Second-generation anti-carcinoembryonic antigen designer T cells resist activation-induced cell death, proliferate on tumor contact, secrete cytokines, and exhibit superior antitumor activity in vivo: a preclinical evaluation.
Second-generation anti-carcinoembryonic antigen designer T cells resist activation-induced cell death, proliferate on tumor contact, secrete cytokines, and exhibit superior antitumor activity in vivo: a preclinical evaluation.
复制标题
DOI：
10.1158/1078-0432.ccr-07-4910
复制
发表时间：
2008-12-15
期刊：
影响因子：
--
通讯作者：
Junghans RP
中科院分区：
文献类型：
--
作者：
Emtage PC;Lo AS;Gomes EM;Liu DL;Gonzalo-Daganzo RM;Junghans RP
本报告描述了用于人体试验的第二代 (gen) 抗癌胚 (CEA) 设计 T 细胞的开发和临床前资格测试。祖细胞第一代免疫球蛋白 T 细胞受体 (IgTCR) 仅传输信号 1，有效介导嵌合免疫受体 (CIR) 定向的细胞毒性，但表达 T 细胞会死于激活诱导的细胞死亡 (AICD)。第二代 CIR（两个信号称为“Tandem”）旨在传输 TCR 信号 1 和 CD28 信号 2，使 T 细胞对 AICD 产生耐药性，并在体内提供持久的抗肿瘤作用。创建的 CIR 将 CD28、TCR zeta 和 CEA 特异性单链抗体结构域 (sFv) 的部分组合成单个分子 (IgCD28TCR)。按照设计，基因修饰的串联 T 细胞表现出对 AICD 具有抗性的新特性，在肿瘤接触时显示出加速增殖。串联 T 细胞在靶向和裂解 CEA+ 肿瘤方面比第一代 T 细胞更有效。串联 T 细胞在肿瘤接触时分泌高水平的 IL2 和 IFNγ，这是第一代 T 细胞所缺乏的，但分泌量已耗尽，这表明即使对于这些第二代药物，在治疗中也需要补充 IL2。最后，第二代 T 细胞在动物模型中更有效地抑制肿瘤。先进的一代抗 CEA 设计 T 细胞具有有望在体内产生更有效、更持久的抗肿瘤免疫反应的特性。这些临床前数据证明了该药物的人类使用资格，该药物目前正在 BB-IND 10791 下的 CEA+ 癌症患者中进行试验。
This report describes the development and preclinical qualification tests of 2nd generation (gen) anti-carcinoembryonic (CEA) designer T cells for use in human trials. The progenitor 1st generation immunoglobulin-T cell receptor (IgTCR) that transmits Signal 1-only effectively mediated chimeric immune receptor (CIR)-directed cytotoxicity, but expressor T cells succumbed to activation-induced cell death (AICD). The 2nd generation CIR (termed “Tandem” for two signals) was designed to transmit TCR Signal 1 and CD28 Signal 2 to render T cells resistant to AICD and provide prolonged anti-tumor effect in vivo. A CIR was created that combines portions of CD28, TCR zeta and a single chain antibody domain (sFv) specific for CEA into a single molecule (IgCD28TCR). As designed, the gene-modified Tandem T cells exhibit the new property of being resistant to AICD, showing instead an accelerated proliferation on tumor contact. Tandem T cells are more potent than 1st generation in targeting and lysing CEA+ tumor. Tandem T cells secrete high levels of IL2 and IFNγ on tumor contact that 1st generation T cells lacked, but secretion was exhaustible, suggesting need for IL2 supplementation in therapy even for these 2nd generation agents. Finally, 2nd generation T cells were more effective in suppressing tumor in animal models. An advanced generation anti-CEA designer T cell is described with features that promise a more potent and enduring anti-tumor immune response in vivo. These preclinical data qualify the human use of this agent that is currently undergoing trial in patients with CEA+ cancers under BB-IND 10791.