63a7\u4e0d\u540c\u4e9a\u7fa4\u7684T\u7ec6\u80de\uff1aICOS\u4e3b\u8981\u4f5c\u7528\u4e8eCD4+<\/sup> T\u7ec6\u80de\uff0c\u8bf1\u5bfcTh17\u7ec6\u80de\u5206\u5316\uff1b4-1BB\u4e3b\u8981\u4f5c\u7528\u4e8eCD8+<\/sup> T\u7ec6\u80de\uff1bOX40\u4e3b\u8981\u4f5c\u7528\u4e8eCD4+<\/sup> T\u7ec6\u80de\uff0c\u8bf1\u5bfcTh1\u7ec6\u80de\u5206\u5316\uff1b\u800cCD27\u53ef\u80fd\u540c\u6837\u53c2\u4e0e\u4e86\u521d\u59cbCD4+<\/sup>\u548cCD8+<\/sup> T\u7ec6\u80de\u7684\u5e94\u7b54\u53ca\u6269\u589e\u9636\u6bb5\u3002\u4e0d\u540c\u5171\u523a\u6fc0\u5206\u5b50\u80de\u5185\u4fe1\u53f7\u4f5c\u7528CAR T\u7ec6\u80de\u8c03\u63a7\u7ec6\u80de\u56e0\u5b50\u7684\u8868\u8fbe\u4e5f\u4e0d\u76f8\u540c\uff1aCD28\u80de\u5185\u4fe1\u53f7\u8bf1\u5bfcCAR T\u7ec6\u80de\u8868\u8fbe\u66f4\u9ad8\u7684IL-2\uff1b\u800cICOS\u80de\u5185\u4fe1\u53f7\u8bf1\u5bfcCAR T\u7ec6\u80de\u8868\u8fbeIL-17\u7b49\u708e\u6027\u7ec6\u80de\u56e0\u5b50\uff1bOX40\u80de\u5185\u4fe1\u53f7\u80fd\u591f\u6291\u5236CAR T\u7ec6\u80de\u6297\u708e\u56e0\u5b50IL-10\u7684\u8868\u8fbe\uff1bCD27\u867d\u7136\u6ca1\u6709\u53d1\u73b0\u5176\u8bf1\u5bfcCAR T\u7ec6\u80de\u7684\u7ec6\u80de\u56e0\u5b50\u8868\u8fbe\uff0c\u4f46CD27\u53ef\u4ee5\u8bf1\u5bfcT\u7ec6\u80deIL-7R\u7684\u91cd\u65b0\u8868\u8fbe\uff0c\u4fc3\u8fdbT\u7ec6\u80de\u5bf9IL-7\u7684\u53cd\u5e94\u6027\u3002\u4e0d\u540c\u7684\u6dcb\u5df4\u7ec6\u80de\u4e9a\u7fa4\u3001\u7ec6\u80de\u5206\u5316\u6c34\u5e73\u3001\u4ee3\u8c22\u9014\u5f84\u3001\u4ee5\u53ca\u4e0d\u540c\u7ec6\u80de\u56e0\u5b50\u7684\u8868\u8fbe\u5747\u5bf9CAR T\u7ec6\u80de\u7684\u6297\u80bf\u7624\u514d\u75ab\u8d77\u5230\u4e0d\u540c\u7684\u4f5c\u7528\u3002\u9488\u5bf9\u8840\u6db2\u80bf\u7624\uff0cCAR T\u7ec6\u80de\u80fd\u5145\u5206\u63a5\u89e6\u80bf\u7624\u7ec6\u80de\uff0cCAR T\u7ec6\u80de\u5728\u4f53\u5185\u7684\u6301\u4e45\u6027\u5c31\u663e\u5f97\u5c24\u4e3a\u91cd\u8981\u3002\u5176\u4e2d\uff0c4-1BB\u6fc0\u6d3b\u589e\u5f3aCD8+<\/sup> CAR T\u7ec6\u80de\u7684\u6297\u51cb\u4ea1\u548c\u7ef4\u6301\u8bb0\u5fc6T\u7ec6\u80de\u529f\u80fd\uff0c\u662f\u8840\u6db2\u7624\u6cbb\u7597\u4e2dCAR\u7ed3\u6784\u80de\u5185\u5171\u523a\u6fc0\u5206\u5b50\u5f88\u597d\u7684\u9009\u62e9\u3002\u5bf9\u4e8e\u5b9e\u4f53\u7624\u6291\u5236\u6027\u7684\u514d\u75ab\u5fae\u73af\u5883\uff0c\u57fa\u4e8e\u80bf\u7624\u7684\u5f02\u8d28\u6027\u548c\u514d\u75ab\u5fae\u73af\u5883\u5dee\u5f02\uff0c\u9700\u8981\u63a2\u8ba8\u9009\u62e9CAR\u7ed3\u6784\u4e2d\u4f55\u79cd\u80de\u5185\u5171\u523a\u6fc0\u4fe1\u53f7\uff0c\u624d\u80fd\u6ee1\u8db3CAR T\u7ec6\u80de\u957f\u671f\u5b58\u6d3b\uff1b\u7ef4\u6301CAR T\u7ec6\u80de\u7684\u5f3a\u6548\u7684\u6297\u80bf\u7624\u4f5c\u7528\uff1b\u540c\u65f6\u5bf9CD4+<\/sup> \u4e0eCD8+<\/sup> T\u7ec6\u80de\u90fd\u6709\u4f5c\u7528\uff0c\u5e2e\u52a9CAR T\u7ec6\u80de\u7a81\u7834\u5b9e\u4f53\u7624\u514d\u75ab\u6cbb\u7597\u7684\u74f6\u9888\uff0c\u5b9e\u73b0CAR T\u7ec6\u80de\u5728\u80bf\u7624\u6cbb\u7597\u4e2d\u7684\u7cbe\u51c6\u5e94\u7528\u3002<\/p>\n\n\n\n

\u7efc\u4e0a\u6240\u8ff0\uff0c\u901a\u8fc7\u7814\u7a76\u4e0d\u540c\u5171\u523a\u6fc0\u5206\u5b50\u5bf9T\u7ec6\u80de\u7684\u8c03\u63a7\u4f5c\u7528\u53ca\u5176\u80de\u5185\u4fe1\u53f7\u589e\u5f3aCAR T\u7ec6\u80de\u7684\u673a\u5236\uff0c\u6709\u52a9\u4e8e\u5728\u4e0d\u540c\u80bf\u7624\u514d\u75ab\u5fae\u73af\u5883\u80cc\u666f\u4e0b\uff0cCAR T\u7ec6\u80de\u6cbb\u7597\u7684\u7b56\u7565\u9009\u62e9\u3002\u660e\u786e\u9002\u7528\u4e0d\u540c\u514d\u75ab\u6291\u5236\u6761\u4ef6\u4e0b\u7684CAR\u53d7\u4f53\u8bbe\u8ba1\u548c\u7cbe\u51c6\u5e94\u7528\uff0c\u8fdb\u800c\u5145\u5206\u53d1\u6325CAR T\u7ec6\u80de\u5728\u80bf\u7624\u6cbb\u7597\u4e2d\u7684\u4f5c\u7528\u6f5c\u529b\uff0c\u4e3a\u5b9e\u73b0\u5176\u6700\u5927\u7684\u4e34\u5e8a\u5e94\u7528\u4ef7\u503c\u5960\u5b9a\u7406\u8bba\u548c\u5b9e\u9a8c\u57fa\u7840\u3002<\/p>\n\n\n\n

\u53c2\u8003\u6587\u732e<\/strong><\/strong><\/p>\n\n\n\n

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26 Guedan S, Chen X, Madar A, et al. ICOS-based chimeric antigen receptors program bipolar TH17\/TH1 cells. Blood. 2014;124(7):1070-80.<\/p>\n\n\n\n

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29 Ahmad HT, Mansooreh J, Fereshteh M, et al. Changes in lymphocytes’ telomerase activity by 4-1BB costimulation. Journal of cancer research and therapeutics. 2014;10(4):998-1003.<\/p>\n\n\n\n

30 Menk AV, Scharping NE, Rivadeneira DB, et al. 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. The Journal of experimental medicine. 2018;215(4):1091-100.<\/p>\n\n\n\n

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35 Zapata JM, Perez-Chacon G, Carr-Baena P, et al. CD137 (4-1BB) Signalosome: Complexity Is a Matter of TRAFs. Frontiers in immunology. 2018;9:2618.<\/p>\n\n\n\n

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40 Burris HA, Infante JR, Ansell SM, et al. Safety and Activity of Varlilumab, a Novel and First-in-Class Agonist Anti-CD27 Antibody, in Patients With Advanced Solid Tumors. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;35(18):2028-36.<\/p>\n\n\n\n

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43 Dolfi DV, Boesteanu AC, Petrovas C, et al. Late signals from CD27 prevent Fas-dependent apoptosis of primary CD8+ T cells. J Immunol. 2008;180(5):2912-21.<\/p>\n\n\n\n

44 Arens R, Schepers K, Nolte MA, et al. Tumor rejection induced by CD70-mediated quantitative and qualitative effects on effector CD8+ T cell formation. The Journal of experimental medicine. 2004;199(11):1595-605.<\/p>\n\n\n\n

45 Hendriks J, Xiao Y, Borst J. CD27 promotes survival of activated T cells and complements CD28 in generation and establishment of the effector T cell pool. The Journal of experimental medicine. 2003;198(9):1369-80.<\/p>\n\n\n\n

46 Takeda K, Oshima H, Hayakawa Y, et al. CD27-mediated activation of murine NK cells. J Immunol. 2000;164(4):1741-5.<\/p>\n\n\n\n

47 Peperzak V, Veraar EA, Xiao Y, et al. CD8+ T cells produce the chemokine CXCL10 in response to CD27\/CD70 costimulation to promote generation of the CD8+ effector T cell pool. J Immunol. 2013;191(6):3025-36.<\/p>\n\n\n\n

48 Song DG, Ye Q, Poussin M, et al. CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo. Blood. 2012;119(3):696-706.<\/p>\n\n\n\n

49 Song D-G, Powell DJ. Pro-survival signaling via CD27 costimulation drives effective CAR T-cell therapy. OncoImmunology. 2014;1(4):547-9.<\/p>\n\n\n\n

50 Dong H, Franklin NA, Roberts DJ, et al. CD27 stimulation promotes the frequency of IL-7 receptor-expressing memory precursors and prevents IL-12-mediated loss of CD8(+) T cell memory in the absence of CD4(+) T cell help. J Immunol. 2012;188(8):3829-38.<\/p>\n\n\n\n

51 Croft M. The role of TNF superfamily members in T-cell function and diseases. Nature reviews Immunology. 2009;9(4):271-85.<\/p>\n\n\n\n

52 So T, Choi H, Croft M. OX40 complexes with phosphoinositide 3-kinase and protein kinase B (PKB) to augment TCR-dependent PKB signaling. J Immunol. 2011;186(6):3547-55.<\/p>\n\n\n\n

53 Pacella I, Procaccini C, Focaccetti C, et al. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proceedings of the National Academy of Sciences of the United States of America. 2018;115(28):E6546-e55.<\/p>\n\n\n\n

54 Taraban VY, Rowley TF, O’Brien L, et al. Expression and costimulatory effects of the TNF receptor superfamily members CD134 (OX40) and CD137 (4-1BB), and their role in the generation of anti-tumor immune responses. European journal of immunology. 2002;32(12):3617-27.<\/p>\n\n\n\n

55 Sun G, Sun X, Li W, et al. Critical role of OX40 in the expansion and survival of CD4 T-cell-derived double-negative T cells. Cell death & disease. 2018;9(6):616.<\/p>\n\n\n\n

56 Salek-Ardakani S, Song J, Halteman BS, et al. OX40 (CD134) controls memory T helper 2 cells that drive lung inflammation. The Journal of experimental medicine. 2003;198(2):315-24.<\/p>\n\n\n\n

57 Hillerdal V, Ramachandran M, Leja J, et al. Systemic treatment with CAR-engineered T cells against PSCA delays subcutaneous tumor growth and prolongs survival of mice. BMC cancer. 2014;14:30.<\/p>\n\n\n\n

58 Finney HM, Akbar AN, Lawson AD. Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. J Immunol. 2004;172(1):104-13.<\/p>\n\n\n\n

59 Wilkie S, Picco G, Foster J, et al. Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor. J Immunol. 2008;180(7):4901-9.<\/p>\n\n\n\n

60 Hombach AA, Chmielewski M, Rappl G, et al. Adoptive immunotherapy with redirected T cells produces CCR7- cells that are trapped in the periphery and benefit from combined CD28-OX40 costimulation. Human gene therapy. 2013;24(3):259-69.<\/p>\n\n\n\n

61 Hombach AA, Heiders J, Foppe M, et al. OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4(+) T cells. Oncoimmunology. 2012;1(4):458-66.<\/p>\n\n\n\n

62 Zhang H, Li F, Cao J, et al. A chimeric antigen receptor with antigen-independent OX40 signaling mediates potent antitumor activity. Sci Transl Med. 2021;13(578).<\/p>\n\n\n\n

63 Hombach AA, Abken H. Costimulation by chimeric antigen receptors revisited the T cell antitumor response benefits from combined CD28-OX40 signalling. International journal of cancer. 2011;129(12):2935-44.<\/p>\n","protected":false},"excerpt":{"rendered":"

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