Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers.,Molecular Therapy

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Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers.
Molecular Therapy ( IF 12.1 ) Pub Date : 2019-07-30 , DOI: 10.1016/j.ymthe.2019.07.015
Andrew R Haas ₁ , Janos L Tanyi ₂ , Mark H O'Hara ₃ , Whitney L Gladney ₄ , Simon F Lacey ₅ , Drew A Torigian ₆ , Michael C Soulen ₆ , Lifeng Tian ₅ , Maureen McGarvey ₇ , Anne Marie Nelson ₇ , Caitlin S Farabaugh ₂ , Edmund Moon ₁ , Bruce L Levine ₅ , J Joseph Melenhorst ₅ , Gabriela Plesa ₄ , Carl H June ₅ , Steven M Albelda ₁ , Gregory L Beatty ₃

Affiliation

Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA.
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.

This phase I study investigated the safety and activity of lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin (CART-meso) 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 × 107 or 1-3 × 108 CART-meso cells/m2 with or without 1.5 g/m2 cyclophosphamide. Lentiviral-transduced CART-meso cells were well tolerated; one dose-limiting toxicity (grade 4, sepsis) occurred at 1-3 × 107/m2 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 anti-chimeric 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.

中文翻译：

慢病毒转导的嵌合抗原受体修饰 T 细胞在晚期实体癌中识别间皮素的 I 期研究。

该 I 期研究调查了针对间皮素 (CART-meso) 的慢病毒转导的嵌合抗原受体 (CAR) 修饰的自体 T 细胞在恶性胸膜间皮瘤、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（每个适应症 n = 5）接受单次 CART-meso 细胞输注治疗。CART-meso 细胞是通过慢病毒转导设计的，其结构由源自小鼠单克隆抗体 SS1 的抗间皮素单链可变片段与 4-1BB 和 CD3zeta 的细胞内信号域融合而成。患者接受 1-3 × 107 或 1-3 × 108 CART-meso 细胞/m2，有或没有 1.5 g/m2 环磷酰胺。慢病毒转导的 CART-meso 细胞耐受性良好；一种剂量限制性毒性（4 级，败血症）发生在 1-3 × 107/m2 CART-meso 且无环磷酰胺时。最好的总体反应是病情稳定（11/15 名患者）。CART-meso 细胞在血液中扩增并在第 6-14 天达到峰值水平，但短暂存在。环磷酰胺预处理增强了 CART-meso 扩张，但没有改善超过 28 天的持久性。在 7/10 的肿瘤活检中检测到 CART-meso DNA。在 8/14 名患者的血液中检测到人抗嵌合抗体 (HACA)。CART-meso 细胞耐受性良好，在所有患者的血液中都能扩增，但临床活性有限。评估全人抗间皮素 CAR 的研究正在进行中。CART-meso 细胞在血液中扩增并在第 6-14 天达到峰值水平，但短暂存在。环磷酰胺预处理增强了 CART-meso 扩张，但没有改善超过 28 天的持久性。在 7/10 的肿瘤活检中检测到 CART-meso DNA。在 8/14 名患者的血液中检测到人抗嵌合抗体 (HACA)。CART-meso 细胞耐受性良好，在所有患者的血液中都能扩增，但临床活性有限。评估全人抗间皮素 CAR 的研究正在进行中。CART-meso 细胞在血液中扩增并在第 6-14 天达到峰值水平，但短暂存在。环磷酰胺预处理增强了 CART-meso 扩张，但没有改善超过 28 天的持久性。在 7/10 的肿瘤活检中检测到 CART-meso DNA。在 8/14 名患者的血液中检测到人抗嵌合抗体 (HACA)。CART-meso 细胞耐受性良好，在所有患者的血液中都能扩增，但临床活性有限。评估全人抗间皮素 CAR 的研究正在进行中。CART-meso 细胞耐受性良好，在所有患者的血液中都能扩增，但临床活性有限。评估全人抗间皮素 CAR 的研究正在进行中。CART-meso 细胞耐受性良好，在所有患者的血液中都能扩增，但临床活性有限。评估全人抗间皮素 CAR 的研究正在进行中。

更新日期：2019-07-30

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