人γδT细胞过继免疫治疗的临床前研究
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摘要
T淋巴细胞可按照其表达的T细胞抗原受体(TCR)的不同分为两种:αβT淋巴细胞和_γδT淋巴细胞。其中_γδT淋巴细胞数量少,识别抗原广泛且无MHC分子限制性,对自体、同种异体或异种肿瘤细胞均可显示明显的杀伤活性,因此,_γδT细胞作为过继免疫治疗的候选细胞引起了越来越多的国内外学者的关注。但由于_γδT细胞在外周血及肿瘤组织中分布频率较低(＜10%),从而造成分离纯化的过程十分繁琐。深入的_γδT细胞功能研究及其可能的临床应用在很大程度上取决于该细胞亚群的有效分离与纯化。在这一领域,人们做了很多有益的尝试,其中本课题组建立的固相化抗TCR_γδ抗体选择性扩增的方法可获得高纯度的_γδT细胞,并可使TCR的受体谱保持相对完整。为了将_γδT细胞真正用于临床过继免疫治疗,有必要优化其培养条件,力求获得高纯度大量的_γδT细胞。为此,本研究对_γδT细胞体外培养条件进行了摸索,以期获得_γδT细胞体外培养的最佳条件,同时对其功能也进行了验证性的研究,希望为_γδT细胞最终临床应用奠定重要的实验基础和提供理论指导。本研究的主要研究内容与结果如下:
1.过继治疗用_γδT细胞制品研究
参照国家药品监督管理局2003年3月22日颁布的《人体细胞治疗研究和制剂质量控制技术指导原则》(以下简称指导原则)的要求,对过继治疗用的_γδT细胞进行制剂制备程序规范化与标准化的研究。研究结果表明固相抗体法可在体外有效地扩增来自健康人和肿瘤病人PBMC的_γδT细胞。
2._γδT细胞制品安全性研究
主要包括急性毒性、过敏性、溶血性和局部刺激性等主要的、局部的、全身给药相关的特殊安全性实验及致瘤性检测。研究结果表明_γδT细胞制品无明显的毒、副反应,对过继免疫治疗的受者无致瘤性的危险。
3._γδT细胞制品有效性评价
通过表型鉴定、体外杀伤实验检测_γδT细胞生物学效力,验证_γδT细胞对肿瘤的杀伤作用及合适的效靶细胞比例,寻找合适的靶肿瘤。实验结果显示,体外培养扩增的外周血_γδT细胞对多种组织来源的恶性肿瘤细胞系包括人胰腺癌细胞系PANC-1、人肺癌细胞系NCI-H520、人卵巢上皮癌细胞系SKOV3和淋巴瘤细胞系Daudi均有着较强的细胞毒作用,且随着效靶比增高而有所增强。且外周血_γδT细胞对化疗耐药SKOV3也有着良好的体外杀伤作用,提示了_γδT细胞制剂在临床治疗上与化疗配伍使用的可能。
4.动物体内实验
①建立小鼠移植瘤模型,观察体外扩增的免疫功能正常小鼠脾_γδT细胞过继免疫治疗效果;②建立裸鼠皮下肿瘤模型,观察人_γδT细胞对肿瘤的治疗效果及其与化疗有无协同或拮抗作用;③建立人外周血PBMC免疫重建的SCID小鼠皮下肿瘤模型,模拟正常人体免疫环境,回输人_γδT细胞,观察治疗效果。通过动物体内实验为制定临床给药方案提供依据。实验结果显示_γδT细胞对荷人肺癌细胞系NCI-H520细胞裸鼠、荷人卵巢癌细胞系SKOV3细胞裸鼠和SCID小鼠,均有良好的体内抑瘤作用,其治疗效果与剂量呈正相关;_γδT细胞治疗效果与抗癌药物顺铂的疗效相似。小鼠脾_γδT细胞对小鼠卵巢癌细胞系OV2944肿瘤也有较强的体内抑瘤作用。
综上所述,固相抗体法可以有效地扩增外周血_γδT细胞,且扩增方法简便、安全、有效。体外扩增的外周血_γδT细胞对多种恶性肿瘤有着良好的体内外杀伤效应。外周血_γδT细胞作为一种能够简便获得足够数量而且有效的效应细胞,有望在今后的过继免疫治疗中发挥作用。本研究结果为申报临床Ⅰ期试验提供了重要的临床前研究资料。本研究突出的成果在于我们在实验动物中首次发现过继_γδT细胞治疗实体肿瘤的效果与化疗药物(顺铂)接近。如果这一效果在临床试验中得到重复的话,将是T细胞过继治疗领域当中里程碑式的事件。
T cells can be divided into two subgroups: TCRαβlymphocytes and TCRγδlymphocytes based on their expression of T cell receptors (TCR) on the cell surfaces. AlthoughγδT cells account for no more than 10% of the peripheral blood mononuclear cells (PBMC), they display unique nature of antigen recognition and appear to play an important role in host defense against tumor growth.γδT cells could recognize and bind to antigen molecules directly, including peptides and lipoid proteinosis molecules and so on.γδT cell invokes great interests of many immunologists for its unique nature of antigen recognition and cytotoxic activity in recent years.
In order to evaluate their functional activity against tumors, large numbers of cells are required. In our laboratory, the research on the tumor immunology ofγδT cells has already been performed and the solid-phase monoclonal anti-TCRy5 antibody was used to isolate and expand theγδT cells from PBMC and obtainγδT cells with high purity. In the present study, we tried to find the best culture conditions and obtain the most effectiveγδT cells for the clinical adoptive immunotherapy . The conditions and processes forγδT cells expanded in vitro were optimized and the relative functional studies were performed to validated the results. We hope to establish experiment foundation and provide theory instruction for the clinical application ofγδT cells. The research mainly included:
1.γδT cells preparation for adoptive therapy. According to the request of "Human cell therapy research and quality control technical guidelines" (abbreviated as guidelines) published by State Drug Administration on 22th March, 2003, we performed the normalization and standardigation research ofγδT cells preparation for adoptive therapy. It showed thatγδT cells with high purity could be obtained from PBMC of healthy individuals and patients with malignant carcinoma using the solid-phase monoclonal anti-TCRγδAb methods.
2. Safety investigation ofγδT cells preparation. The safety test mainly included tumorigenicity test, systemic and local safety tests such as acute toxicity, allergy, hemolytic and local irritation which were related to local or systemic administration. The results indicated thatγδT cells preparation had neither acute toxicity nor tumorigenicity to the acceptor.
3. Effectiveness evaluation ofγδT cells preparation. The study included detecting the biological characteristic ofγδT cells through phenotype analysis and cytotoxic experiments in vitro. In this study, we validated the cytotoxic effects ofγδT cells to tumor cells, determinated the suitable propotion of effective cells to target cells and find out the suitable taget tumor cells. The results demonstratedγδT cells expanded from human PBMC could kill various solid tumor cells, such as human ovarian carcinoma (SKOV3), lung carcinoma (NCI-H520), pancreatic carcinoma (PANC-1), and hematological B lymphoma (Daudi) cell lines within a wide range of effector to target ratios. Furthermore,γδT cells expanded from healthy individual PBMC could kill SKOV3 cells and cis-platinum resistant SKOV3 cells within a wide range of effector to target ratios, suggesting thatγδT cells might be used in future clinical treatment combined with chemotherapy.
4. Anti-tumor effect on tumor-bearing animals in vivo was observed , including the effects of adoptive immunotherapy with healthy mice spleenγδT cells using mice tumor model, the effects of adoptive immunotherapy with healthy humanγδT cells and the relation between adoptive immunotherapy and chemotherapy using nude mice xenograft tumor model and the effects of adoptive immunotherapy with healthy humanγδT cells xenograft tumor model in immune-reconstituted SCID mice with healthy human PBMC . The results demonstrated that adoptive transferring ofγδT cells was effective in inhibiting SKOV3 ovary tumor cells growth in Hu-PBMC-SCID mice and nude mice; adoptive transferring ofγδT cells was effective in inhibiting NCI-H520 lung cancer cells growth in nude mice;γδT cells from spleen of mice can effectively inhibited tumor growth of OV2944 in vivo.
In conclusion, the present study demonstrated thatγδT cells with high purity could be obtained using this solid-phase method. The purity ofγδT cells expanded could reach 90% and 70% from normal controls and patients with malignant carcinoma, respectively. The methods was proved to be safe, effective and simple. TheseγδT cells displayed significant cytotoxicities against a variety of tumor cell lines both in vivo and in vitro. The results demonstrated thatγδT cells might be suitable for clinical trials of adoptive immunotherapy.
1.过继治疗用_γδT细胞制品研究
参照国家药品监督管理局2003年3月22日颁布的《人体细胞治疗研究和制剂质量控制技术指导原则》(以下简称指导原则)的要求,对过继治疗用的_γδT细胞进行制剂制备程序规范化与标准化的研究。研究结果表明固相抗体法可在体外有效地扩增来自健康人和肿瘤病人PBMC的_γδT细胞。
2._γδT细胞制品安全性研究
主要包括急性毒性、过敏性、溶血性和局部刺激性等主要的、局部的、全身给药相关的特殊安全性实验及致瘤性检测。研究结果表明_γδT细胞制品无明显的毒、副反应,对过继免疫治疗的受者无致瘤性的危险。
3._γδT细胞制品有效性评价
通过表型鉴定、体外杀伤实验检测_γδT细胞生物学效力,验证_γδT细胞对肿瘤的杀伤作用及合适的效靶细胞比例,寻找合适的靶肿瘤。实验结果显示,体外培养扩增的外周血_γδT细胞对多种组织来源的恶性肿瘤细胞系包括人胰腺癌细胞系PANC-1、人肺癌细胞系NCI-H520、人卵巢上皮癌细胞系SKOV3和淋巴瘤细胞系Daudi均有着较强的细胞毒作用,且随着效靶比增高而有所增强。且外周血_γδT细胞对化疗耐药SKOV3也有着良好的体外杀伤作用,提示了_γδT细胞制剂在临床治疗上与化疗配伍使用的可能。
4.动物体内实验
①建立小鼠移植瘤模型,观察体外扩增的免疫功能正常小鼠脾_γδT细胞过继免疫治疗效果;②建立裸鼠皮下肿瘤模型,观察人_γδT细胞对肿瘤的治疗效果及其与化疗有无协同或拮抗作用;③建立人外周血PBMC免疫重建的SCID小鼠皮下肿瘤模型,模拟正常人体免疫环境,回输人_γδT细胞,观察治疗效果。通过动物体内实验为制定临床给药方案提供依据。实验结果显示_γδT细胞对荷人肺癌细胞系NCI-H520细胞裸鼠、荷人卵巢癌细胞系SKOV3细胞裸鼠和SCID小鼠,均有良好的体内抑瘤作用,其治疗效果与剂量呈正相关;_γδT细胞治疗效果与抗癌药物顺铂的疗效相似。小鼠脾_γδT细胞对小鼠卵巢癌细胞系OV2944肿瘤也有较强的体内抑瘤作用。
综上所述,固相抗体法可以有效地扩增外周血_γδT细胞,且扩增方法简便、安全、有效。体外扩增的外周血_γδT细胞对多种恶性肿瘤有着良好的体内外杀伤效应。外周血_γδT细胞作为一种能够简便获得足够数量而且有效的效应细胞,有望在今后的过继免疫治疗中发挥作用。本研究结果为申报临床Ⅰ期试验提供了重要的临床前研究资料。本研究突出的成果在于我们在实验动物中首次发现过继_γδT细胞治疗实体肿瘤的效果与化疗药物(顺铂)接近。如果这一效果在临床试验中得到重复的话,将是T细胞过继治疗领域当中里程碑式的事件。
T cells can be divided into two subgroups: TCRαβlymphocytes and TCRγδlymphocytes based on their expression of T cell receptors (TCR) on the cell surfaces. AlthoughγδT cells account for no more than 10% of the peripheral blood mononuclear cells (PBMC), they display unique nature of antigen recognition and appear to play an important role in host defense against tumor growth.γδT cells could recognize and bind to antigen molecules directly, including peptides and lipoid proteinosis molecules and so on.γδT cell invokes great interests of many immunologists for its unique nature of antigen recognition and cytotoxic activity in recent years.
In order to evaluate their functional activity against tumors, large numbers of cells are required. In our laboratory, the research on the tumor immunology ofγδT cells has already been performed and the solid-phase monoclonal anti-TCRy5 antibody was used to isolate and expand theγδT cells from PBMC and obtainγδT cells with high purity. In the present study, we tried to find the best culture conditions and obtain the most effectiveγδT cells for the clinical adoptive immunotherapy . The conditions and processes forγδT cells expanded in vitro were optimized and the relative functional studies were performed to validated the results. We hope to establish experiment foundation and provide theory instruction for the clinical application ofγδT cells. The research mainly included:
1.γδT cells preparation for adoptive therapy. According to the request of "Human cell therapy research and quality control technical guidelines" (abbreviated as guidelines) published by State Drug Administration on 22th March, 2003, we performed the normalization and standardigation research ofγδT cells preparation for adoptive therapy. It showed thatγδT cells with high purity could be obtained from PBMC of healthy individuals and patients with malignant carcinoma using the solid-phase monoclonal anti-TCRγδAb methods.
2. Safety investigation ofγδT cells preparation. The safety test mainly included tumorigenicity test, systemic and local safety tests such as acute toxicity, allergy, hemolytic and local irritation which were related to local or systemic administration. The results indicated thatγδT cells preparation had neither acute toxicity nor tumorigenicity to the acceptor.
3. Effectiveness evaluation ofγδT cells preparation. The study included detecting the biological characteristic ofγδT cells through phenotype analysis and cytotoxic experiments in vitro. In this study, we validated the cytotoxic effects ofγδT cells to tumor cells, determinated the suitable propotion of effective cells to target cells and find out the suitable taget tumor cells. The results demonstratedγδT cells expanded from human PBMC could kill various solid tumor cells, such as human ovarian carcinoma (SKOV3), lung carcinoma (NCI-H520), pancreatic carcinoma (PANC-1), and hematological B lymphoma (Daudi) cell lines within a wide range of effector to target ratios. Furthermore,γδT cells expanded from healthy individual PBMC could kill SKOV3 cells and cis-platinum resistant SKOV3 cells within a wide range of effector to target ratios, suggesting thatγδT cells might be used in future clinical treatment combined with chemotherapy.
4. Anti-tumor effect on tumor-bearing animals in vivo was observed , including the effects of adoptive immunotherapy with healthy mice spleenγδT cells using mice tumor model, the effects of adoptive immunotherapy with healthy humanγδT cells and the relation between adoptive immunotherapy and chemotherapy using nude mice xenograft tumor model and the effects of adoptive immunotherapy with healthy humanγδT cells xenograft tumor model in immune-reconstituted SCID mice with healthy human PBMC . The results demonstrated that adoptive transferring ofγδT cells was effective in inhibiting SKOV3 ovary tumor cells growth in Hu-PBMC-SCID mice and nude mice; adoptive transferring ofγδT cells was effective in inhibiting NCI-H520 lung cancer cells growth in nude mice;γδT cells from spleen of mice can effectively inhibited tumor growth of OV2944 in vivo.
In conclusion, the present study demonstrated thatγδT cells with high purity could be obtained using this solid-phase method. The purity ofγδT cells expanded could reach 90% and 70% from normal controls and patients with malignant carcinoma, respectively. The methods was proved to be safe, effective and simple. TheseγδT cells displayed significant cytotoxicities against a variety of tumor cell lines both in vivo and in vitro. The results demonstrated thatγδT cells might be suitable for clinical trials of adoptive immunotherapy.
引文
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