Hijikata Yasuki, Okazaki Toshihiko, Tanaka Yoshihiro, Murahashi Mutsunori, Yamada Yuichi, Yamada Kazunari, Takahashi Atsushi, Inoue Hiroyuki, Kishimoto Junji, Nakanishi Yoichi, Oda Yoshinao, Nakamura Yusuke, Tani Kenzaburo
Department of Advanced Cell and Molecular Therapy, Kyushu University Hospital, Fukuoka, Japan.
ARO Advanced Medical Center, Kyushu University Hospital, Fukuoka, Japan.
PLoS One. 2018 Jan 2;13(1):e0187878. doi: 10.1371/journal.pone.0187878. eCollection 2018.
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-A24:02- or A02:01-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.
本研究的目的是调查低剂量环磷酰胺（CPA）联合细胞免疫疗法在晚期实体瘤患者中的安全性和耐受性。本研究针对一种新型肿瘤相关抗原，即环指蛋白43（RNF43）。符合条件的患者对标准疗法耐药，HLA-A24:02或A02:01阳性，且肿瘤细胞中RNF43表达高。患者先接受300mg/m²的CPA治疗，随后接受自体淋巴细胞治疗，这些自体淋巴细胞预先与自体RNF43肽脉冲树突状细胞（DCs）、RNF43肽脉冲DCs和全身性低剂量白细胞介素-2一起培养。主要终点是安全性，次要终点是对治疗的免疫和临床反应。本试验共纳入10例患者。主要观察到，未出现大于3级的不良事件。10例患者中有6例在第49天病情稳定（SD），另外4例患者病情进展。此外，1例病情稳定的患者在第二次试验后出现部分缓解。病情稳定患者中调节性T细胞（Tregs）的频率在给予CPA后显著降低。病情稳定患者中产生干扰素-γ的肿瘤反应性CD8+T细胞比例随时间增加。我们成功证明，免疫细胞疗法与CPA联合使用是安全的，可能诱导肿瘤特异性免疫反应和临床疗效，并且RNF43阳性晚期实体瘤患者的Tregs比例降低。
