Adapting 5MCAR technology for the treatment of peripheral T cell lymphoma

项目总结 CD4T细胞利用5模块分子对MHCII分子(PMHCII)提呈的多肽抗原作出反应 由一个受体模块[T细胞受体(TCR)]，三个信号模块(CD3，CD3， CD3)和辅受体模块(CD4)。根据这一蓝图，我们设计了一种仿生5模组。 嵌合抗原受体(5MCAR)系统由嵌合受体模块组成，由pMHCII和pMHCII构建 TCR组件(CRMpMHCII)，与CD3信令模块组装并与代理组件一起工作 辅受体(SCOR)对特定的TCR产生信号。正如我们最近报道的(小林等人 ，PNAS 2020)，5MCAR-CTL可以特异性地靶向并杀伤表达TCRs的致病CD4T细胞 绑定CRMpMHCII。鉴于外周T细胞淋巴瘤(PTCL)是一种独特的致病T细胞 细胞的治疗选择是有限的，患者预后很差，我们有动力问我们的5MCAR 这项技术可以发展成针对患者的PTCL疗法。因为PTCL通常源自 转化的cd4T细胞，并表达代表肿瘤特异性抗原的克隆型tcr。 认为它们是5MCAR-CTL的理想靶点。因此，当前研究的目标是建立一个 我们的5MCAR技术用于筛选CRMpMHCII库中的模拟表位CRMpMHCII 响应PTCL的克隆型TCR的信号，然后使用识别的模拟表位CRMpMHCII来 通过其克隆型TCR产生针对PTCL的5MCAR-CTL。完成后，已建立的 工作流程将为将我们的5MCAR技术应用于个性化治疗提供蓝图 PTCL患者。

PROJECT SUMMARY CD4+ T cells respond to peptide antigens presented by MHCII molecules (pMHCII) using a 5-module molecular machines composed of a receptor module [the T cell receptor (TCR)], three signaling modules (CD3, CD3, CD3), and a coreceptor module (CD4). Drawing upon this blueprint, we designed a biomimetic 5-module chimeric antigen receptor (5MCAR) system composed of a chimeric receptor module, built with pMHCII and TCR components (CRMpMHCII), that assembles with the CD3 signaling modules and works with a surrogate coreceptor (ScoR) to generate signals in response to specific TCRs. As we recently reported (Kobayashi, et al., PNAS 2020), 5MCAR-CTLs can specifically target and kill pathogenic CD4+ T cells that express TCRs that bind the CRMpMHCII. Given that peripheral T cell lymphomas (PTCLs) represent a unique type of pathogenic T cell for which treatment options are limited, and patient prognosis is poor, we are motivated to ask if our 5MCAR technology can be developed into a patient-specific PTCL therapy. As PTCLs are often derived from transformed CD4+ T cells and express a clonotypic TCR that represents a tumor-specific antigen, we consider them to be ideal targets for 5MCAR-CTLs. Accordingly, the goal of the current study is to establish a workflow whereby our 5MCAR technology is used to screen libraries of CRMpMHCII for mimotope CRMpMHCII that signal in response to the clonotypic TCR of a PTCL, and then use the identified mimotope CRMpMHCII to generate 5MCAR-CTLs for targeting the PTCL via its clonotypic TCR. When completed, the established workflow will provide a blueprint for adapting our 5MCAR technology into a personalized therapy to treat patients with PTCLs.