Abstract：
BACKGROUND: 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.
METHODS: 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/m2 plus platinum [cisplatin 75 mg/m2 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 × 106 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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: Amphera BV and EU HORIZON.
METHODS: 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/m2 plus platinum [cisplatin 75 mg/m2 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 × 106 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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: Amphera BV and EU HORIZON.
摘要：
背景：树突状细胞免疫疗法已被证明是安全的，并在人类中诱导免疫应答。我们旨在建立负载有同种异体肿瘤细胞裂解物的树突状细胞的功效(MesoPher，AmpheraBV,\'s-Hertogenbosch,荷兰）作为胸膜间皮瘤患者的维持治疗。
方法：在此开放标签中，随机化，2/3阶段研究，组织学证实不可切除的胸膜间皮瘤患者，18岁或以上，东部肿瘤协作组的表现状态评分为0-1，并且在四至六个周期的标准化疗（培美曲塞500mg/m2加铂[顺铂75mg/m2或卡铂5的曲线下面积]）后疾病未进展来自比利时的四个中心，法国,和荷兰。参与者被随机分配(1：1)，使用块随机化(块大小为4)，按中心和组织学分层（上皮样与其他），MesoPher治疗加上最好的支持性护理或单独的最佳支持性护理。患者最多接受5次MesoPher输注,在第1、15和29天以及第18和30周给予治疗。在每个时间点，参与者接受了25×106个树突状细胞的注射(2/3的树突状细胞静脉给药,1/3的树突状细胞皮内给药).最好的支持性护理是根据当地机构标准。主要终点是总生存期，在随机分配接受治疗的所有参与者中进行评估（完整分析集），并在所有随机分配的参与者中进行安全性评估，如果他们是MesoPher组，他们接受了白细胞去除术。这项研究在ClinicalTrials.gov注册，NCT03610360，并为应计关闭。
结果：在2018年6月21日至2021年6月10日之间，对176例患者进行了筛查，并随机分配到MesoPher组（n=88）或最佳支持治疗组（n=88）。MesoPher组的一名参与者没有进行白细胞去除术。平均年龄为68岁（SD8），176人中有149人（85%）是男性，27人（15%）为女性，173（98%）是白人，两个是亚洲人(1%)，和一个（1％）是其他种族。截至数据截止（2023年6月24日），在中位随访15·1个月(IQR9·5-22·4)后，MesoPher组的中位总生存期为16·8个月(95%CI12·4-20·3;88例死亡中的61[69%]),最佳支持治疗组为18·3个月(14·3-21·9;88例死亡中的59[67%])(风险比1·10[95%CI0·77-1·57];log-rankp=0·62).最常见的3-4级治疗引起的不良事件是胸痛（MesoPher组87个中的3个[3%]，最佳支持治疗组88个中的2个[2%]），呼吸困难（无vs2[2%]），贫血（2[2%]vs无），恶心（无vs2[2%]），和肺炎（无vs2[2%]）。没有因治疗引起的不良事件而死亡的记录。治疗相关的不良事件包括输液相关反应（发烧，发冷,和疲劳)，发生在MesoPher组87例患者中的64例（74%），和注射部位反应(瘙痒，红斑,和硬结)，发生在73例（84%）患者中，严重程度均为1-2级。没有确定与治疗相关的死亡。
结论：MesoPher未显示胸膜间皮瘤患者的总生存期改善。免疫检查点疗法现已成为胸膜间皮瘤的标准治疗方法。MesoPher和免疫检查点治疗的组合需要进一步的随机研究，这可能会增加疗效而不增加主要毒性。
背景：AmpheraBV和EUHORIZON。
方法：在此开放标签中，随机化，2/3阶段研究，组织学证实不可切除的胸膜间皮瘤患者，18岁或以上，东部肿瘤协作组的表现状态评分为0-1，并且在四至六个周期的标准化疗（培美曲塞500mg/m2加铂[顺铂75mg/m2或卡铂5的曲线下面积]）后疾病未进展来自比利时的四个中心，法国,和荷兰。参与者被随机分配(1：1)，使用块随机化(块大小为4)，按中心和组织学分层（上皮样与其他），MesoPher治疗加上最好的支持性护理或单独的最佳支持性护理。患者最多接受5次MesoPher输注,在第1、15和29天以及第18和30周给予治疗。在每个时间点，参与者接受了25×106个树突状细胞的注射(2/3的树突状细胞静脉给药,1/3的树突状细胞皮内给药).最好的支持性护理是根据当地机构标准。主要终点是总生存期，在随机分配接受治疗的所有参与者中进行评估（完整分析集），并在所有随机分配的参与者中进行安全性评估，如果他们是MesoPher组，他们接受了白细胞去除术。这项研究在ClinicalTrials.gov注册，NCT03610360，并为应计关闭。
结果：在2018年6月21日至2021年6月10日之间，对176例患者进行了筛查，并随机分配到MesoPher组（n=88）或最佳支持治疗组（n=88）。MesoPher组的一名参与者没有进行白细胞去除术。平均年龄为68岁（SD8），176人中有149人（85%）是男性，27人（15%）为女性，173（98%）是白人，两个是亚洲人(1%)，和一个（1％）是其他种族。截至数据截止（2023年6月24日），在中位随访15·1个月(IQR9·5-22·4)后，MesoPher组的中位总生存期为16·8个月(95%CI12·4-20·3;88例死亡中的61[69%]),最佳支持治疗组为18·3个月(14·3-21·9;88例死亡中的59[67%])(风险比1·10[95%CI0·77-1·57];log-rankp=0·62).最常见的3-4级治疗引起的不良事件是胸痛（MesoPher组87个中的3个[3%]，最佳支持治疗组88个中的2个[2%]），呼吸困难（无vs2[2%]），贫血（2[2%]vs无），恶心（无vs2[2%]），和肺炎（无vs2[2%]）。没有因治疗引起的不良事件而死亡的记录。治疗相关的不良事件包括输液相关反应（发烧，发冷,和疲劳)，发生在MesoPher组87例患者中的64例（74%），和注射部位反应(瘙痒，红斑,和硬结)，发生在73例（84%）患者中，严重程度均为1-2级。没有确定与治疗相关的死亡。
结论：MesoPher未显示胸膜间皮瘤患者的总生存期改善。免疫检查点疗法现已成为胸膜间皮瘤的标准治疗方法。MesoPher和免疫检查点治疗的组合需要进一步的随机研究，这可能会增加疗效而不增加主要毒性。
背景：AmpheraBV和EUHORIZON。
