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首页> 外文期刊>The lancet oncology >Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: A phase 1 dose-escalation trial
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Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: A phase 1 dose-escalation trial

机译：转移性去势抵抗性前列腺癌患者的联合免疫疗法与粒细胞巨噬细胞集落刺激因子转导的异基因前列腺癌细胞和伊匹单抗的联合治疗

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Background: The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to assess the safety of combined treatment with GVAX and ipilimumab in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: We did an open-labelled, single-centre, dose-escalation study of ipilimumab concurrent with a fixed dose of GVAX, with a subsequent expansion phase, both at the VU University Medical Centre (Amsterdam, Netherlands). Eligible patients had documented mCRPC and had not been previously treated with chemotherapy. All patients received a 5×10 8 cell priming dose of GVAX intradermally on day 1 with subsequent intradermal injections of 3×10 8 cells every 2 weeks for 24 weeks. The vaccinations were combined with intravenous ipilimumab every 4 weeks. We enrolled patients in cohorts of three; each cohort received an escalating dose of ipilimumab at 0·3, 1·0, 3·0, or 5·0 mg/kg. Our primary endpoint was safety. This study is registered with ClinicalTrials.gov, number NCT01510288. Findings: We enrolled 12 patients into our dose-escalation cohort. We did not record any severe immune-related adverse events at the first two dose levels. At the 3·0 mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis; at the 5·0 mg/kg dose level, two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due to observed clinical activity and toxic events, we decided to expand the 3·0 mg/kg dose level, rather than enrol a further three patients at the 5·0 mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade 3 hepatitis-all immune-related adverse events. The most common adverse events noted in all 28 patients were injection-site reactions (grade 1-2 events seen in all patients), fatigue (grade 1-2 in 20 patients, grade 3 in two), and pyrexia (grade 1-2 in 15 patients, grade 3 in one). 50% or greater declines in prostate-specific antigen from baseline was recorded in seven patients (25%); all had received 3·0 mg/kg or 5·0 mg/kg ipilimumab. Interpretation: GVAX combined with 3·0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further research on the combined treatment of patients with mCRPC with vaccination and ipilimumab is warranted. Funding: Cell Genesys Inc, Prostate Cancer Foundation, Dutch Cancer Society (KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer Center Amsterdam.
机译：背景：粒细胞巨噬细胞集落刺激因子转导的同种异体前列腺癌细胞疫苗（GVAX）具有抗前列腺癌的活性。临床前研究表明，与ipilimumab（一种可阻断细胞毒性T淋巴细胞抗原4的抗体）联合使用时，具有有效的协同作用。我们旨在评估GVAX和ipilimumab联合治疗对转移性去势抵抗性前列腺癌（mCRPC）患者的安全性。方法：我们在VU大学医学中心（荷兰阿姆斯特丹）进行了开放标签，单中心剂量递增的依匹莫单抗联合固定剂量的GVAX以及随后的扩展阶段的研究。符合条件的患者已记录了mCRPC，并且先前未接受过化疗。所有患者在第1天皮内接受5×10 8细胞初次剂量的GVAX，随后每2周皮内注射3×10 8细胞，持续24周。每4周将疫苗与静脉注射ipilimumab合并使用。我们招募了三个患者。每个队列接受递增剂量的依匹莫单抗，剂量为0·3、1·0、3·0或5·0 mg / kg。我们的主要目标是安全。该研究已在ClinicalTrials.gov上注册，编号为NCT01510288。结果：我们招募了12名患者进入我们的剂量递增研究队列。在前两个剂量水平，我们没有记录任何严重的免疫相关不良事件。在3·0 mg / kg剂量水平下，一名患者患有2级，而两名患者患有3级垂体炎。在5·0 mg / kg剂量水平下，两名患者患有3级垂体炎，一名患者发生了4级结节性肺泡炎（剂量限制性毒性作用）。由于观察到的临床活动和毒性事件，我们决定扩大3·0 mg / kg的剂量水平，而不是再以5·0 mg / kg的水平招募3名患者。 16名患者参加了扩展研究，其中2名发展为2级垂体炎，3名结肠炎（1级为1级和2级为2级）和1级3级与肝炎有关的所有与免疫有关的不良事件。在所有28位患者中注意到的最常见不良事件是注射部位反应（在所有患者中均出现1-2级事件），疲劳（在20位患者中为1-2级，在三分之二中）和发烧（1-2级）在15位患者中，三级合一）。七名患者（25％）的前列腺特异性抗原从基线下降了50％或更多;所有人都接受了3·0 mg / kg或5·0 mg / kg的ipilimumab。解释：GVAX联合3·0 mg / kg伊匹木单抗对于mCRPC患者是可以耐受且安全的。有必要进一步研究将mCRPC患者与疫苗和ipilimumab联合治疗。资金来源：Cell Genesys Inc，前列腺癌基金会，荷兰癌症协会（KWF-VU 2006-3697）和Stichting VUmc阿姆斯特丹癌症中心基金会。

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