Engineering von ROR1-spezifischen CD8+ T-Zellen zur adoptiven Immuntherapie bei chronischer lymphatischer Leukämie

使用基于抗体和T细胞的疗法治疗癌症是有吸引力的，因为免疫系统具有区分正常细胞和病变细胞的独特潜力。靶向CD 20的单克隆抗体现在常规用于治疗B细胞恶性肿瘤，并且表达嵌合抗原受体（CAR）的遗传修饰的T细胞的过继转移正在临床试验中进行测试，所述嵌合抗原受体（CAR）具有胞外结构域，所述胞外结构域由对与T细胞CD 3 ζ链和/或共刺激结构域连接的细胞表面分子具有特异性的抗体的单链可变片段组成。用免疫疗法靶向B细胞肿瘤上的谱系特异性分子的缺点是正常B细胞也被消除。孤儿酪氨酸激酶受体ROR 1通过B细胞慢性淋巴细胞白血病（B-CLL）的表达谱被鉴定为高表达基因，并且也在套细胞淋巴瘤和B细胞急性淋巴细胞白血病的子集上表达，但不在任何正常成人细胞中表达。ROR 1在原代B-CLL的细胞表面均匀表达，我们已经开发了一种CAR，当在T细胞中表达时，该CAR赋予原代B-CLL的特异性识别。在这个项目中，我们将开发针对肿瘤细胞识别和T细胞信号传导进行优化的ROR 1-汽车，并在临床前模型中评估ROR 1特异性过继性T细胞治疗的安全性。

The use of antibody and T-cell based therapies for the treatment of cancer is attractive because of the unique potential of the immune system to distinguish normal from diseased cells. Monoclonal antibodies targeting CD20 are now routinely used to treat B-cell malignancies and the adoptive transfer of genetically modified T-cells that express a chimeric antigen receptor (CAR) with an exodomain comprised of a single chain variable fragment of an antibody specific for a cell surface molecule linked to the T-cell CD3 zeta chain and/or co-stimulatory domains is being tested in clinical trials. A disadvantage of targeting lineage-specific molecules on B-cell tumors with immunotherapy is that normal B-cells are also eliminated. The orphan tyrosine kinase receptor ROR1 was identified as a highly expressed gene by expression profiling of Bcell chronic lymphocytic leukemia (B-CLL) and is also expressed on mantle cell lymphoma and a subset of B-cell acute lymphoblastic leukemias, but not in any normal adult cells. ROR1 is uniformly expressed at the cell surface on primary B-CLL, and we have developed a CAR that confers specific recognition of primary B-CLL when expressed in T-cells. In this project, we will develop ROR1-CARs that are optimized for tumor cell recognition and T-cell signaling, and evaluate the safety of ROR1-specific adoptive T-cell therapy in a pre-clinical model.