ANTI-CEA DESIGNER T CELLS IN GASTRIC CANCER, PHASE I TR*

胃癌 I 期 TR 中的抗 CEA 设计 T 细胞*

• 批准号: 7386794
• 负责人: RICHARD P. JUNGHANS
• 金额: $ 20万
• 依托单位: ROGER WILLIAMS HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386794
• 关键词: ANTI; CEA; DESIGNER; CELLS; GASTRIC

DESCRIPTION (provided by applicant): This proposal for OPD sponsorship applies autologous gene-modified T cells in a new type of immuno-gene therapy for gastric cancer. The investigators created chimeric IgTCR as molecular fusion products of a single chain humanized anti-CEA antibody (Ab) binding domain with the zeta signaling chain of the TCR. When expressed by gene therapy techniques in recipient T cells, the resulting "designer T cells" combine the specificity of Ab with the cytotoxic potency of T cells. CEA is expressed at high levels on >80% of gastric cancers, with only minor expression on normal tissues, making CEA a suitable antigen (Ag) for targeting gastric carcinomas. Gastric cancer has a U.S. prevalence of 20,000 patients and takes 12,000 lives annually in the United States; no presently available therapy can cure patients with metastatic disease. Therefore, a cellular therapy against gastric cancer would offer a new therapeutic option to these patients. The investigators previously performed a Phase 1 trial with first generation designer T cells that yield Signal 1 (TCR) on tumor contact. This study showed adequate patient tolerance and yielded preliminary indications of efficacy, but of limited duration. In vitro correlates suggested that activation-induced cell death (AICD) contributed to lack of in vivo persistence of the infused T cells. This prompted a product redesign to add CD28 co-stimulation (Signal 2) on tumor contact via an IgCD28TCR. In preclinical tests, these second generation (2nd gen) designer T cells with Signal 1+2 resisted AICD, with improved survival on contact with CEA+ tumor targets, resulting in superior anti-tumor activity in vitro and in vivo in animal models. Specific Aims are the following: (1) to conduct Phase 1 trial of 2nd gen designer T cells, a. to assess safety (toxicity/tolerance), and establish maximum tolerated dose/maximum practical dose (MTD/MPD); (2) to assess pharmacokinetics, pharmacodynamics and incidental measures of response. Phase 2 efficacy tests will follow in the post-award period. The hypothesis is that the addition of Signal 2 stimulation will improve the potency and duration of designer T cell action without serious treatment-related toxicities. The investigators anticipate that the survival advantage of these 2nd gen anti-CEA T cells will ultimately translate into extended clinical responses in patients with advanced gastric carcinomas.

描述（由申请人提供）： 这项 OPD 赞助提案将自体基因修饰 T 细胞应用于新型胃癌免疫基因疗法。 研究人员创建了嵌合 IgTCR，作为单链人源化抗 CEA 抗体 (Ab) 结合域与 TCR zeta 信号链的分子融合产物。 当通过基因治疗技术在受体 T 细胞中表达时，产生的“设计 T 细胞”结合了 Ab 的特异性和 T 细胞的细胞毒性效力。 CEA 在 >80% 的胃癌中高水平表达，而在正常组织中仅少量表达，这使得 CEA 成为靶向胃癌的合适抗原 (Ag)。 胃癌在美国有 20,000 名患者患病，每年夺去 12,000 人的生命；目前没有可用的疗法可以治愈患有转移性疾病的患者。 因此，针对胃癌的细胞疗法将为这些患者提供新的治疗选择。 研究人员此前使用第一代设计 T 细胞进行了 1 期试验，这些 T 细胞在肿瘤接触时产生信号 1 (TCR)。 这项研究显示出足够的患者耐受性并产生了初步的疗效迹象，但持续时间有限。 体外相关研究表明，活化诱导的细胞死亡 (AICD) 导致输注的 T 细胞在体内缺乏持久性。 这促使产品重新设计，通过 IgCD28TCR 在肿瘤接触上添加 CD28 共刺激（信号 2）。 在临床前测试中，这些具有 Signal 1+2 的第二代 (2nd gen) 设计 T 细胞可抵抗 AICD，在与 CEA+ 肿瘤靶标接触时存活率提高，从而在动物模型中产生优异的体外和体内抗肿瘤活性。 具体目标如下： (1) 进行第二代设计 T 细胞的第一阶段试验，评估安全性（毒性/耐受性），并确定最大耐受剂量/最大实际剂量（MTD/MPD）； (2) 评估药代动力学、药效学和反应的附带措施。 第二阶段功效测试将在授予后进行。 假设添加 Signal 2 刺激将提高设计 T 细胞作用的效力和持续时间，而不会产生严重的治疗相关毒性。 研究人员预计，这些第二代抗 CEA T 细胞的生存优势最终将转化为晚期胃癌患者的延长临床反应。