The Graduate School of Biomedical Sciences, University of Texas Health San Antonio, Texas.
Department of Medicine, University of Texas Health San Antonio, Texas.
Clin Cancer Res. 2021 Jul 1;27(13):3661-3673. doi: 10.1158/1078-0432.CCR-20-4594. Epub 2021 Mar 26.
Immunotherapy 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.
Mice 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.
DD 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 IL6 .
Treg 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.
免疫疗法可治疗部分癌症，但不能治疗卵巢癌。调节性 T 细胞（Tregs）会阻碍抗卵巢癌免疫，但缺乏有效的人类 Treg 靶向治疗方法。我们测试了用 denileukin diftitox（DD）联合 IFNα消除 Treg 作为卵巢癌免疫疗法的效果。
用同源 ID8 卵巢癌细胞进行挑战的小鼠接受 DD、IFNα或两者联合治疗。0 期/1 期临床试验测试了一种剂量递增的 DD 输注，以实现功能性 Treg 减少、安全性和耐受性。2 期临床试验在 DD 单独治疗临床失败的情况下加入 IFNα2a。
DD 消除了 Tregs，改善了小鼠的抗肿瘤免疫和生存。IFNα 与 DD 联合显著改善了抗肿瘤免疫和生存。IFNα 没有改变 Treg 数量或功能，但通过诱导树突状细胞 IL6 增强了与 DD 联合的肿瘤特异性免疫并降低了肿瘤 Treg 功能。DD 在 0 期/1 期的各种恶性肿瘤患者中单独使用具有良好的耐受性，可消耗功能性血液 Tregs 并改善免疫。0 期/1 期的一名卵巢癌患者出现部分临床缓解，促使进行卵巢癌 2 期临床试验，但 DD 单独使用在 2 期临床试验中失败。另一项 2 期临床试验在 DD 失败时添加聚乙二醇化 IFNα2a，在两位患者中产生了免疫和临床获益，随后因 DD 短缺而停止。DD 单独使用具有良好的耐受性。添加 IFNα 增加了毒性，但可耐受，并通过树突状细胞诱导的 IL6 减少了血液中的人类 Treg 数量和功能。
Treg 耗竭在临床上是有用的，但单独使用不太可能治愈卵巢癌。合理的治疗药物组合可以挽救 Treg 耗竭单独治疗的临床失败，即使两种药物单独使用都不能提供有意义的临床获益。
