Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers
Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers
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DOI：
10.1016/j.ymthe.2019.07.015
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发表时间：
2019-11-06
影响因子：
12.4
通讯作者：
Beatty, Gregory L.
中科院分区：
文献类型：
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作者：
Haas, Andrew R.;Tanyi, Janos L.;Beatty, Gregory L.
这项I期研究调查了慢病毒转导的嵌合抗原受体（CAR）修饰的针对间皮素重定向的自体T细胞（CARTmeso）在恶性胸膜间皮瘤、卵巢癌和胰腺导管腺癌患者中的安全性和活性。15名化疗难治性癌症患者（每种适应症n = 5）接受单次CART-meso细胞输注治疗。CART-meso细胞通过慢病毒转导用构建体进行工程化，所述构建体由来源于小鼠单克隆抗体SS 1的抗间皮素单链可变片段与4-1BB和CD 3 ζ的胞内信号传导结构域融合组成。患者接受1-3 x 10（7）或1-3 x 10（8）CART-meso细胞/m2，伴或不伴1.5 g/m2环磷酰胺。慢病毒转导的CART-meso细胞耐受性良好;在不使用环磷酰胺的情况下，在1-3 x 10（7）/m（2）CART-meso时发生了一次剂量限制性毒性（4级，脓毒症）。最佳总体缓解为疾病稳定（11/15例患者）。CART-meso细胞在血液中扩增，并在第6-14天达到峰值水平，但持续短暂。环磷酰胺预处理增强了CART-meso扩增，但在28天后没有改善持久性。CART-meso DNA在7/10的肿瘤活检中被检测到。8/14例患者的血液中检测到人抗嵌合抗体（HACA）。CART-meso细胞在所有患者的血液中耐受良好并扩增，但显示出有限的临床活性。评估完全人抗间皮素CAR的研究正在进行中。
This phase I study investigated the safety and activity of lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin (CARTmeso) in patients with malignant pleural mesothelioma, ovarian carcinoma, and pancreatic ductal adenocarcinoma. Fifteen patients with chemotherapy-refractory cancer (n = 5 per indication) were treated with a single CART-meso cell infusion. CART-meso cells were engineered by lentiviral transduction with a construct composed of the anti-mesothelin single-chain variable fragment derived from the mouse monoclonal antibody SS1 fused to intracellular signaling domains of 4-1BB and CD3zeta. Patients received 1-3 x 10(7) or 1-3 x 10(8) CART-meso cells/m(2) with or without 1.5 g/m(2) cyclophosphamide. Lentiviral-transduced CART-meso cells were well tolerated; one dose-limiting toxicity (grade 4, sepsis) occurred at 1-3 x 10(7)/m(2) CART-meso without cyclophosphamide. The best overall response was stable disease (11/15 patients). CART-meso cells expanded in the blood and reached peak levels by days 6-14 but persisted transiently. Cyclophosphamide pre-treatment enhanced CART-meso expansion but did not improve persistence beyond 28 days. CART-meso DNA was detected in 7/10 tumor biopsies. Human antichimeric antibodies (HACA) were detected in the blood of 8/14 patients. CART-meso cells were well tolerated and expanded in the blood of all patients but showed limited clinical activity. Studies evaluating a fully human anti-mesothelin CAR are ongoing.