Ipilimumab for Patients with Relapse after Allogeneic Transplantation.
Ipilimumab for Patients with Relapse after Allogeneic Transplantation.
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DOI：
10.1056/nejmoa1601202
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发表时间：
2016-07-14
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影响因子：
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通讯作者：
Leukemia and Lymphoma Society Blood Cancer Research Partnership
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作者：
Davids MS;Kim HT;Bachireddy P;Costello C;Liguori R;Savell A;Lukez AP;Avigan D;Chen YB;McSweeney P;LeBoeuf NR;Rooney MS;Bowden M;Zhou CW;Granter SR;Hornick JL;Rodig SJ;Hirakawa M;Severgnini M;Hodi FS;Wu CJ;Ho VT;Cutler C;Koreth J;Alyea EP;Antin JH;Armand P;Streicher H;Ball ED;Ritz J;Bashey A;Soiffer RJ;Leukemia and Lymphoma Society Blood Cancer Research Partnership
异基因造血干细胞移植（HSCT）后供体介导的免疫抗肿瘤活性丧失可导致血液系统癌症复发。我们假设通过靶向细胞毒性T淋巴细胞相关蛋白4与伊匹单抗建立的免疫检查点阻断可以通过移植物抗肿瘤效应恢复抗肿瘤反应性。我们进行了一项1/1b期多中心、化疗药物启动的研究，以确定易普利姆玛在同种异体HSCT后复发性血液癌患者中的安全性和有效性。患者接受伊匹单抗诱导治疗，剂量为3或10 mg/kg体重，每3周一次，共4剂，具有临床获益的患者每12周一次额外剂量，最多60周。共入组28例患者。在6例患者（21%）中观察到免疫相关不良事件，包括1例死亡，在4例患者（14%）中观察到移植物抗宿主病（GVHD），无法进一步给予伊匹单抗。在接受3 mg/kg剂量的患者中，没有出现符合正式反应标准的反应。在接受10 mg/kg剂量的22例患者中，5例（23%）完全缓解，2例（9%）部分缓解，6例（27%）肿瘤负荷降低。4例髓外急性髓系白血病患者和1例骨髓增生异常综合征发展为急性髓系白血病患者完全缓解。4例患者的持续反应超过1年。反应与细胞毒性CD 8 + T细胞的原位浸润、调节性T细胞的活化降低以及血液中效应T细胞亚群的扩增相关。我们的早期数据显示，尽管发生了免疫介导的毒性作用和GVHD，但在同种异体HSCT后复发性血液系统癌症患者中给予易普利姆玛是可行的。观察到持久的反应与这些癌症的几种组织学亚型相关，包括髓外急性髓系白血病。（由美国国立卫生研究院和其他机构资助; ClinicalTrials.gov编号，NCT 01822509。
Loss of donor-mediated immune antitumor activity after allogeneic hematopoietic stem-cell transplantation (HSCT) permits relapse of hematologic cancers. We hypothesized that immune checkpoint blockade established by targeting cytotoxic T-lymphocyte–associated protein 4 with ipilimumab could restore antitumor reactivity through a graft-versus-tumor effect. We conducted a phase 1/1b multicenter, investigator-initiated study to determine the safety and efficacy of ipilimumab in patients with relapsed hematologic cancer after allogeneic HSCT. Patients received induction therapy with ipilimumab at a dose of 3 or 10 mg per kilogram of body weight every 3 weeks for a total of 4 doses, with additional doses every 12 weeks for up to 60 weeks in patients who had a clinical benefit. A total of 28 patients were enrolled. Immune-related adverse events, including one death, were observed in 6 patients (21%), and graft-versus-host disease (GVHD) that precluded further administration of ipilimumab was observed in 4 patients (14%). No responses that met formal response criteria occurred in patients who received a dose of 3 mg per kilogram. Among 22 patients who received a dose of 10 mg per kilogram, 5 (23%) had a complete response, 2 (9%) had a partial response, and 6 (27%) had decreased tumor burden. Complete responses occurred in 4 patients with extramedullary acute myeloid leukemia and 1 patient with the myelodysplastic syndrome developing into acute myeloid leukemia. Four patients had a durable response for more than 1 year. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells in the blood. Our early-phase data showed that administration of ipilimumab was feasible in patients with recurrent hematologic cancers after allogeneic HSCT, although immune-mediated toxic effects and GVHD occurred. Durable responses were observed in association with several histologic subtypes of these cancers, including extramedullary acute myeloid leukemia. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01822509.)