A phase I clinical trial of RNF43 peptide-related immune cell therapy combined with low-dose cyclophosphamide in patients with advanced solid tumors.
A phase I clinical trial of RNF43 peptide-related immune cell therapy combined with low-dose cyclophosphamide in patients with advanced solid tumors.
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DOI：
10.1371/journal.pone.0187878
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Tani K
中科院分区：
文献类型：
--
作者：
Hijikata Y;Okazaki T;Tanaka Y;Murahashi M;Yamada Y;Yamada K;Takahashi A;Inoue H;Kishimoto J;Nakanishi Y;Oda Y;Nakamura Y;Tani K
本研究的目的是探讨联合细胞免疫治疗与低剂量环磷酰胺（CPA）在晚期实体瘤患者中的安全性和耐受性。这项研究针对一种新的肿瘤相关抗原，环指蛋白43（RNF 43）。符合条件的患者对标准治疗具有抗性，HLA-A*24：02-或A*02：01-阳性，并且在其肿瘤细胞中表现出高RNF 43表达。他们被给予300 mg/m2 CPA，然后是自体淋巴细胞，与自体RNF 43肽脉冲树突状细胞（DC），RNF 43肽脉冲DC和全身低剂量白细胞介素-2初步培养。主要终点是安全性，而次要终点是免疫学和临床治疗反应。本试验共入组10例患者。首先，未观察到大于3级的不良事件。10例患者中有6例在第49天显示疾病稳定（SD），而其他4例患者显示疾病进展。此外，1例SD患者在第二次试验后表现出部分缓解。CPA治疗后SD患者的调节性T细胞（TCRs）频率显著降低。在SD患者中，产生干扰素-γ的肿瘤反应性CD 8 + T细胞的比例随着时间的推移而增加。我们成功地证明了免疫细胞疗法和CPA的组合是安全的，可能诱导肿瘤特异性免疫应答和临床疗效，并且伴随着RNF 43阳性晚期实体瘤患者中TcR的比率降低。
The objective of this study was to investigate the safety and the tolerability of combined cellular immunotherapy with low-dose cyclophosphamide (CPA) in patients with advanced solid tumors. This study targeted a novel tumor-associated antigen, ring finger protein 43 (RNF43). Eligible patients were resistant to standard therapy, HLA-A*24:02- or A*02:01-positive and exhibiting high RNF43 expression in their tumor cells. They were administered 300 mg/m2 CPA followed by autologous lymphocytes, preliminarily cultured with autologous RNF43 peptide-pulsed dendritic cells (DCs), RNF43 peptide-pulsed DCs and systemic low dose interleukin-2. The primary endpoint was safety whereas the secondary endpoint was immunological and clinical response to treatment. Ten patients, in total, were enrolled in this trial. Primarily, no adverse events greater than Grade 3 were observed. Six out of 10 patients showed stable disease (SD) on day 49, while 4 other patients showed progressive disease. In addition, one patient with SD exhibited a partial response after the second trial. The frequency of regulatory T cells (Tregs) in patients with SD significantly decreased after CPA administration. The ratio of interferon-γ-producing, tumor-reactive CD8+ T cells increased with time in patients with SD. We successfully showed that the combination of immune cell therapy and CPA was safe, might induce tumor-specific immune responses and clinical efficacy, and was accompanied by a decreased ratio of Tregs in patients with RNF43-positive advanced solid tumors.
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克服感染和癌症中的T细胞耗尽。
影响因子：
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DOI：
10.1158/1078-0432.ccr-14-2675
发表时间：
2015-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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作者：
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通讯作者：
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