Department of Surgical oncology, Erasmus Medical Center, Rotterdam, The Netherlands.
Data Mining and Modeling for Biomedicine Group, VIB-UGent Center for Inflammation Research Elewaut Unit Molecular Immunology and Inflammatory Unit, Gent, Oost-Vlaanderen, Belgium.
J Immunother Cancer. 2023 Aug;11(8). doi: 10.1136/jitc-2023-007070.
BACKGROUND: Malignant peritoneal mesothelioma (MPM) is an aggressive malignancy with a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival outcomes, but recurrence rates remain high. Dendritic cell-based immunotherapy (DCBI) showed promising results in patients with pleural mesothelioma. The primary aim of this trial was to determine feasibility of adjuvant DCBI after CRS-HIPEC. METHODS: This open-label, single-center, phase II clinical trial, performed in the Erasmus MC Cancer Institute Rotterdam, the Netherlands, included patients with epithelioid MPM. 4-6 weeks before CRS-HIPEC leukapheresis was performed. 8-10 weeks after surgery, DCBI was administered three times biweekly. Feasibility was defined as administration of at least three adjuvant vaccinations in 75% of patients. Comprehensive immune cell profiling was performed on peripheral blood samples prior to and during treatment. RESULTS: All patients who received CRS-HIPEC (n=16) were successfully treated with adjuvant DCBI. No severe toxicity related to DCBI was observed. Median progression-free survival (PFS) was 12 months (IQR 5-23) and median overall survival was not reached. DCBI was associated with increased proliferation of circulating natural killer cells and CD4+ T-helper (Th) cells. Co-stimulatory molecules, including ICOS, HLA-DR, and CD28 were upregulated predominantly on memory or proliferating Th-cells and minimally on CD8+ cytotoxic T-lymphocytes (CTLs) after treatment. However, an increase in CD8+ terminally differentiated effector memory (Temra) cells positively correlated with PFS, whereas co-expression of ICOS and Ki67 on CTLs trended towards a positive correlation. CONCLUSIONS: Adjuvant DCBI after CRS-HIPEC in patients with MPM was feasible and safe, and showed promising survival outcomes. DCBI had an immune modulatory effect on lymphoid cells and induced memory T-cell activation. Moreover, an increase of CD8+ Temra cells was more pronounced in patients with longer PFS. These data provide rationale for future combination treatment strategies. TRIAL REGISTRATION NUMBER: NTR7060; Dutch Trial Register (NTR).
背景：恶性腹膜间皮瘤（MPM）是一种侵袭性恶性肿瘤，预后不良。细胞减灭术（CRS）和腹腔内热灌注化疗（HIPEC）可改善生存结果，但复发率仍然很高。树突状细胞为基础的免疫疗法（DCBI）在胸膜间皮瘤患者中显示出良好的效果。本试验的主要目的是确定 CRS-HIPEC 后辅助 DCBI 的可行性。
方法：这是一项在荷兰鹿特丹伊拉斯姆斯大学医学中心进行的开放标签、单中心、二期临床试验，纳入上皮样 MPM 患者。在 CRS-HIPEC 前 4-6 周进行白细胞分离术。手术后 8-10 周，每两周进行三次 DCBI 治疗。将至少 75%的患者接受三次辅助接种定义为可行。在治疗前和治疗期间对患者的外周血样本进行全面免疫细胞分析。
结果：所有接受 CRS-HIPEC 治疗的患者（n=16）均成功接受辅助 DCBI 治疗。未观察到与 DCBI 相关的严重毒性。中位无进展生存期（PFS）为 12 个月（IQR 5-23），总生存期未达到。DCBI 与循环自然杀伤细胞和 CD4+辅助性 T 细胞（Th）的增殖增加有关。共刺激分子，包括 ICOS、HLA-DR 和 CD28，主要在治疗后记忆性或增殖性 Th 细胞上调，而在 CD8+细胞毒性 T 淋巴细胞（CTL）上最小上调。然而，CD8+终末分化效应记忆（Temra）细胞的增加与 PFS 呈正相关，而 CTL 上 ICOS 和 Ki67 的共表达呈正相关趋势。
结论：MPM 患者 CRS-HIPEC 后辅助 DCBI 是可行且安全的，且生存结果有希望。DCBI 对淋巴细胞具有免疫调节作用，并诱导记忆性 T 细胞激活。此外，在 PFS 较长的患者中，CD8+Temra 细胞的增加更为明显。这些数据为未来的联合治疗策略提供了依据。
试验注册号：NTR7060；荷兰试验注册处（NTR）。
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