Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, Kashiwa, Japan
Tokyo Midtown Clinic, Minato-ku, Japan.
J Immunother Cancer. 2024 Oct 8;12(10):e009765. doi: 10.1136/jitc-2024-009765.
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)-A02:01, or HLA-A02:06 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.
我们旨在开发一种包含新型 Wilms 瘤 1（WT1）肽脉冲树突状细胞（WT1-DC）疫苗和多药化疗的化学免疫疗法方案，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、临床结果和 WT1 特异性免疫反应。
患有 III 期疾病（局部晚期（LA-PDAC；n=6））、IV 期疾病（转移性（M-PDAC；n=3））或手术后复发（n=1）的 UR-PDAC 患者入组本研究。这些患者先接受一个周期的nab-紫杉醇加吉西他滨单独治疗，然后在不进行化疗的情况下接受 15 次 WT1-DC 疫苗治疗。新型 WT1 肽鸡尾酒由一种多功能辅助肽组成，该肽特异性针对主要组织相容性复合物 II 类、人类白细胞抗原（HLA）-A02:01 或 HLA-A02:06，以及一种针对 HLA-A*24:02 的杀伤肽。
该化学免疫治疗方案耐受性良好。在 9 名可进行预后分析的患者中，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-DTH 阳性患者（n=5）。在化疗免疫治疗期间，8 名患者被认为有资格进行转化手术，并接受 R0 切除（LA-PDAC 4 例，M-PDAC 1 例，复发 1 例）或 R1 切除（M-PDAC 1 例），1 例 LA-PDAC 患者被认为不可切除。R0 切除的 LA-PDAC 患者中有 3 例长期 WT1-DTH 阳性。这 3 例患者在胰腺肿瘤微环境（TME）中观察到 T 细胞和程序性细胞死亡蛋白-1+细胞的明显浸润。所有长期 WT1-DTH 阳性患者在开始治疗后至少 4.5 年仍存活。在长期 WT1-DTH 阳性患者中，与短期 WT1-DTH 阳性患者相比，WT1 特异性循环 CD4+或 CD8+T 细胞产生 IFN-γ或 TNF-α的百分比在两次接种后明显更高。此外，在接受 12 次疫苗接种后，长期 WT1-DTH 阳性 PDAC 患者的循环调节性 T 细胞和髓源性抑制细胞的百分比明显低于短期 WT1-DTH 阳性患者。
通过包括 WT1-DC 疫苗的化学免疫治疗方案在 UR-PDAC 患者中强烈激活 WT1 特异性免疫反应，可能调节 TME 并实现转化手术，从而带来临床获益（在线补充文件 1）。
jRCTc030190195。
