Lenalidomide-induced upregulation of CD80 on tumor cells correlates with T-cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia
Lenalidomide-induced upregulation of CD80 on tumor cells correlates with T-cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia
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DOI：
10.3324/haematol.2009.005835
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发表时间：
2009-09-01
期刊：
影响因子：
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通讯作者：
Wiestner, Adrian
中科院分区：
文献类型：
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作者：
Aue, Georg;Njuguna, Ndegwa;Wiestner, Adrian
在慢性淋巴细胞白血病中，来那度胺引起惊人的免疫激活，可能导致肿瘤细胞的清除。我们进行了这项研究，以探讨来那度胺在慢性淋巴细胞白血病中的作用机制及其独特毒性的基础。设计与方法复发性慢性淋巴细胞白血病患者接受来那度胺20mg （n=10）或10mg （n=8）每日治疗，为期3周，疗程为6周。相关研究评估了共刺激分子在肿瘤细胞、t细胞活化、细胞因子水平和淋巴细胞亚群变化中的表达。结果来那度胺可上调慢性淋巴细胞白血病和套细胞淋巴瘤细胞的共刺激分子CD80，但对体外正常外周血B细胞无作用。t细胞活化在慢性淋巴细胞白血病中明显，在套细胞淋巴瘤中较弱，但在正常外周血单个核细胞中不存在，并与B细胞CD80的上调相关。强烈的CD80上调和t细胞活化预示着更严重的副作用，83%的患者在首次给药后8-72小时内表现为细胞因子释放综合征。血清各种细胞因子水平，包括肿瘤坏死因子- α，在治疗期间升高。CD80在肿瘤细胞上的上调与外周血白血病细胞的快速清除相关。相反，细胞因子释放综合征的严重程度和体外t细胞活化程度都与临床反应无关。结论来那度胺治疗慢性淋巴细胞白血病时，CD80对肿瘤细胞和t细胞活化的调控与来那度胺的独特毒性有关。然而，t细胞活化对于药物的抗肿瘤作用似乎是必不可少的。这为来那度胺与氟达拉滨或阿仑单抗联合使用提供了理论依据。
BackgroundIn chronic lymphocytic leukemia lenalidomide causes striking immune activation, possibly leading to clearance of tumor cells. We conducted this study to investigate the mechanism of action of lenalidomide and the basis for its unique toxicities in chronic lymphocytic leukemia.Design and MethodsPatients with relapsed chronic lymphocytic leukemia were treated with lenalidomide 20 mg (n=10) or 10 mg (n=8) daily for 3 weeks on a 6-week cycle. Correlative studies assessed expression of co-stimulatory molecules on tumor cells, T-cell activation, cytokine levels, and changes in lymphocyte subsets.ResultsLenalidomide upregulated the co-stimulatory molecule CD80 on chronic lymphocytic leukemia and mantle cell lymphoma cells but not on normal peripheral blood B cells in vitro. T-cell activation was apparent in chronic lymphocytic leukemia, weak in mantle cell lymphoma, but absent in normal peripheral blood mononuclear cells and correlated with the upregulation of CD80 on B cells. Strong CD80 upregulation and T-cell activation predicted more severe side effects, manifesting in 83% of patients as a cytokine release syndrome within 8-72 h after the first dose of lenalidomide. Serum levels of various cytokines, including tumor necrosis factor-alpha, increased during treatment. CD80 upregulation on tumor cells correlated with rapid clearance of leukemic cells from the peripheral blood. In contrast, neither the severity of the cytokine release syndrome nor the degree of T-cell activation in vitro correlated with clinical response.ConclusionsUpregulation of CD80 on tumor cells and T-cell activation correlate with unique toxicities of lenalidomide in chronic lymphocytic leukemia. However, T-cell activation appears to be dispensable for the drug's anti-tumor effects. This provides a rationale for combinations of lenalidomide with fludarabine or alemtuzumab.