ANTICEA IGTCR MODIFIED T CELLS FOR CANCER THERAPY

癌胚抗原（CEA）表达为肿瘤相关的免疫球蛋白。 抗原在大量的人类恶性肿瘤。 CEA表达于 60- 90%的转移性结直肠癌， 在美国，60%的转移性乳腺癌是致命的（第2位 女性杀手），和超过30%的肺部恶性肿瘤（第二。 男性和女性中的1个杀手），肝脏，胰腺，头颈部，膀胱， 子宫颈和前列腺，约有150，000例CEA+死亡 每年的恶性肿瘤 因此，一种有效的治疗方法， 针对CEA抗原的特异性定向抗肿瘤免疫将 对这个国家的肿瘤疾病有重大影响。T淋巴细胞 用免疫球蛋白-T细胞受体（IgTCR）嵌合基因转导 提供免疫效应物的新设计者谱系的产生 细胞 在本研究中，人源化单链抗CEA抗体 片段（sFv）与TCR的ζ链融合。 T细胞 用该载体转导的细胞特异性结合CEA并经历活化 以MHC非依赖性方式针对CEA+靶细胞。 整体 本申请的目的是评价 I期和II期抗CEA-嵌合TCR转导的T细胞 癌症临床试验，以评估抗CEA-IgTCR的药代动力学 转导的T细胞通过其在血液和组织中的持久性， 遵循其他免疫学和肿瘤学参数， 在CEA+肿瘤患者中的抗肿瘤功效。 校长 假设是单链IgTCR-ζ构建体表达， 外周血T细胞将重定向那些T细胞以裂解CEA+肿瘤 细胞在体外和体内，并将介导回归建立 体内CEA+肿瘤。 治疗将包括收集患者 通过白细胞去除术，通过逆转录病毒修饰T细胞， 介导的嵌合IgTCR基因的插入，并扩增嵌合IgTCR基因。 转导的T细胞现在对CEA肿瘤抗原具有特异性。 然后将这些细胞重新输注回患者体内， 反应受到监控。 平行实验室工作将被指导 创造第二代试剂来改进现有技术 用于T细胞转导和IgTCR修饰的T细胞的选择性扩增 为便利这一模式的实施和扩大，

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.