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）： 本项目将自体基因修饰的T细胞应用于胃癌的新型免疫基因治疗。 研究人员创建了嵌合IgTCR作为单链人源化抗CEA抗体（Ab）结合结构域与TCR的zeta信号传导链的分子融合产物。 当通过基因治疗技术在受体T细胞中表达时，所产生的“设计者T细胞”联合收割机将Ab的特异性与T细胞的细胞毒性效力结合。 CEA在>80%的胃癌中以高水平表达，在正常组织中仅少量表达，使得CEA成为靶向胃癌的合适抗原（Ag）。 胃癌在美国的患病率为20，000名患者，每年在美国夺去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，细胞治疗胃癌将为这些患者提供一种新的治疗选择。 研究人员之前进行了第一代设计T细胞的1期试验，这些T细胞在肿瘤接触时产生信号1（TCR）。 本研究显示患者耐受性良好，并产生了初步的疗效指征，但持续时间有限。 体外相关性表明，活化诱导的细胞死亡（AICD）导致输注的T细胞缺乏体内持久性。 这促使产品重新设计，以通过IgCD 28 TCR在肿瘤接触时添加CD 28共刺激（信号2）。 在临床前试验中，这些具有信号1+2的第二代（第二代）设计者T细胞抵抗AICD，在与CEA+肿瘤靶标接触时具有改善的存活率，导致动物模型中体外和体内的上级抗肿瘤活性。 具体目的如下：（1）进行第二代设计者T细胞的I期试验，a.评估安全性（毒性/耐受性），并建立最大耐受剂量/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测量。 2期疗效试验将在授予后进行。 该假设是，添加信号2刺激将改善设计者T细胞作用的效力和持续时间，而没有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长期临床反应。