The B-cell tumor-associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor
The B-cell tumor-associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor
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DOI：
10.1182/blood-2010-05-283309
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发表时间：
2010-11-25
期刊：
影响因子：
20.3
通讯作者：
Riddell, Stanley R.
中科院分区：
文献类型：
--
作者：
Hudecek, Michael;Schmitt, Thomas M.;Riddell, Stanley R.
经修饰以表达对B细胞谱系表面分子（例如CD 20）具有特异性的嵌合抗原受体的单克隆抗体和T细胞在B细胞恶性肿瘤中发挥抗肿瘤活性，但消耗正常B细胞。受体酪氨酸激酶样孤儿受体1（ROR 1）被鉴定为在B细胞慢性淋巴细胞白血病（B-CLL）中高表达的基因，而不是正常B细胞，这表明它可能作为肿瘤特异性治疗靶点。我们分析了ROR 1在正常的非造血和造血细胞，包括B细胞前体，和造血恶性肿瘤的表达。ROR 1具有癌胚基因的特征，在未分化的胚胎干细胞、B-CLL和套细胞淋巴瘤中表达，但除了在脂肪组织和B细胞发育的早期低水平外，在主要成人组织中不表达。我们构建了ROR 1特异性嵌合抗原受体，当其在来自健康供体或CLL患者的T细胞中表达时，赋予对原发性B-CLL和套细胞淋巴瘤的特异性识别，包括涉及维持恶性肿瘤的罕见药物流出化疗抗性肿瘤细胞，但不成熟的正常B细胞。靶向ROR 1的T细胞疗法可能对B-CLL和其他ROR 1阳性肿瘤有效。然而，ROR 1在一些正常组织上的表达表明对正常细胞亚群的潜在毒性。（血。2010; 116（22）：4532-4541）
Monoclonal antibodies and T cells modified to express chimeric antigen receptors specific for B-cell lineage surface molecules such as CD20 exert antitumor activity in B-cell malignancies, but deplete normal B cells. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) was identified as a highly expressed gene in B-cell chronic lymphocytic leukemia (B-CLL), but not normal B cells, suggesting it may serve as a tumor-specific target for therapy. We analyzed ROR1-expression in normal nonhematopoietic and hematopoietic cells including B-cell precursors, and in hematopoietic malignancies. ROR1 has characteristics of an oncofetal gene and is expressed in undifferentiated embryonic stem cells, B-CLL and mantle cell lymphoma, but not in major adult tissues apart from low levels in adipose tissue and at an early stage of B-cell development. We constructed a ROR1-specific chimeric antigen receptor that when expressed in T cells from healthy donors or CLL patients conferred specific recognition of primary B-CLL and mantle cell lymphoma, including rare drug effluxing chemotherapy resistant tumor cells that have been implicated in maintaining the malignancy, but not mature normal B cells. T-cell therapies targeting ROR1 may be effective in B-CLL and other ROR1-positive tumors. However, the expression of ROR1 on some normal tissues suggests the potential for toxicity to subsets of normal cells. (Blood. 2010; 116(22): 4532-4541)