Department of Pulmonary Medicine, Erasmus University Medical Centre, Rotterdam, Netherlands; Erasmus Cancer Institute, Erasmus University Medical Centre, Rotterdam, Netherlands.
Department of Pulmonary Medicine, Erasmus University Medical Centre, Rotterdam, Netherlands; Erasmus Cancer Institute, Erasmus University Medical Centre, Rotterdam, Netherlands.
Lancet Oncol. 2024 Jul;25(7):865-878. doi: 10.1016/S1470-2045(24)00191-8. Epub 2024 Jun 4.
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 vs 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 ClinicalTrials.gov, NCT03610360, 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 vs two [2%] of 88 in the best supportive care group), dyspnoea (none vs two [2%]), anaemia (two [2%] vs none), nausea (none vs two [2%]), and pneumonia (none vs 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.
树突状细胞免疫疗法已被证明安全，并在人体中引发免疫反应。我们旨在确定负载同种异体肿瘤细胞裂解物（MesoPher，Amphera BV，'s-Hertogenbosch，荷兰）的树突状细胞作为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，从比利时、法国和荷兰的四个中心招募了组织学证实无法切除的胸膜间皮瘤、年龄在 18 岁或以上、东部合作肿瘤学组表现状态评分 0-1 分、并且在接受四到六周期标准化疗（培美曲塞 500mg/m2 加铂[顺铂 75mg/m2 或卡铂曲线下面积 5]）后疾病无进展的患者。参与者使用基于块的随机分组（块大小为 4），按中心和组织学（上皮样与其他）分层，随机分配（1:1）接受 MesoPher 治疗加最佳支持治疗或单独最佳支持治疗。患者最多接受五剂 MesoPher 输注，在第 1、15 和 29 天以及第 18 和 30 周进行治疗。在每个时间点，参与者接受 25×10 个树突状细胞的注射（三分之二的树突状细胞静脉内给药，三分之一皮内给药）。最佳支持治疗根据当地机构标准进行。主要终点是总生存期，在所有随机分配至治疗的参与者（全分析集）中评估，以及在所有随机分配参与者（如果他们在 MesoPher 组中，则接受白细胞分离术）中评估安全性。这项研究在 ClinicalTrials.gov 上注册，NCT03610360，目前已关闭入组。
2018 年 6 月 21 日至 2021 年 6 月 10 日，筛选了 176 名患者，并随机分配至 MesoPher 组（n=88）或最佳支持治疗组（n=88）。MesoPher 组中有 1 名患者未接受白细胞分离术。平均年龄为 68 岁（标准差 8），176 名患者中 149 名（85%）为男性，27 名（15%）为女性，173 名（98%）为白人，2 名（1%）为亚洲人，1 名（1%）为其他种族。截至数据截止日期（2023 年 6 月 24 日），中位随访 15.1 个月（95%置信区间 9.5-22.4）后，MesoPher 组的中位总生存期为 16.8 个月（95%CI 12.4-20.3；88 例死亡 61 例[69%]），最佳支持治疗组为 18.3 个月（14.3-21.9；88 例死亡 59 例[67%]）（风险比 1.10[95%CI 0.77-1.57]；对数秩检验 p=0.62）。最常见的 3-4 级治疗相关不良事件是胸痛（MesoPher 组 87 例中有 3 例[3%]，最佳支持治疗组 88 例中有 2 例[2%]）、呼吸困难（无 vs 2 例[2%]）、贫血（2 例[2%] vs 无）、恶心（无 vs 2 例[2%]）和肺炎（无 vs 2 例[2%]）。没有死亡被认为与治疗相关不良事件有关。与治疗相关的不良事件包括输液相关反应（发热、寒战和疲劳），在 MesoPher 组 87 例患者中有 64 例（74%）发生，以及注射部位反应（瘙痒、红斑和硬结），在 73 例患者中有 73 例（84%）发生，所有这些反应的严重程度均为 1-2 级。没有死亡被确定与治疗有关。
MesoPher 并未显示出在胸膜间皮瘤患者中总生存期的改善。免疫检查点疗法现在是胸膜间皮瘤的标准治疗方法。需要进一步进行 MesoPher 与免疫检查点疗法联合的随机研究，这可能会增加疗效而不会增加主要毒性。
Amphera BV 和欧盟地平线。
