Generation of tumor antigen-specific T cell lines from pediatric patients with acute lymphoblastic leukemia--implications for immunotherapy.
Generation of tumor antigen-specific T cell lines from pediatric patients with acute lymphoblastic leukemia--implications for immunotherapy.
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DOI：
10.1158/1078-0432.ccr-13-0955
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发表时间：
2013-09-15
期刊：
影响因子：
--
通讯作者：
Bollard CM
中科院分区：
文献类型：
--
作者：
Weber G;Caruana I;Rouce RH;Barrett AJ;Gerdemann U;Leen AM;Rabin KR;Bollard CM
虽然儿童急性淋巴细胞白血病（ALL）的现代治愈率超过80%，但在高危疾病和复发患者中，尤其是当异基因造血干细胞移植不可行时，前景仍然很差。因此，需要采取改善结果和防止复发的战略。使用抗原特异性T细胞的免疫疗法可以具有抗白血病活性，而没有在强化化疗中观察到的毒性，因此代表了改善ALL高危患者结局的有吸引力的策略。我们探讨了从50例接受维持治疗的ALL患者（26例NCI高危和24例标准风险）的外周血中体外产生肿瘤抗原特异性T细胞的可行性。外周血单核细胞刺激自体树突状细胞脉冲与完整的肽库WT 1，生存素，MAGE-A3和PRAME，抗原经常表达在ALL母细胞。尽管淋巴细胞计数较低且不考虑NCI风险组，但从所有患者成功扩增了T细胞系。在IFNγ-ELISpot和51 Cr-释放测定中评估，在初始刺激后在超过50%的患者中观察到抗原特异性，并且在3次刺激后增加至超过90%。此外，在短期和长期共培养实验中，通过减少自体白血病原始细胞观察到肿瘤特异性应答。这项研究支持使用过继转移自体肿瘤抗原特异性T细胞的免疫治疗来预防复发并改善高危ALL患者的预后。
Although modern cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 80%, the outlook remains poor in patients with high risk disease and those who relapse, especially when allogeneic hematopoietic stem cell transplantation is not feasible. Strategies to improve outcome and prevent relapse are therefore required. Immunotherapy with antigen-specific T cells can have anti-leukemic activity without the toxicities seen with intensive chemotherapy and therefore represents an attractive strategy to improve the outcome of high risk patients with ALL. We explored the feasibility of generating tumor antigen-specific T cells ex vivo from the peripheral blood of 50 patients with ALL (26 NCI high risk and 24 standard risk) receiving maintenance therapy. Peripheral blood mononuclear cells were stimulated with autologous dendritic cells pulsed with complete peptide libraries of WT1, Survivin, MAGE-A3 and PRAME, antigens frequently expressed on ALL blasts. T-cell lines were successfully expanded from all patients, despite low lymphocyte counts and irrespective of NCI risk group. Antigen-specificity was observed in over 50% of patients after the initial stimulation and increased to over 90% after 3 stimulations as assessed in IFNγ-ELISpot and 51Cr-release assays. Moreover, tumor-specific responses were observed by reduction of autologous leukemia blasts in short- and long-term co-culture experiments. This study supports the use of immunotherapy with adoptively transferred autologous tumor antigen-specific T cells to prevent relapse and improve the prognosis of patients with high risk ALL.