A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti-PD-1 Agent Pembrolizumab.
A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti-PD-1 Agent Pembrolizumab.
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DOI：
10.1158/2159-8290.cd-21-0407
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发表时间：
2021-11
期刊：
影响因子：
28.2
通讯作者：
Sadelain M
中科院分区：
文献类型：
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作者：
Adusumilli PS;Zauderer MG;Rivière I;Solomon SB;Rusch VW;O'Cearbhaill RE;Zhu A;Cheema W;Chintala NK;Halton E;Pineda J;Perez-Johnston R;Tan KS;Daly B;Araujo Filho JA;Ngai D;McGee E;Vincent A;Diamonte C;Sauter JL;Modi S;Sikder D;Senechal B;Wang X;Travis WD;Gönen M;Rudin CM;Brentjens RJ;Jones DR;Sadelain M
恶性胸膜疾病，包括转移性肺癌和乳腺癌以及恶性胸膜间皮瘤（MPM），是具有较差治疗反应的侵袭性实体瘤。我们开发并进行了一项首次在人体内进行的区域递送的自体间皮素靶向嵌合抗原受体（CAR）T细胞疗法的I期研究。在27名患者（25名患有MPM）中胸膜内施用0.3M-60M CAR T细胞/kg是安全的并且耐受性良好。39%的患者在外周血中检测到CAR T细胞> 100天。在我们证明PD-1阻断增强小鼠中CAR T细胞功能后，18名MPM患者也安全地接受了pembrolizumab。在这些患者中，CAR T细胞输注的中位总生存期为23.9个月（1年总生存期，83%）。8例患者病情稳定持续≥ 6个月; 2例患者在PET扫描中显示完全代谢缓解。应在实体瘤患者中进一步评估CAR T细胞和PD-1阻断剂的联合免疫治疗。
Malignant pleural diseases, comprising metastatic lung and breast cancers and malignant pleural mesothelioma (MPM), are aggressive solid tumors with poor therapeutic response. We developed and conducted a first-in-human, phase I study of regionally delivered, autologous, mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy. Intrapleural administration of 0.3M-60M CAR T cells/kg in 27 patients (25 with MPM) was safe and well tolerated. CAR T-cells were detected in peripheral blood for >100 days in 39% of patients. Following our demonstration that PD-1 blockade enhances CAR T-cell function in mice, 18 patients with MPM also received pembrolizumab safely. Among those patients, median overall survival from CAR T-cell infusion was 23.9 months (1-year overall survival, 83%). Stable disease was sustained for ≥6 months in 8 patients; 2 exhibited complete metabolic response on PET scan. Combination immunotherapy with CAR T cells and PD-1 blockade agents should be further evaluated in patients with solid tumors.