Purpose: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed in hematopoietic and epithelial cancers but has limited expression on normal adult tissues. This phase 1 study evaluated the safety of targeting ROR1 with autologous T-lymphocytes engineered to express a ROR1 chimeric antigen receptor (CAR). Secondary objectives evaluated persistence, trafficking, and antitumor activity of CAR T cells. Patients & Methods: Twenty-one patients with ROR1+ tumors received CAR T cells at one of four dose levels (DL): 3.3x105/1x106/3.3x106/1x107 cells/kg, administered after lymphodepletion with Cyclophosphamide/Fludarabine (Cy/Flu) or Oxaliplatin/Cyclophosphamide (Ox/Cy). Cohort A included patients with chronic lymphocytic leukemia (CLL, n=3); cohort B included patients with triple-negative breast cancer (TNBC, n=10) or non-small-cell lung cancer (NSCLC, n=8). A second infusion was administered to one patient in cohort A with residual CLL in the marrow and three patients in cohort B with stable disease after first infusion. Results: Treatment was well tolerated apart from one dose limiting toxicity at DL4 in a patient with advanced NSCLC. Two of the three (67%) CLL patients showed robust CAR T expansion and a rapid antitumor response. In patients with NSCLC and TNBC, CAR T cells expanded to variable levels, infiltrated tumor poorly, and one of eighteen patients (5.5%) achieved partial response by RECIST 1.1. Conclusion: ROR1 CAR T cells were well tolerated in most patients. Antitumor activity was observed in CLL but was limited in TNBC and NSCLC. Immunogenicity of the CAR and lack of sustained tumor infiltration were identified as limitations.

中文翻译：

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ROR1 特异性 CAR T 细胞在晚期造血和上皮恶性肿瘤中的 1 期研究


目的：受体酪氨酸激酶样孤儿受体 1 （ROR1） 在造血癌和上皮癌中表达，但在正常成人组织中的表达有限。这项 1 期研究评估了用工程改造为表达 ROR1 嵌合抗原受体 （CAR） 的自体 T 淋巴细胞靶向 ROR1 的安全性。次要目标评估了 CAR T 细胞的持久性、运输和抗肿瘤活性。患者和方法：21名ROR1+肿瘤患者接受了四种剂量水平（DL（3.3x105/1x106/3.3x106/1x107细胞/kg的CAR T细胞，在淋巴细胞清除后用环磷酰胺/氟达拉滨（Cy/Flu）或奥沙利铂/环磷酰胺（Ox/Cy）给药。队列 A 包括慢性淋巴细胞白血病 （CLL， n=3） 患者;队列 B 包括三阴性乳腺癌 （TNBC， n=10） 或非小细胞肺癌 （NSCLC， n=8） 患者。对队列 A 中 1 例骨髓中有残留 CLL 的患者和队列 B 中 3 例首次输注后病情稳定的患者进行第二次输注。结果： 除了 DL4 的剂量限制毒性外，晚期 NSCLC 患者的治疗耐受性良好。3 例 CLL 患者中有 2 例 （67%） 表现出强劲的 CAR T 扩增和快速的抗肿瘤反应。在 NSCLC 和 TNBC 患者中，CAR T 细胞扩增至不同水平，浸润肿瘤较差，18 例患者中有 1 例 （5.5%） 通过 RECIST 1.1 获得部分缓解。结论： 大多数患者对 ROR1 CAR T 细胞的耐受性良好。在 CLL 中观察到抗肿瘤活性，但在 TNBC 和 NSCLC 中受到限制。CAR 的免疫原性和缺乏持续的肿瘤浸润被确定为局限性。