肿瘤细胞治疗研究
英文原题：Dendritic cells pulsed with multifunctional Wilms' tumor 1 (WT1) peptides combined with multiagent chemotherapy modulate the tumor microenvironment and enable conversion surgery in pancreatic cancer.
在UR-PDAC患者中，通过包含WT1-DC疫苗的联合化学免疫治疗方案强效激活WT1特异性免疫应答，可能调节TME并使转换手术成为可能，从而带来临床获益（在线补充文件1）。
背景：我们旨在开发一种化学免疫治疗方案，由新型 Wilms 肿瘤 1（WT1）肽负载树突状细胞（WT1-DC）疫苗联合多药化疗组成，并研究接受该治疗的不可切除晚期胰腺导管腺癌（UR-PDAC）患者的安全性、临床结局和 WT1 特异性免疫应答。方法：本 I 期研究纳入 10 例 UR-PDAC 患者，包括 III 期局部晚期疾病（LA-PDAC；n = 6）、IV 期转移性疾病（M-PDAC；n = 3）或术后复发（n = 1）。患者先接受 1 个周期的 nab-paclitaxel 联合 gemcitabine 单独治疗，随后不受化疗安排影响接受 15 次 WT1-DC 疫苗接种。新型 WT1 肽混合物由多功能辅助肽和杀伤肽组成：前者特异性识别主要组织相容性复合体 II 类、HLA-A*02:01 或 HLA-A*02:06，后者特异性识别 HLA-A*24:02。结果：该化学免疫治疗方案耐受性良好。在 9 例可进行预后分析的患者中，WT1 肽特异性迟发型超敏（WT1-DTH）长期阳性患者（n = 4）的临床结局显著优于短期阳性患者（n = 5）。化学免疫治疗期间，8 例患者被认为适合转化手术并接受切除：4 例 LA-PDAC、1 例 M-PDAC 和 1 例复发病例接受 R0 切除，另 1 例 M-PDAC 接受 R1 切除；1 例 LA-PDAC 患者仍被判定为不可切除。接受 R0 切除的 4 例 LA-PDAC 患者中有 3 例 WT1-DTH 长期阳性，这 3 例患者的胰腺肿瘤微环境（TME）中均见明显 T 细胞和程序性死亡蛋白 1（PD-1）阳性细胞浸润。所有 WT1-DTH 长期阳性患者在治疗开始后至少存活 4.5 年。接种 2 次疫苗后，长期阳性患者中产生 IFN 或 TNF 的 WT1 特异性循环 CD4+ 或 CD8+ T 细胞比例显著高于短期阳性患者。接种 12 次疫苗后，WT1-DTH 长期阳性的 PDAC 患者循环调节性 T 细胞和髓源性抑制细胞比例均显著低于短期阳性患者。结论：对于 UR-PDAC 患者，包含 WT1-DC 疫苗的联合化学免疫治疗方案可强效激活 WT1 特异性免疫应答，可能调节 TME 并促成转化手术，从而带来临床获益（在线补充文件 1）。试验注册编号：jRCTc030190195。
BACKGROUND: 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. METHODS: 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. RESULTS: 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- or TNF- 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. CONCLUSIONS: 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). TRIAL REGISTRATION NUMBER: jRCTc030190195.
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