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

使用抗体和基于T细胞的疗法来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疾病细胞的独特潜力。针对CD20的单抗现在被常规用于治疗B细胞恶性肿瘤，过继转移表达嵌合抗原受体(CAR)的转基因T细胞正在进行临床试验，该T细胞表达嵌合抗原受体(CAR)，其外区由针对T细胞CD3 Zeta链和/或共刺激结构域的细胞表面分子的单链可变片段组成。用免疫疗法靶向B细胞肿瘤的谱系特异性分子的一个缺点是，正常的B细胞也会被消除。孤儿酪氨酸激酶受体ROR1是B细胞慢性淋巴细胞白血病(B-CLL)的高表达基因，在套细胞淋巴瘤和B细胞急性淋巴细胞白血病中也有表达，但在正常成人细胞中不表达。ROR1在原代B-CLL的细胞表面统一表达，我们开发了一种CAR，当在T细胞中表达时，可以特异性识别原代B-CLL。在这个项目中，我们将开发针对肿瘤细胞识别和T细胞信号进行优化的ROR1-CARS，并在临床前模型中评估ROR1特异性过继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.