IFNα Augments Clinical Efficacy of Regulatory T-cell Depletion with Denileukin Diftitox in Ovarian Cancer.
IFNα Augments Clinical Efficacy of Regulatory T-cell Depletion with Denileukin Diftitox in Ovarian Cancer.
复制标题
IFNα 增强了 Denileukin Diftitox 消除卵巢癌调节性 T 细胞的临床疗效。
DOI：
10.1158/1078-0432.ccr-20-4594
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Curiel,Tyler
中科院分区：
文献类型：
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作者：
Thibodeaux,SuzanneR;Barnett,BrianB;Pandeswara,Srilakshmi;Wall,ShawnaR;Hurez,Vincent;Dao,Vinh;Sun,Lishi;Daniel,BenjaminJ;Brumlik,MichaelJ;Drerup,Justin;Padrón,Álvaro;Whiteside,Teresa;Kryczek,Ilona;Zou,Weiping;Curiel,Tyler
目的免疫疗法可以治疗某些癌症，但不能治疗卵巢癌。调节性T细胞(Treg)阻碍抗卵巢癌免疫，但缺乏有效的人类Treg导向治疗。方法对同基因卵巢癌患者随机分为两组，分别用去干扰素α和/或DD+干扰素α治疗卵巢癌。0/I期试验测试了一次剂量递增的DD输注对功能性Treg减少、安全性和耐受性的影响。II期试验在单纯DD失败的情况下，在DD基础上加入干扰素α2a。干扰素α可显著提高糖尿病小鼠的抗肿瘤免疫能力和生存时间。干扰素α不改变树突状细胞的数量或功能，但通过诱导树突状细胞IL6增强肿瘤特异性免疫功能，并通过诱导树突状细胞IL 6而降低肿瘤的树突状细胞功能。在0/I期的各种恶性肿瘤患者中，DD本身的耐受性很好，耗尽了功能血树，并提高了免疫力。一名0/I期的卵巢癌患者经历了部分临床反应，促使进行了II期卵巢癌试验，但DD单独未能通过II期试验。另一项II期试验将聚乙二醇化干扰素α2a添加到失败的DD中，在DD短缺停止之前，在两名患者中产生了免疫学和临床益处。仅DD一人就被很好地耐受。加入干扰素α可增加毒性，但可耐受，并减少血液中人Treg的数量，并在体外通过树突状细胞诱导IL6发挥作用。结论Treg耗竭在临床上是有用的，但单独治疗卵巢癌的可能性不大。合理的治疗药物组合可以挽救单独使用Treg耗竭的临床失败，即使两种药物都没有提供有意义的临床益处。
PurposeImmunotherapy treats some cancers, but not ovarian cancer. Regulatory T cells (Tregs) impede anti-ovarian cancer immunity but effective human Treg-directed treatments are lacking. We tested Treg depletion with denileukin diftitox (DD) ± IFNα as ovarian cancer immunotherapy.Patients and MethodsMice with syngeneic ID8 ovarian cancer challenge were treated with DD, IFNα, or both. The phase 0/I trial tested one dose-escalated DD infusion for functional Treg reduction, safety, and tolerability. The phase II trial added IFNα2a to DD if DD alone failed clinically.ResultsDD depleted Tregs, and improved antitumor immunity and survival in mice. IFNα significantly improved antitumor immunity and survival with DD. IFNα did not alter Treg numbers or function but boosted tumor-specific immunity and reduced tumor Treg function with DD by inducing dendritic cell IL6. DD alone was well tolerated, depleted functional blood Tregs and improved immunity in patients with various malignancies in phase 0/I. A patient with ovarian cancer in phase 0/I experienced partial clinical response prompting a phase II ovarian cancer trial, but DD alone failed phase II. Another phase II trial added pegylated IFNα2a to failed DD, producing immunologic and clinical benefit in two of two patients before a DD shortage halt. DD alone was well tolerated. Adding IFNα increased toxicities but was tolerable, and reduced human Treg numbers in blood, and function through dendritic cell–induced IL6in vitro.ConclusionsTreg depletion is clinically useful but unlikely alone to cure ovarian cancer. Rational treatment agent combinations can salvage clinical failure of Treg depletion alone, even when neither single agent provides meaningful clinical benefit.