特定间皮素嵌合抗原受体mRNA工程修饰的T细胞能诱导抗肿瘤...

nhdr123

Mesothelin-Specific Chimeric Antigen Receptor

mRNA-Engineered T Cells Induce Antitumor Activity

in Solid Malignancies

特定间皮素嵌合抗原受体mRNA工程修饰的T细胞在实体恶性肿瘤中能诱导抗肿瘤活性

abstract:

Off-targettoxicity due to the expression of target antigens in normal tissue represents amajor obstacle to the use of chimeric antigen receptor (CAR)-engineered T cellsfor treatment of solid malignancies. To circumvent this issue, we established aclinical platform for engineering T cells with transient CAR expression byusing in vitro transcribed mRNA encoding a CAR that includes both the CD3-z and4-1BB costimulatory domains. We present two case reports fromongoing trialsindicating that adoptive transfer ofmRNA CAR T cells that targetmesothelin(CARTmeso cells) is feasible and safe without overt evidence of off-tumoron-target toxicity against normal tissues. CARTmeso cells persisted transientlywithin the peripheral blood after intravenous administration and

migrated toprimary andmetastatic tumor sites. Clinical and laboratory evidence ofantitumor activitywas shown in both patients, and the CARTmeso cells elicitedan antitumor immune response revealed by the development of novel antiselfantibodies. These data show the potential of using mRNA-engineered T cells toevaluate, in a controlled manner, potential off-tumor on-target toxicities andshow that short-lived CAR T cells can induce epitope spreading andmediateantitumor activity in patients with advanced cancer. Thus, these findingssupport the development ofmRNA CAR-based strategies for carcinoma and othersolid tumors.

摘要：

无靶毒性的出现是由于靶抗原在正常组织中的表达，这导致了使用嵌合抗原受体（CAR）修饰的 T细胞来治疗实体恶性肿瘤产生了一个大障碍。为了规避这个问题，我们建立了临床平台用于T细胞的瞬时表达CAR，采用体外转录的mRNA编码CAR，包括CD3-Z和4-1BB共刺激域。我们正在进行的两个试验表明过继转移的mRNA CAR T细胞的间皮素没有明显的证据表明其对正常组织是可行安全的。 CARTmeso细胞持续瞬时静脉内给药后内外周血和迁移到原发性和转移性肿瘤部位。抗肿瘤活性的临床和实验室证据表明在这两个患者中，CARTmeso细胞引发的新颖antiself抗体的开发显示出抗肿瘤免疫应答反应。这些数据表明CAR T细胞在晚期癌症患者中可诱导表位扩展和介导的抗肿瘤活性。因此，这些发现支持了癌基因以CAR为基础的战略和其他实体瘤的发展