Development of fully-human anti-CD30 chimeric antigen receptors

全人抗CD30嵌合抗原受体的开发

• 批准号: 10926262
• 负责人: James Kochenderfer
• 金额: $ 15.61万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10926262
• 关键词: Antigens; CAR T cell therapy; CD28 gene; Cell Culture Techniques; Chimeric Proteins; Clinical; Clinical Protocols; Clinical Trials; Development; Generations; Goals; Hodgkin Disease; Human; Immune response; In Vitro; Ki-1 Large-Cell Lymphoma; Large-Cell Lymphomas; Lentivirus Vector; Lymphoma; Manuscripts; Methods; Modeling; Mus; Patients; Phase I Clinical Trials; Proteins; Reporting; Risk; Series; T-Cell Activation; T-Lymphocyte; TNFRSF8 gene; Testing; Toxic effect; Transmembrane Domain; Work; chimeric antigen receptor; chimeric antigen receptor T cells; design; human tissue; improved; large cell Diffuse non-Hodgkin' s lymphoma; novel therapeutics; pre-clinical; receptor; response; tumor

We designed 4 different single chain Fv molecules as antigen-recognition domains for anti-CD30 CARs and compared CARs with these different scFvs in vitro. We selected the optimal scFv, and tested it in different CAR designs in vitro and in mouse tumor models. We have identified an optimal scFv and CAR design for further development. This work led to 2 CARs that are both highly effective in mice. We have selected one of these CARs for a phase I clinical trial. Simultaneous work has been completed that has led to generation of a clinical-grade lentiviral vector encoding this CAR. We completed work on a clinical protocol for a clinical trial of the fully-human anti-CD30 CAR. We have completed preclinical work to improve anti-CD30 CAR design and T-cell culture methods with an emphasis on comparing different hinge and transmembrane domains as well as comparing CD28 versus 4-1BB costimulatory domains . A clinical trial of T cells expressing an anti-CD30 CAR has opened, and we have treated 21 patients on this trial. Unfortunately, the longest objective duration of response in these patients has been only 3 months. We have ended this clinical trial of anti-CD30 CAR T cells due to toxicity plus lack of efficacy, and now we are preparing a manuscript to report the results.

我们将4种不同的单链FV分子设计为抗CD30汽车的抗原识别域，并在体外将汽车与这些不同的SCFV进行了比较。我们选择了最佳SCFV，并在体外和小鼠肿瘤模型中对其进行了测试。我们已经确定了最佳的SCFV和汽车设计，以进一步开发。这项工作导致了2辆在小鼠中都非常有效的汽车。我们已经在I期临床试验中选择了其中一辆汽车。同时完成的工作已经完成，这导致了编码这辆车的临床级慢病毒载体的产生。我们完成了针对全人​​类抗CD30汽车的临床试验的临床方案的工作。我们已经完成了临床前工作，以改善抗CD30汽车设计和T细胞培养方法，重点是比较不同的铰链和跨膜结构域，并比较CD28与4-1BB的cotimultoveration域。表达抗CD30汽车的T细胞的临床试验已经打开，我们在该试验中对21例患者进行了治疗。不幸的是，这些患者最长的客观反应持续时间仅为3个月。由于毒性加上缺乏疗效，我们已经结束了抗CD30 CAR T细胞的临床试验，现在我们正在准备手稿以报告结果。