Th17-inducing autologous dendritic cell vaccination promotes antigen-specific cellular and humoral immunity in ovarian cancer patients.
Th17-inducing autologous dendritic cell vaccination promotes antigen-specific cellular and humoral immunity in ovarian cancer patients.
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Th17诱导的自体树突状细胞疫苗可促进卵巢癌患者的抗原特异性细胞和体液免疫。
DOI：
10.1038/s41467-020-18962-z
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发表时间：
2020-10-14
影响因子：
16.6
通讯作者：
Cannon MJ
中科院分区：
文献类型：
--
作者：
Block MS;Dietz AB;Gustafson MP;Kalli KR;Erskine CL;Youssef B;Vijay GV;Allred JB;Pavelko KD;Strausbauch MA;Lin Y;Grudem ME;Jatoi A;Klampe CM;Wahner-Hendrickson AE;Weroha SJ;Glaser GE;Kumar A;Langstraat CL;Solseth ML;Deeds MC;Knutson KL;Cannon MJ
在卵巢癌（OC）中，产生IL-17的T细胞（Th 17）预测生存率提高，而调节性T细胞预测生存率降低。我们以前开发了一种疫苗，其中患者来源的树突状细胞（DC）被编程为诱导Th 17对OC抗原叶酸受体α（FRα）的应答。在这里，我们报告了一项单臂开放标签I期临床试验的结果，该试验旨在确定疫苗的安全性和耐受性（主要结局）以及无复发生存率（次要结局）。还评价了免疫原性。招募完成，共有19例IIIC-IV期OC患者在常规治疗后首次缓解。使用我们的Th 17诱导方案产生DC，并用来自FRα的HLA II类表位进行脉冲。将负载成熟抗原的DC皮内注射。所有患者均已完成研究相关干预。未观察到3级或更高级别的不良事件。疫苗接种导致大多数患者产生Th 1、Th 17和对FRα的抗体应答。Th 1和抗体应答与延长的无复发生存期相关。针对FRα的抗体依赖性细胞介导的细胞毒活性也与RFS延长相关。在18例可评价疗效的患者中，39%（7/18）在数据删失时保持无复发，中位随访时间为49.2个月。因此，接种Th 17诱导FRα负载的DC是安全的，诱导抗原特异性免疫，并与延长缓解相关。叶酸受体α（FRα）在大多数高级别浆液性卵巢癌中过表达，已被提议作为候选疫苗抗原。在此，作者报告了在卵巢癌患者的早期I期临床试验中，用FRα衍生表位脉冲的Th 17诱导树突状细胞的安全性和免疫原性。
In ovarian cancer (OC), IL-17-producing T cells (Th17s) predict improved survival, whereas regulatory T cells predict poorer survival. We previously developed a vaccine whereby patient-derived dendritic cells (DCs) are programmed to induce Th17 responses to the OC antigen folate receptor alpha (FRα). Here we report the results of a single-arm open-label phase I clinical trial designed to determine vaccine safety and tolerability (primary outcomes) and recurrence-free survival (secondary outcome). Immunogenicity is also evaluated. Recruitment is complete with a total of 19 Stage IIIC-IV OC patients in first remission after conventional therapy. DCs are generated using our Th17-inducing protocol and are pulsed with HLA class II epitopes from FRα. Mature antigen-loaded DCs are injected intradermally. All patients have completed study-related interventions. No grade 3 or higher adverse events are seen. Vaccination results in the development of Th1, Th17, and antibody responses to FRα in the majority of patients. Th1 and antibody responses are associated with prolonged recurrence-free survival. Antibody-dependent cell-mediated cytotoxic activity against FRα is also associated with prolonged RFS. Of 18 patients evaluable for efficacy, 39% (7/18) remain recurrence-free at the time of data censoring, with a median follow-up of 49.2 months. Thus, vaccination with Th17-inducing FRα-loaded DCs is safe, induces antigen-specific immunity, and is associated with prolonged remission. The folate receptor alpha (FRα) is overexpressed in the majority of high-grade serous ovarian cancers and has been proposed as a candidate vaccine antigen. Here the authors report the safety and immunogenicity of Th17-inducing dendritic cells pulsed with FRα-derived epitopes in an early phase I clinical trial with ovarian cancer patients.
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