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: 9556663
• 负责人: James Kochenderfer
• 金额: $ 9.45万
• 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/9556663
• 关键词: Antigens; CD28 gene; Cell Culture Techniques; Cell Therapy; Chimeric Proteins; Clinical; Clinical Protocols; Clinical Trials; Development; Dose; Generations; Goals; Hodgkin Disease; Human; Immune response; In Vitro; Institutional Review Boards; Ki-1 Large-Cell Lymphoma; Lead; Lentivirus Vector; Lymphoma; Methods; Modeling; Mus; Partial Remission; Patients; Phase I Clinical Trials; Proteins; Protocols documentation; Risk; Series; T-Cell Activation; T-Lymphocyte; TNFRSF8 gene; Testing; Toxic effect; Transmembrane Domain; Work; chimeric antigen receptor; design; human tissue; improved; large cell Diffuse non-Hodgkin' s lymphoma; novel therapeutics; pre-clinical; receptor; tumor

We have 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 have completed work on a clinical protocol for a clinical trial of the fully-human anti-CD30 CAR, and this protocol has been approved by the NCI Institutional Review Board. We continue 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 the first 2 treated patients have obtained partial remissions with mild toxicity. We will continue to accrue patients to this dose-escalation phase I clinical trial.

我们已经将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。我们已经完成了针对全人​​类抗CD30汽车的临床试验的临床方案的工作，该方案已获得NCI机构审查委员会的批准。我们继续进行临床前的工作，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域，并比较CD28与4-1BB的COTALIMULATION域。表达抗CD30汽车的T细胞的临床试验已经打开，并且前2例接受治疗的患者已经获得了轻度毒性的部分缓解。我们将继续吸引患者参加该剂量升级的I期临床试验。