ANTICEA IGTCR MODIFIED T CELLS FOR CANCER THERAPY

癌胚抗原(CEA)表达为一种与肿瘤相关的 抗原存在于大量的人类恶性肿瘤中。CEA表示在 60%-90%的转移性结直肠癌是第二大癌症 美国的杀手，60%的转移性乳腺癌(排名第二 女性杀手)，超过30%的肺部恶性肿瘤(No. 男性和女性的1个杀手)，肝脏，胰腺，头和颈部，膀胱， 宫颈和前列腺癌，CEA+约有150,000人死亡 每年都有恶性肿瘤。因此，一种有效的疗法可以 特别是针对CEA抗原的直接抗肿瘤免疫将 对这个国家的肿瘤学疾病有重大影响。T淋巴细胞 免疫球蛋白-T细胞受体嵌合基因转导 为创建新的免疫效应器设计者谱系提供准备 细胞。在本研究中，一种人源化单链抗CEA抗体 片段(SFV)与TCR的Zeta链融合。T细胞 用此载体转导后，可与CEA特异性结合并进行激活 以不依赖MHC的方式对抗CEA+靶细胞。整体而言 该应用程序的目的是评估其安全性和有效性。 抗CEA嵌合TCR转导的T细胞在I、II期的表达 肿瘤临床试验，评价抗CEA-IgTCR的药代动力学 转导的T细胞在血液和组织中的持久性，并 遵循其他免疫学和肿瘤学参数，可能表明 CEA阳性肿瘤患者的抗肿瘤疗效。校长 假设是单链IgTCR-Zeta通过 外周血T细胞会将这些T细胞重定向到溶解CEA+肿瘤 细胞在体外和体内，并将介导消退建立 体内CEA阳性肿瘤。治疗将包括收集病人 淋巴细胞通过白细胞分离，通过逆转录病毒修饰T细胞- 介导性插入嵌合的IgTCR基因，并扩展 转导的T细胞现在是CEA肿瘤抗原的特异性。 然后将这些细胞重新注入患者体内，并产生毒性和 对响应进行监控。将指导平行的实验室工作 在创造第二代试剂以改进现有技术方面 用于T细胞转导和IgTCR修饰T细胞的选择性扩增 为这一模式的实施和推广提供便利。

Carcinoembryonic antigen (CEA) is expressed as a tumor-associated antigen in a large number of human malignancies. CEA is expressed on 60-90 percent of metastatic colorectal carcinomas, the number two cancer killer in United States, 60 percent of metastatic breast cancer (No. 2 killer in women), and more than 30 percent malignancies of the lung (No. 1 killer in men and women), liver, pancreas, head and neck, bladder, cervix, and prostate, with approximately 150,000 deaths in CEA+ malignancies each year. Therefore, an effective therapy which can specifically direct anti-tumor immunity against the CEA antigen would have a major impact on oncologic diseases in this country. T lymphocytes transduced with immunoglobulin-T cell receptor (IgTCR) chimeric genes provide for the creation of new designer lineages of immune effector cells. In the present study, a humanized single chain anti-CEA antibody fragment (sFv) was fused to the zeta chain of the TCR. T cell transduced with this vector specifically bind CEA and undergo activation in an MHC-independent manner against CEA+ target cells. The overall objectives of this application are to evaluate the safety and efficacy of antiCEA-chimeric TCR transduced T cells in phase I and Phase II cancer clinical trials, to assess the pharmacokinetics of antiCEA-IgTCR transduced T cells by their persistence in blood and tissues, and to follow other immunologic and oncologic parameters that may indicate anti-tumor efficacy in patients with CEA+ tumors. The principal hypothesis is that expression of a single chain IgTCR-zeta construct by peripheral blood T cells will redirect those T cells to lyse CEA+ tumor cells in vitro and in vivo, and will mediate regression of established CEA+ tumors in vivo. Therapy will consist of collecting patient lymphocytes by leukapheresis, modifying the T cells by retroviral- mediated insertion of the chimeric IgTCR genes, and expanding the transduced T cells which are now specific for the CEA tumor antigen. These cells are then reinfused back into the patients, and toxicity and response are monitored. Parallel laboratory efforts will be directed at creating second-generation reagents to improve current technologies for T cell transduction and selective expansion of IgTCR-modified T cells to facilitate the implementation and expansion of this modality.