Development of switch promoters driven by activation signals from the chimeric antigen receptors.

由嵌合抗原受体的激活信号驱动的开关启动子的开发。

• 批准号: 24700995
• 负责人: UCHIBORI Ryosuke
• 金额: $ 2.83万
• 依托单位: Jichi Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2012
• 资助国家: 日本
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-24700995/
• 关键词: キメラ抗原受容体; 細胞・遺伝子治療; がん; シグナル伝達; 分子スイッチ

Chimeric antigen receptor (CAR)-based immunotherapy shows therapeutic efficacy. However additional genetic modification is necessary for enhancement of the efficacy and safety of CAR-T cells. For example, production of an antitumor cytokine from CAR-T cells can potentially enhance their tumor-killing activity, but there are concerns that constitutive expression of anticancer molecules will cause systemic side effects. Therefore, it is important that exogenous gene expression is confined to the tumor sites. In this study, we aimed at developing switch promoters that would respond to activation signals from a CAR. We prepared a switch cassette that was arranged in order of two SV40 polyAs, four NFAT-REs, a minimal IL-2 promoter, ZsGreen1, and a BGH polyA sequence. Genes encoding switch cassettes were transferred into CD19-targeted CAR-expressing PBMCs. ZsGreen1 expression in PBMCs was strongly induced by co-culture with CD19-positive target cells.

基于嵌合抗原受体（CAR）的免疫疗法显示出治疗效果。然而，为了增强 CAR-T 细胞的功效和安全性，额外的基因改造是必要的。例如，CAR-T细胞产生的抗肿瘤细胞因子可能会增强其肿瘤杀伤活性，但有人担心抗癌分子的组成型表达会引起全身副作用。因此，重要的是外源基因表达仅限于肿瘤部位。在这项研究中，我们的目标是开发能够响应 CAR 激活信号的开关启动子。我们制备了一个开关盒，其按两个 SV40 PolyA、四个 NFAT-RE、一个最小 IL-2 启动子、ZsGreen1 和一个 BGH PolyA 序列的顺序排列。编码开关盒的基因被转移到表达 CD19 的 CAR 表达的 PBMC 中。与 CD19 阳性靶细胞共培养可强烈诱导 PBMC 中的 ZsGreen1 表达。

项目成果

CD19 target-engineered T-cells accumulate at tumor lesions in human B-cell lymphoma xenograft mouse models.

• DOI: 10.1016/j.bbrc.2013.07.030
• 发表时间: 2013-08-16
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Tsukahara T;Ohmine K;Yamamoto C;Uchibori R;Ido H;Teruya T;Urabe M;Mizukami H;Kume A;Nakamura M;Mineno J;Takesako K;Riviere I;Sadelain M;Brentjens R;Ozawa K
• 通讯作者: Ozawa K

Development of switch promoters driven by activation signals from the chimeric antigen receptors.

由嵌合抗原受体的激活信号驱动的开关启动子的开发。

• 作者: Uchibori R;Ninomiya S;Tsukahara T;Ohmine K;Urabe M;Mizukami H;Kume A;Mineno J;Ozawa K.
• 通讯作者: Ozawa K.

DEVELOPMENT OF SIN RETROVIRAL VECTORS EQUIPPED WITH SWITCH PROMOTERS DRIVEN BY ACTIVATION SIGNALS FROM THE CHIMERIC ANTIGEN RECEPTORS.

配备有由嵌合抗原受体激活信号驱动的开关启动子的SIN逆转录病毒载体的开发。

• 作者: Uchibori R;Ninomiya S;Tsukahara T;Ido H;Teruya T;Ohmine K;Urabe M;Mizukami H;Kume A;Riviere I;Sadelain M;Brentjens RJ;Mineno J;Ozawa K.
• 通讯作者: Ozawa K.

Development of switch promoters driven by activation signals from the chimeric antigen receptors

由嵌合抗原受体的激活信号驱动的开关启动子的开发

• 发表时间: 2013
• 作者: Uchibori R;Ninomiya S;Tsukahara T;Ohmine K;Urabe M;Mizukami H;Kume A;Mineno J;Ozawa K
• 通讯作者: Ozawa K

Development of switch promoters that would respond to activation signals from the chimeric antigen receptors.

开发能够响应嵌合抗原受体激活信号的开关启动子。

• 作者: Uchibori R;Ninomiya S;Tsukahara T;Ido H;Teruya T;Ohmine K;Urabe M;Mizukami H;Kume A;Riviere I;Sadelain M;Brentjens RJ;Mineno J;Ozawa K.
• 通讯作者: Ozawa K.