干扰微环境基础上个体化、特异性肿瘤免疫治疗的疗效分析
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摘要
目的:细胞因子诱导的杀伤细胞( cytokine-induced killer cells, CIK)是一种新型的免疫活性细胞,它是由白细胞介素( interleukin, IL)2、γ-干扰素( interferon, IFN-γ)和CD3单克隆抗体等诱导而成的对多种肿瘤细胞具有杀伤活性的细胞毒性T淋巴细胞。由于该种细胞同时表达CD3和CD56两种膜蛋白分子,故又称为自然杀伤(natural killer,NK)细胞样T淋巴细胞。由于它具有增殖速度快,抗肿瘤能力高,而且在细胞的数量上能满足临床的需要,因而在临床具有较好的应用前景。树突状细胞(dendritic cells, DC)是公认的专职抗原递呈细胞( antigen presenting cell, APC) ,可有效的刺激初始T细胞活化并诱导特异性的抗原免疫反应,从而将先天性和获得性免疫有机联系在一起,是免疫反应的始动者。抗原特异性细胞毒T淋巴细胞(Antigen specific cytotoxicity T lymphocytes, CTL),是由负载抗原的成熟DC所激活的抗原特异性杀伤细胞,能够特异性的辨认抗原,参与特异性细胞免疫。本文将对我院近两年来,应用干扰微环境基础上个体化、特异性肿瘤免疫治疗新方法,治疗59例实体肿瘤患者的疗效,进行系统的评估,为指导临床治疗,提供可靠的临床研究试验数据。
方法:采集49例Ⅳ期恶性肿瘤患者及10例恶性肿瘤根治术后患者外周血单个核细胞,贴壁细胞经IL-4,GM-CSF,TNF-a诱导,并经流式细胞仪检测证实为DC,悬浮细胞经CD3单抗、γ-干扰素、IL-2诱导,并经流式细胞仪检测证实为CIK细胞。培养十天后,细胞总数达到5×109。DC分次淋巴引流区皮下注射,CIK细胞静脉输注。
结果:治疗组49例患者的临床症状及影像学表现均有不同程度的好转,卡氏评分均有明显提高,生活质量得到明显提高。测定16例患者微环境干扰后Treg的变化,均有不同程度的降低,结果显示有统计学意义(P<0.05)。预防性治疗组10例患者,除两例患者肿瘤出现复发外,其余患者均未见复发。
结论:干扰微环境基础上个体化、特异性肿瘤免疫治疗,能有效的防治根式术后肿瘤复发;并能有效延缓Ⅳ期肿瘤进展,或达到肿瘤缩小或消失的明显疗效,有效改善患者生活质量,有效延长病人生存期。
Objective:Cytokine-induced killer cells is a new kind of immunologic cells.It is induced by IL-2.IFN-γand so on.It is a kind of cytotoxic lymphocytes which can be used in many kind of tumor treatment.It is named natural killer-like T lymphocytes because of expression of CD3, CD3 monoclonal antibody and CD 56 membrine protein molecules.It can be widely used in clinical treatment because it proliferates quickly ,treats tumor more effectively and the number of the cells can meet our needs in clinical. Dendritic cells are accepted as the most effective antigen-presenting cell.It can provoke T lymphocytes’activation effectively and induce specific immune response.It combines congenital immunity with acquired immunity.So it starts immune response. Antigen specific cytotoxicity T lymphocytes( CTL)is a kind of cells which is activated by mature DC activated by antigen of tumor.It can recognize the antigen of tumor specially,and participate in the specific cell immunal response.This is about our works on this treatment this years.We want to analyze the effects of this treatment on tumor treatment so that we can have a more systemically,completely and deeply known of DC-CIK.
Methods: Peripheral blood mononuclear cells were isolated from 59 patients with malignant tumors. The attached cells were induced by TL-4 ,GM-CSF , and TNF-a ,and then confirmed as DCs by flow cytometry ; the suspension cells were induced by CD3 monoclonal antibody ,γ-INF ,and IL-2 .After ten days’cultivation,the number of the cells will achieve 4-5×109 and then confirmed as CIK cells by flow cytometry. Then DCs were injected in drain lymph node hypodermically , while CIK cells were injected in intravenous injection.
Results:49 patients accepted this treatment for curing tumor.Their symptoms and manifestation on medical imaging has changed better obviously. Karnofsky Performance Status Score (KPS) has been raised.The quality of life has been improved.The decrease of Treg of 16 patients after interference on micro environment changes significantly(P<0.05).
10 patients accepted this treatment after operation.The tumor of 8 patients has been inhibited effectively except 2 patients.
Conclusion: Individuallized,specialized immunal therapy on tumor based on microenvironment interference can prevent tumor relapsing after operation,and can delaying the progressing of tumor .It can make the tumor smaller, even disappear.The patients can live better and longer.
方法:采集49例Ⅳ期恶性肿瘤患者及10例恶性肿瘤根治术后患者外周血单个核细胞,贴壁细胞经IL-4,GM-CSF,TNF-a诱导,并经流式细胞仪检测证实为DC,悬浮细胞经CD3单抗、γ-干扰素、IL-2诱导,并经流式细胞仪检测证实为CIK细胞。培养十天后,细胞总数达到5×109。DC分次淋巴引流区皮下注射,CIK细胞静脉输注。
结果:治疗组49例患者的临床症状及影像学表现均有不同程度的好转,卡氏评分均有明显提高,生活质量得到明显提高。测定16例患者微环境干扰后Treg的变化,均有不同程度的降低,结果显示有统计学意义(P<0.05)。预防性治疗组10例患者,除两例患者肿瘤出现复发外,其余患者均未见复发。
结论:干扰微环境基础上个体化、特异性肿瘤免疫治疗,能有效的防治根式术后肿瘤复发;并能有效延缓Ⅳ期肿瘤进展,或达到肿瘤缩小或消失的明显疗效,有效改善患者生活质量,有效延长病人生存期。
Objective:Cytokine-induced killer cells is a new kind of immunologic cells.It is induced by IL-2.IFN-γand so on.It is a kind of cytotoxic lymphocytes which can be used in many kind of tumor treatment.It is named natural killer-like T lymphocytes because of expression of CD3, CD3 monoclonal antibody and CD 56 membrine protein molecules.It can be widely used in clinical treatment because it proliferates quickly ,treats tumor more effectively and the number of the cells can meet our needs in clinical. Dendritic cells are accepted as the most effective antigen-presenting cell.It can provoke T lymphocytes’activation effectively and induce specific immune response.It combines congenital immunity with acquired immunity.So it starts immune response. Antigen specific cytotoxicity T lymphocytes( CTL)is a kind of cells which is activated by mature DC activated by antigen of tumor.It can recognize the antigen of tumor specially,and participate in the specific cell immunal response.This is about our works on this treatment this years.We want to analyze the effects of this treatment on tumor treatment so that we can have a more systemically,completely and deeply known of DC-CIK.
Methods: Peripheral blood mononuclear cells were isolated from 59 patients with malignant tumors. The attached cells were induced by TL-4 ,GM-CSF , and TNF-a ,and then confirmed as DCs by flow cytometry ; the suspension cells were induced by CD3 monoclonal antibody ,γ-INF ,and IL-2 .After ten days’cultivation,the number of the cells will achieve 4-5×109 and then confirmed as CIK cells by flow cytometry. Then DCs were injected in drain lymph node hypodermically , while CIK cells were injected in intravenous injection.
Results:49 patients accepted this treatment for curing tumor.Their symptoms and manifestation on medical imaging has changed better obviously. Karnofsky Performance Status Score (KPS) has been raised.The quality of life has been improved.The decrease of Treg of 16 patients after interference on micro environment changes significantly(P<0.05).
10 patients accepted this treatment after operation.The tumor of 8 patients has been inhibited effectively except 2 patients.
Conclusion: Individuallized,specialized immunal therapy on tumor based on microenvironment interference can prevent tumor relapsing after operation,and can delaying the progressing of tumor .It can make the tumor smaller, even disappear.The patients can live better and longer.
引文
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3 Wang F S,Liu M X,Zhang B,et,al.Antitumor activity of human autologous cytokine-induced killer cells against hepatocellular carcinomar cells in vitro and in vivo.World J gastoenteral 2002,8(3):464-468
4 Schmidt,Wolf IG, Lefterova P, Mehta BA, et al. Phenotyp ic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp Hematol,1993, 21 (13) : 1673-1679
5 Hoyle C,Bang C D,Chang P,et,al.Expansion of Philadelphia chromosome negative CD3+CD56+ cytotoxic cells from chronic myeloid leukemia patients in vitro and in vivo efficacy in severe combined immunodeficiency desease mice. Blood, 1998, 92: 3318-3327
6 Marten A, Ziske C, Schottken B, et al. Interaction between dendritic cells and cytokine-induced killer cells lead to an activation of bothpopulations. Immunother, 2001, 24 (6):502-510
7 VernerisMR, KornackerM,Mailander V, et al. Resistance of ex vivo expanded CD3 + CD56 + T cells to Fas-mediated apop tosis . Cancer Immunol Immunother, 2000, 49 (6) : 335-345
8 CooperMA, Fehniger TA, FuchsA, et al. NK cell and DC interactions Immunlo, 2004, 5 (1) : 47-52
9岑溪南,朱平,石永进,等.细胞因子诱导的杀伤细胞可诱导bcr-abl阳性的K562细胞凋亡.中国实验学杂志, 2002, 10 ( 3 ) : 201-204
10 Fosepb C, Alvarnas, YebCbing, et al. Expansion of cytotoxic CD3 + CD56 + cells from peripheral blood p rogentitor cells of patientsundergoing autologous hematologic cell transportation . Biology ofBlood andMarrow Transp lation, 2001, 7: 216-222
11 Steinman RM, Cohn ZA1 Identification of a novel cell type in peripheral lymphoid organs of mice1 I1 Morphology , quantitation , tissue distribution. J Exp Med , 1973 , 137 : 1142-1162
12 Grave R , Nino AM, Le CM, et al1 Influence of antibody on the reference of different antibodies assay. Immunol Method , 1984 , 72:177-1811
13 Strong SE , Voss S , Wilcox R , et al1 Strategies for antigen loading of dendritic cells to enhance the anti-tumor immune response CancerRes ,2002 ,62(6) :1884-1889
14 Hart DN1 Dendritic cells : unique leukocyte populations which control the primary immune response.Blood , 1997 ,90 :3245-3287
15 Flores Rom L1 In vivo maturation and migration of dendritic cells. Immunology , 2001 ,102(3) :255-262
16 Holliday GM, Le S. Transforming growth factor-be reproduced by progress or tumor inhibits ,while II-be produced by reg1-or tumor enhances ,Langerhans cell migration from skin.In Immune,2001,13 (9):1147-l154
17 OhmJE. Car bone DE VEGF as a mediator of tumor-associated immunodeficiency. Immune Res ,2001 ,23 (2-3) :263-272
18 Schuurhuis DH , loan-Facsinay A , Nagelkerken B ,et a1.Antigen -antibody immune complexes empower dendritic efficiently prime specific CD8+ CTL responses in vivo. Immunol ,2002 ,168 (5) :2240-2246
1李淑艳,邢淑贤.CIK细胞的特点及其在肿瘤生物治疗中的作用.癌变畸变突变.2007,19(9):424-426
2 Tuyaerts S,Meirvenne SV,Bonehill A et al.Expression of human GITRL on myeloid dindritic cells enhances their immunostimulatory function but does not abrogate the suppressive effect of CD4+CD25+ regulatory t cells.Ournal of Leukocyte Biology 2007,82:1-13
3全晓红.肿瘤生物治疗的研究热点与展望.赤峰学院学报(自然科学版)Journal of Chifeng University(Natural Science Edition)2007,12(4):342-346
4 Gong JL,Najmosama N,Chen DS,et al.Fusions ofhuman ovarian carcinoma cells with autologus or allogeneic dendritic cells induce antitumor immunity.Immunol, 2000,165(3):1705-1711
5 Kugler A,Stuhler G,Walden P, et al.Regression of human metastatic renal cell carcinoma after vaccinationwith tumor cell-dendritic cell hybrids.Nat Med , 2000,6(21):332-336
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8于津浦,任秀宝等。CIK细胞-肿瘤过继免疫治疗的新希望.中国肿瘤临床2001,28, 7
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33 Zoll B,Lefterova P,Csipai M,et.al,Generation of cytokine-induced killer cells using exogenous interleukin-2,-7or-12. Cancer immunol immunolther,1998,47(4):221-226
34 Zoll B,Lefterova P,Ebert O,et,al.Modulation of cell surface markers on NK-like T lymphocytes by using IL-2,IL-7or IL-12 in vivo stimulation. Cytokine,2000,12(9):1385-1390
35 Lefterova P,Marten A,Buttgereit P,et,al.Targeting of natural kille-like T immulogic effector cells against leukemia and lymphoma cells by reverse antibody-dependent cellular cytotoxicity. Immunolther,2000,23(3):304-310
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39 Marten A, Ziske C, Schottken B, et al. Interaction between dendritic cells and c ytokine2induced killer cells lead to an activation of both populations. Immunother, 2001, 24 (6) : 502-510
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2 Schmidt-Wolf IG,Lefterova P ,Mehta BA , et al . Phenotypic characterization and identification of effector cell recognition of cytokine-induced killer cells. Exp Hematol ,1993 ,21(13) :1673-1679
3 Wang F S,Liu M X,Zhang B,et,al.Antitumor activity of human autologous cytokine-induced killer cells against hepatocellular carcinomar cells in vitro and in vivo.World J gastoenteral 2002,8(3):464-468
4 Schmidt,Wolf IG, Lefterova P, Mehta BA, et al. Phenotyp ic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp Hematol,1993, 21 (13) : 1673-1679
5 Hoyle C,Bang C D,Chang P,et,al.Expansion of Philadelphia chromosome negative CD3+CD56+ cytotoxic cells from chronic myeloid leukemia patients in vitro and in vivo efficacy in severe combined immunodeficiency desease mice. Blood, 1998, 92: 3318-3327
6 Marten A, Ziske C, Schottken B, et al. Interaction between dendritic cells and cytokine-induced killer cells lead to an activation of bothpopulations. Immunother, 2001, 24 (6):502-510
7 VernerisMR, KornackerM,Mailander V, et al. Resistance of ex vivo expanded CD3 + CD56 + T cells to Fas-mediated apop tosis . Cancer Immunol Immunother, 2000, 49 (6) : 335-345
8 CooperMA, Fehniger TA, FuchsA, et al. NK cell and DC interactions Immunlo, 2004, 5 (1) : 47-52
9岑溪南,朱平,石永进,等.细胞因子诱导的杀伤细胞可诱导bcr-abl阳性的K562细胞凋亡.中国实验学杂志, 2002, 10 ( 3 ) : 201-204
10 Fosepb C, Alvarnas, YebCbing, et al. Expansion of cytotoxic CD3 + CD56 + cells from peripheral blood p rogentitor cells of patientsundergoing autologous hematologic cell transportation . Biology ofBlood andMarrow Transp lation, 2001, 7: 216-222
11 Steinman RM, Cohn ZA1 Identification of a novel cell type in peripheral lymphoid organs of mice1 I1 Morphology , quantitation , tissue distribution. J Exp Med , 1973 , 137 : 1142-1162
12 Grave R , Nino AM, Le CM, et al1 Influence of antibody on the reference of different antibodies assay. Immunol Method , 1984 , 72:177-1811
13 Strong SE , Voss S , Wilcox R , et al1 Strategies for antigen loading of dendritic cells to enhance the anti-tumor immune response CancerRes ,2002 ,62(6) :1884-1889
14 Hart DN1 Dendritic cells : unique leukocyte populations which control the primary immune response.Blood , 1997 ,90 :3245-3287
15 Flores Rom L1 In vivo maturation and migration of dendritic cells. Immunology , 2001 ,102(3) :255-262
16 Holliday GM, Le S. Transforming growth factor-be reproduced by progress or tumor inhibits ,while II-be produced by reg1-or tumor enhances ,Langerhans cell migration from skin.In Immune,2001,13 (9):1147-l154
17 OhmJE. Car bone DE VEGF as a mediator of tumor-associated immunodeficiency. Immune Res ,2001 ,23 (2-3) :263-272
18 Schuurhuis DH , loan-Facsinay A , Nagelkerken B ,et a1.Antigen -antibody immune complexes empower dendritic efficiently prime specific CD8+ CTL responses in vivo. Immunol ,2002 ,168 (5) :2240-2246
1李淑艳,邢淑贤.CIK细胞的特点及其在肿瘤生物治疗中的作用.癌变畸变突变.2007,19(9):424-426
2 Tuyaerts S,Meirvenne SV,Bonehill A et al.Expression of human GITRL on myeloid dindritic cells enhances their immunostimulatory function but does not abrogate the suppressive effect of CD4+CD25+ regulatory t cells.Ournal of Leukocyte Biology 2007,82:1-13
3全晓红.肿瘤生物治疗的研究热点与展望.赤峰学院学报(自然科学版)Journal of Chifeng University(Natural Science Edition)2007,12(4):342-346
4 Gong JL,Najmosama N,Chen DS,et al.Fusions ofhuman ovarian carcinoma cells with autologus or allogeneic dendritic cells induce antitumor immunity.Immunol, 2000,165(3):1705-1711
5 Kugler A,Stuhler G,Walden P, et al.Regression of human metastatic renal cell carcinoma after vaccinationwith tumor cell-dendritic cell hybrids.Nat Med , 2000,6(21):332-336
6 Schmidt-Wolf IG,Lefterova P ,Mehta BA ,et al. Phenotypic characterizationand identification of effector cell recognition of cytokine-inducedkiller cells. Exp Hematol ,1993 ,21(13) :1673-1679
7 Schmidt-Wolf IG,Lefterova P ,Mehta BA , et al . Phenotypiccharacterization and identification of effector cells involved in tumor cell rec2 ognition of cytokine-induced killer cells. Exp Hematol , 1993 , 21(13) :1673-1679
8于津浦,任秀宝等。CIK细胞-肿瘤过继免疫治疗的新希望.中国肿瘤临床2001,28, 7
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