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

项目摘要 CD 4 + T细胞使用5-模块分子免疫应答MHCII分子（pMHCII）呈递的肽抗原。 由受体模块[T细胞受体（TCR）]，三个信号传导模块（CD 3受体，CD 3受体， CD 3受体）和辅助受体模块（CD 4）。根据这个蓝图，我们设计了一个仿生5模块， 嵌合抗原受体（5 MCAR）系统，由嵌合受体模块组成，用pMHCII构建， TCR组件（CRMpMHCII），与CD 3信号传导模块组装并与替代物一起工作 在一些实施方案中，TCR是辅助受体（ScoR），以响应于特定TCR产生信号。正如我们最近报道的（小林等 例如，PNAS 2020），5 MCAR-CTL可以特异性靶向并杀死表达TCR的致病性CD 4 + T细胞， 结合CRMpMHCII。鉴于外周T细胞淋巴瘤（PTCL）是一种独特的致病性T细胞淋巴瘤， 对于治疗选择有限且患者预后不良的细胞，我们有动机询问我们的5 MCAR是否 该技术可以发展成患者特异性PTCL疗法。由于PTCL通常源自 转化的CD 4 + T淋巴细胞并表达代表肿瘤特异性抗原的克隆型TCR，我们 认为它们是5 MCAR-CTL的理想靶标。因此，本研究的目标是建立一个 我们的5 MCAR技术用于筛选CRMpMHCII文库的模拟表位CRMpMHCII的工作流程， 响应于PTCL的克隆型TCR发出信号，然后使用鉴定的模拟表位CRMpMHCII， 产生用于通过其克隆型TCR靶向PTCL的5 MCAR-CTL。一旦完成， 工作流程将提供一个蓝图，使我们的5 MCAR技术适应个性化治疗， 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.