我们的目的是开发一种化学免疫治疗方案，包括一种新型维尔姆斯氏瘤 1 (WT1) 肽脉冲树突状细胞 (WT1-DC) 疫苗和多药化疗，并研究患有以下疾病的患者的安全性、临床结果和 WT1 特异性免疫反应：接受这种治疗的不可切除的晚期胰腺导管腺癌 (UR-PDAC)。 患有 UR-PDAC 的 III 期疾病（局部晚期 (LA-PDAC；n=6)）、IV 期疾病（转移性 (M-PDAC；n= 3)) 或术后复发疾病 (n=1) 被纳入本 I 期研究。患者仅接受一个周期的白蛋白结合型紫杉醇加吉西他滨治疗，随后接受 15 剂 WT1-DC 疫苗（不依赖于化疗）。新型 WT1 肽混合物由主要组织相容性复合物 II 类、人类白细胞抗原 (HLA)-A*02:01 或 HLA-A*02:06 特异性的多功能辅助肽和 HLA-A 特异性的杀伤肽组成*24:02.化学免疫治疗方案耐受性良好。在预后分析可行的 9 名患者中，长期 WT1 肽特异性迟发型超敏反应 (WT1-DTH) 阳性患者 (n=4) 的临床结果明显优于短期 WT1 患者-DTH 阳性患者 (n=5)。在化学免疫治疗期间，8 名患者被认为有资格进行转化手术，并接受 R0 切除（4 名 LA-PDAC 患者，1 名 M-PDAC 患者，1 名复发）或 R1 切除（1 名 M-PDAC 患者），1 名患有 M-PDAC 的患者接受 R1 切除（1 名 M-PDAC 患者）。 LA-PDAC 被确定为不可切除。在四名 R0 切除 LA-PDAC 患者中，有三名患者观察到长期 WT1-DTH 阳性。这三名患者在胰腺肿瘤微环境 (TME) 中表现出 T 细胞和程序性细胞死亡蛋白 1 细胞的显着浸润。所有长期 WT1-DTH 阳性的患者在开始治疗后至少存活 4.5 年。在长期 WT1-DTH 阳性患者中，两次接种疫苗后产生 IFN-γ 或 TNF-α 的 WT1 特异性循环 CD4 或 CD8 T 细胞的百分比显着高于短期 WT1-DTH 阳性患者。此外，在接种 12 次疫苗后，长期 WT1-DTH 阳性 PDAC 患者的循环调节性 T 细胞和骨髓源性抑制细胞的百分比均显着低于短期 WT1-DTH 阳性患者。 UR-PDAC 患者通过包括 WT1-DC 疫苗在内的联合化学免疫治疗方案产生的 WT1 特异性免疫反应可能会调节 TME 并实现转换手术，从而产生临床益处（在线补充文件 1）。jRCTc030190195.© 作者（s）（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

We aimed to develop a chemoimmunotherapy regimen consisting of a novel Wilms' tumor 1 (WT1) peptide-pulsed dendritic cell (WT1-DC) vaccine and multiagent chemotherapy and to investigate the safety, clinical outcomes, and WT1-specific immune responses of patients with unresectable advanced pancreatic ductal adenocarcinoma (UR-PDAC) who received this treatment.Patients with UR-PDAC with stage III disease (locally advanced (LA-PDAC; n=6)), stage IV disease (metastatic (M-PDAC; n=3)), or recurrent disease after surgery (n=1) were enrolled in this phase I study. The patients received one cycle of nab-paclitaxel plus gemcitabine alone followed by 15 doses of the WT1-DC vaccine independent of chemotherapy. The novel WT1 peptide cocktail was composed of a multifunctional helper peptide specific for major histocompatibility complex class II, human leukocyte antigen (HLA)-A*02:01, or HLA-A*02:06 and a killer peptide specific for HLA-A*24:02.The chemoimmunotherapy regimen was well tolerated. In the nine patients for whom a prognostic analysis was feasible, the clinical outcomes of long-term WT1 peptide-specific delayed-type hypersensitivity (WT1-DTH)-positive patients (n=4) were significantly superior to those of short-term WT1-DTH-positive patients (n=5). During chemoimmunotherapy, eight patients were deemed eligible for conversion surgery and underwent R0 resection (four patients with LA-PDAC, one patient with M-PDAC, and one recurrence) or R1 resection (one patient with M-PDAC), and one patient with LA-PDAC was determined to be unresectable. Long-term WT1-DTH positivity was observed in three of the four patients with R0-resected LA-PDAC. These three patients exhibited notable infiltration of T cells and programmed cell death protein-1+ cells within the pancreatic tumor microenvironment (TME). All patients with long-term WT1-DTH positivity were alive for at least 4.5 years after starting therapy. In patients with long-term WT1-DTH positivity, the percentage of WT1-specific circulating CD4+ or CD8+ T cells that produced IFN-γ or TNF-α was significantly greater than that in patients with short-term WT1-DTH positivity after two vaccinations. Moreover, after 12 vaccinations, the percentages of both circulating regulatory T cells and myeloid-derived suppressor cells were significantly lower in patients with long-term WT1-DTH-positive PDAC than in short-term WT1-DTH-positive patients.Potent activation of WT1-specific immune responses through a combination chemoimmunotherapy regimen including the WT1-DC vaccine in patients with UR-PDAC may modulate the TME and enable conversion surgery, resulting in clinical benefits (Online supplemental file 1).jRCTc030190195.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.