Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma
Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma
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DOI：
10.1182/blood-2012-06-435503
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发表时间：
2013-01-17
期刊：
影响因子：
20.3
通讯作者：
Dhodapkar, Madhav V.
中科院分区：
文献类型：
--
作者：
Richter, Joshua;Neparidze, Natalia;Dhodapkar, Madhav V.
自然杀伤T（iNKT）细胞可以帮助介导对小鼠肿瘤的免疫监视。先前针对人iNKT细胞的研究仅限于晚期癌症的治疗，并且仅导致先天免疫的适度激活。临床骨髓瘤之前是无症状的前驱期。来那度胺显示介导人iNKT细胞的抗原特异性共刺激。我们用3个周期的α-半乳糖神经酰胺负载的单核细胞来源的树突状细胞和低剂量来那度胺联合治疗6例无症状骨髓瘤患者。治疗耐受性良好，导致4例可测量疾病患者中3例肿瘤相关单克隆免疫球蛋白减少。联合治疗导致活化诱导的可测量iNKT细胞减少和NK细胞活化，NKG 2D和CD 56表达增加。治疗还导致单核细胞活化，CD 16表达增加。每个周期的治疗与诱导嗜酸性粒细胞增多以及血清可溶性IL 2受体的增加有关。临床应答与既存或治疗诱导的抗肿瘤T细胞免疫相关。这些数据证明了通过这种组合的几种先天免疫细胞的协同活化和介导肿瘤消退的能力。靶向iNKT细胞的联合疗法可能有益于预防人类癌症（试验注册于clinicaltrials.gov：NCT 00698776）。（血。2013;121（3）：423-430）
Natural killer T (iNKT) cells can help mediate immune surveillance against tumors in mice. Prior studies targeting human iNKT cells were limited to therapy of advanced cancer and led to only modest activation of innate immunity. Clinical myeloma is preceded by an asymptomatic precursor phase. Lenalidomide was shown to mediate antigen-specific costimulation of human iNKT cells. We treated 6 patients with asymptomatic myeloma with 3 cycles of combination of alpha-galactosylceramide-loaded monocyte-derived dendritic cells and low-dose lenalidomide. Therapy was well tolerated and led to reduction in tumor-associated monoclonal immunoglobulin in 3 of 4 patients with measurable disease. Combination therapy led to activation-induced decline in measurable iNKT cells and activation of NK cells with an increase in NKG2D and CD56 expression. Treatment also led to activation of monocytes with an increase in CD16 expression. Each cycle of therapy was associated with induction of eosinophilia as well as an increase in serum soluble IL2 receptor. Clinical responses correlated with pre-existing or treatment-induced antitumor T-cell immunity. These data demonstrate synergistic activation of several innate immune cells by this combination and the capacity to mediate tumor regression. Combination therapies targeting iNKT cells may be of benefit toward prevention of cancer in humans (trial registered at clinicaltrials.gov: NCT00698776). (Blood. 2013;121(3):423-430)