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Development of adoptive immunotherapy by RNF43 specific T cell transfer in combination with dendritic cell

通过 RNF43 特异性 T 细胞转移结合树突状细胞开发过继免疫疗法

基本信息

批准号：
18590688
负责人：
SUEHIRO Youko
金额：
$ 2.49万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590688/
关键词：
adoptive immunotherapy RNF 43 peptide regulatory T cells dendritic cells IL-2 Colon cance cyclophosphamide 活性化リンパ球 RNF43 特異的活性化リンパ球シクロフォスファミド

项目摘要

The purpose of this Phase I clinical study is to observe the safety and the immunological and clinical responses induced by the combined administration of cyclophosphamide, tumor antigen RNF43 pulsed autologous dendritic cells, RNF43 specific autologous T cells and interleukin-2. Our preclinical data demonstrated that the T cells cocultured with RNF43 peptide pulse dendritic cells from peripheral blood of cancer patients had cytotoxic activity to RNF43 positive cell line, and the number of CD45RO and CCR7 was increased which suggested the induction of memory T cell population. After the start of clinical trial, RNF43 mRNA expression levels of 24 solid tumor candidate patients' biopsied samples were determined using real time PCR method. Only 5 colon cancer patients satisfied the inclusion criteria of elevated RNF43 mRNA expression level. So far, one patient of 60-year-old man with colon cancer with metastasis to lung and liver, was enrolled in this clinical trial and received RNF43 specific T cells with dendritic cells and IL-2. [CY 300 mg/m^2 (day-4), DC pulsed T cells 2x10^8 cells (day0), DC 1x10^7cells (day0, 7, 14), IL-2 (day 0, 1, 2, 7, 8, 9, 14, 15, 16)]. The patient was well tolerated and no major adverse events were observed. RNF43 specific CTL was observed after the adoptive cell administration. His clinical response was PD, namely the size of his lung metastasis was stable but that of liver metastasis was increased and the appearance of new brain metastasis. He passed away because of the liver failure after 2 months. Further study is required to determine the safety and clinical effects of this trial.

本I期临床研究的目的是观察环磷酰胺、肿瘤抗原RNF 43致敏的自体树突状细胞、RNF 43特异性自体T细胞和白细胞介素-2联合给药的安全性以及诱导的免疫学和临床应答。我们的临床前研究表明，肿瘤患者外周血中的RNF 43肽脉冲树突状细胞与T细胞共培养后，对RNF 43阳性细胞系具有杀伤活性，CD 45 RO和CCR 7数量增加，提示记忆性T细胞群的诱导。在临床试验开始后，使用真实的时间PCR方法测定24个实体瘤候选患者的活检样品的RNF 43 mRNA表达水平。仅5例结肠癌患者符合RNF 43 mRNA表达水平升高的纳入标准。到目前为止，一名患有结肠癌并转移到肺和肝的60岁男性患者参加了该临床试验，并接受了具有树突状细胞和IL-2的RNF 43特异性T细胞。[CY 300 mg/m^2（第4天），DC脉冲T细胞2x10^8个细胞（第0天），DC 1x10^7个细胞（第0、7、14天），IL-2（第0、1、2、7、8、9、14、15、16天）]。患者耐受性良好，未观察到重大不良事件。在过继细胞施用后观察到RNF 43特异性CTL。他的临床反应是PD，即他的肺转移瘤的大小稳定，但肝转移瘤的大小增加，并出现新的脑转移瘤。两个月后，他因肝功能衰竭去世。需要进一步研究来确定本试验的安全性和临床效果。