Survival and tumor localization of adoptively transferred Melan-A-specific T cells in melanoma patients
Survival and tumor localization of adoptively transferred Melan-A-specific T cells in melanoma patients
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DOI：
10.4049/jimmunol.170.4.2161
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发表时间：
2003-02-15
影响因子：
4.4
通讯作者：
Mackensen, A
中科院分区：
文献类型：
--
作者：
Meidenbauer, N;Marienhagen, J;Mackensen, A
免疫性T细胞疗法已成功用于治疗病毒性和恶性疾病。然而，很少有人知道的命运和运输的转移Ag特异性T细胞。使用允许检测和定量Ag特异性CTL的四聚体（TM）技术，我们评估了过继性T细胞治疗期间晚期黑素瘤患者中循环Melan-A特异性CTL的频率。通过用突变的HLA-A2结合Melan-A（ELAGIGILTV）肽脉冲的树突状细胞体外刺激CD 8（+）T细胞，从HLA-A2.1（+）患者中产生Melan-A特异性CTL。8名患者接受了3次0.25-11 × 10（8）Melan-A特异性CTL静脉内输注，间隔沿着低剂量IL-2。转移的T细胞产物含有平均42.1%的Melan-A-TM+ CTL。治疗前，患者循环CD 8（+）T细胞中Melan-A特异性CTL的频率范围为0.01%至0.07%。转移前和转移后不同时间点的TM频率的表征揭示了循环Melan-A特异性CTL的增加高达2%，与转移的CTL的数量密切相关。TM+ T细胞的频率升高，证明转移后14天，表明长期生存和/或转移的CTL增殖。结合TM分析与流式细胞术为基础的细胞因子分泌测定，未受损的生产IFN-γ证明在体内至少24小时后转移。铟-111标记的Melan-A-特异性CTL表明转移的CTL的本地化转移部位，早在48小时后注射。总之，结果表明，在体外产生的Melan-A-特异性CTL在体内完整存活数周，并优先定位于肿瘤。
Adoptive T cell therapy has been successfully used for treatment of viral and malignant diseases. However, little is known about the fate and trafficking of transferred Ag-specific T cells. Using the tetramer (TM) technology which allows for detection and quantification of Ag-specific CTL, we assessed the frequency of circulating Melan-A-specific CTL in advanced melanoma patients during adoptive T cell therapy. Melan-A-specific CTL were generated from HLA-A2.1(+) patients by in vitro stimulation of CD8(+) T cells with dendritic cells pulsed with a mutated HLA-A2-binding Melan-A (ELAGIGILTV) peptide. Eight patients received three infusions of 0.25-11 X 10(8) Melan-A-specific CTL i.v. at 2-wk intervals along with low-dose IL-2. The transferred T cell product contained a mean of 42.1% Melan-A-TM+ CTL. Before therapy, the frequencies of Melan-A-specific CTL in patients' circulating CD8(+) T cells ranged from 0.01 to 0.07%.. Characterization of the TM frequencies before and at different time points after transfer revealed an increase of circulating Melan-A-specific CTL up to 2%, correlating well with the number of transferred CTL. An elevated frequency of TM+ T cells was demonstrated up to 14 days after transfer, suggesting long-term survival and/or proliferation of transferred CTL. Combining TM analysis with a flow cytometry-based cytokine secretion assay, unimpaired production of IFN-gamma was demonstrated in vivo for at least 24 h after transfer. Indium-111 labeling of Melan-A-specific CTL demonstrated localization of transferred CTL to metastatic sites as early as 48 h after injection. Overall, the results suggest that in vitro-generated Melan-A-specific CTL survive intact in vivo for several weeks and localize preferentially to tumor.