Dendritic cell immunotherapy has proven to be safe and induces an immune response in humans. We aimed to establish the efficacy of dendritic cells loaded with allogeneic tumour cell lysate (MesoPher, Amphera BV, 's-Hertogenbosch, Netherlands) as maintenance therapy in patients with pleural mesothelioma. In this open-label, randomised, phase 2/3 study, patients with histologically confirmed unresectable pleural mesothelioma, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status score of 0–1, and non-progressing disease after four to six cycles of standard chemotherapy (with pemetrexed 500 mg/m plus platinum [cisplatin 75 mg/m or carboplatin area under the curve of 5]) were recruited from four centres in Belgium, France, and The Netherlands. Participants were randomly assigned (1:1), using block randomisation (block size of 4), stratified by centre and histology (epithelioid other), to MesoPher treatment plus best supportive care or best supportive care alone. Patients received up to a maximum of five MesoPher infusions, with treatment administered on days 1, 15, and 29, and weeks 18 and 30. At each timepoint, participants received an injection of 25 × 10 dendritic cells (two-thirds of the dendritic cells were administered intravenously and a third were injected intradermally). Best supportive care was per local institutional standards. The primary endpoint was overall survival, assessed in all participants randomly assigned to treatment (full analysis set) and safety assessed in all randomly assigned participants, and who underwent leukapheresis if they were in the MesoPher group. This study is registered with , , and is closed for accrual. Between June 21, 2018, and June 10, 2021, 176 patients were screened and randomly assigned to the MesoPher group (n=88) or best supportive care alone group (n=88). One participant in the MesoPher group did not undergo leukapheresis. Mean age was 68 years (SD 8), 149 (85%) of 176 were male, 27 (15%) were female, 173 (98%) were White, two were Asian (1%), and one (1%) was other race. As of data cutoff (June 24, 2023), after a median follow up of 15·1 months (IQR 9·5–22·4), median overall survival was 16·8 months (95% CI 12·4–20·3; 61 [69%] of 88 died) in the MesoPher group and 18·3 months (14·3–21·9; 59 [67%] of 88 died) in the best supportive care group (hazard ratio 1·10 [95% CI 0·77–1·57]; log-rank p=0·62). The most common grade 3–4 treatment-emergent adverse events were chest pain (three [3%] of 87 in the MesoPher group two [2%] of 88 in the best supportive care group), dyspnoea (none two [2%]), anaemia (two [2%] none), nausea (none two [2%]), and pneumonia (none two [2%]). No deaths due to treatment-emergent adverse events were recorded. Treatment-related adverse events consisted of infusion-related reactions (fever, chills, and fatigue), which occurred in 64 (74%) of 87 patients in the MesoPher group, and injection-site reactions (itch, erythema, and induration), which occurred in 73 (84%) patients, and all were grade 1–2 in severity. No deaths were determined to be treatment related. MesoPher did not show improvement in overall survival in patients with pleural mesothelioma. Immune checkpoint therapy is now standard of care in pleural mesothelioma. Further randomised studies are needed of combinations of MesoPher and immune checkpoint therapy, which might increase efficacy without adding major toxicities. Amphera BV and EU HORIZON.

中文翻译：

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负载同种异体肿瘤细胞裂解物的树突状细胞加最佳支持治疗与单独最佳支持治疗在胸膜间皮瘤患者中作为化疗后维持治疗 (DENIM)：一项多中心、开放标签、随机、2/3 期研究


树突状细胞免疫疗法已被证明是安全的，并能在人体中诱导免疫反应。我们的目的是确定负载同种异体肿瘤细胞裂解物（MesoPher，Amphera BV，斯海尔托亨博斯，荷兰）的树突状细胞作为胸膜间皮瘤患者维持治疗的疗效。在这项开放标签、随机、2/3 期研究中，患者患有经组织学证实不可切除的胸膜间皮瘤，年龄 18 岁或以上，东部肿瘤合作组表现状态评分为 0-1，并且在 4 至 4 个月后疾病未进展。从比利时、法国和荷兰的四个中心招募了六个周期的标准化疗（培美曲塞 500 mg/m2 加铂 [顺铂 75 mg/m2 或卡铂曲线下面积 5]）。参与者被随机分配（1:1），使用区组随机化（区组大小为 4），按中心和组织学（上皮样其他）分层，接受 MesoPher 治疗加最佳支持治疗或单独接受最佳支持治疗。患者最多接受五次 MesoPher 输注，治疗分别在第 1、15 和 29 天以及第 18 和 30 周进行。在每个时间点，参与者接受了 25 × 10 个树突状细胞的注射（树突状细胞的三分之二）。细胞经静脉注射，第三个细胞经皮内注射）。最佳支持性护理符合当地机构标准。主要终点是总体生存率，对随机分配接受治疗的所有参与者（完整分析集）进行评估，并对所有随机分配的参与者以及接受白细胞分离术的参与者（如果他们属于 MesoPher 组）进行安全性评估。这项研究已在 、 、 进行登记，并已停止计提。 2018年6月21日至2021年6月10日期间，筛选了176名患者并随机分配至MesoPher组（n=88）或单独最佳支持治疗组（n=88）。 MesoPher 组的一名参与者没有接受白细胞分离术。平均年龄为 68 岁 (SD 8)，176 人中有 149 人 (85%) 为男性，27 人 (15%) 为女性，173 人 (98%) 为白人，2 人为亚裔 (1%)，1 人为亚裔 (1%)是其他种族。截至数据截止（2023 年 6 月 24 日），中位随访 15·1 个月 (IQR 9·5–22·4) 后，中位总生存期为 16·8 个月 (95% CI 12·4–20· 3；MesoPher 组中有 61 人 [69%] 死亡），最佳支持治疗组为 18·3 个月（14·3–​​21·9；88 人中 59 [67%] 死亡）（风险比 1·10） [95% CI 0·77–1·57]；对数秩 p=0·62)。最常见的 3-4 级治疗引起的不良事件是胸痛（MesoPher 组 87 例中的 3 例 [3%]，最佳支持治疗组 88 例中的 2 例 [2%]）、呼吸困难（没有 2 例 [2%] ）、贫血（两项 [2%] 无）、恶心（无两项 [2%]）和肺炎（无两项 [2%]）。没有记录因治疗引起的不良事件导致的死亡。治疗相关不良事件包括输注相关反应（发烧、发冷和疲劳），MesoPher 组 87 名患者中有 64 名（74%）发生这种反应，以及注射部位反应（瘙痒、红斑和硬结）， 73 名 (84%) 患者发生这种情况，严重程度均为 1-2 级。没有确定死亡与治疗相关。 MesoPher 没有显示出胸膜间皮瘤患者总生存率的改善。免疫检查点治疗现已成为胸膜间皮瘤的标准治疗方法。需要对 MesoPher 和免疫检查点疗法的组合进行进一步的随机研究，这可能会在不增加主要毒性的情况下提高疗效。 Amphera BV 和 EU HORIZON。