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

描述(由申请人提供)： 这项关于OPD赞助的提案将自体基因修饰的T细胞应用于一种新型的胃癌免疫基因治疗。研究人员创建了嵌合的IgTCR，作为单链人源化抗CEA抗体(Ab)结合域与TCR的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“设计者T细胞”结合了抗体的特异性和T细胞的细胞毒力。CEA在80%的胃癌组织中高水平表达，在正常组织中仅有少量表达，这使CEA成为一种适合于靶向胃癌的抗原。胃癌在美国的患病率为2万人，在美国每年夺走12000人的生命；目前还没有可用的治疗方法可以治愈转移疾病的患者。因此，针对胃癌的细胞治疗将为这些患者提供一种新的治疗选择。 研究人员之前对第一代设计者T细胞进行了一期试验，这些T细胞在与肿瘤接触时产生信号1(TCR)。这项研究表明患者耐受性良好，并产生了疗效的初步迹象，但持续时间有限。体外相关性表明，激活诱导的细胞死亡(AICD)是导致输注的T细胞在体内缺乏持久性的原因之一。这促使产品重新设计，通过IgCD28TCR在肿瘤接触上增加CD28共刺激(信号2)。在临床前测试中，这些带有信号1+2的第二代(第二代)设计T细胞抵抗AICD，与CEA+肿瘤靶点接触后存活率提高，从而在体外和体内动物模型中具有优越的抗肿瘤活性。具体目标如下：(1)进行第二基因设计者T细胞的第一阶段试验，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、药效学和附带反应措施。第二阶段药效测试将在获奖后阶段进行。假设信号2刺激的加入将提高设计者T细胞活动的效力和持续时间，而不会出现与治疗相关的严重毒性。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进展期胃癌患者的延长临床反应。

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.