靶向EBV相关胞内抗原的新型TCR mimic abTCR-T的设计及其活性机制研究

Epstein Barr病毒相关T/NK细胞淋巴增殖性疾病（EBV-T/NK-LPD）多数预后差，治疗手段有限。这类疾病多数表达EBV潜伏感染期抗原，主要形式为胞内抗原或多次跨膜蛋白，难以被传统抗体或CAR-T细胞靶向杀伤。我们拟设计靶向EBV胞内靶点的新型工程化免疫细胞-TCR mimic abTCR-T，利用可识别MHC递呈多肽的TCR mimic抗体作为靶向抗体，通过细胞系实验、动物实验及原代细胞实验明确该abTCR-T的活性作用，同时探索相同抗体来源的抗原识别区构成的abTCR-T及CAR-T的作用差异及分子机制。本研究拟开发靶向胞内靶点的创新TCR mimic abTCR-T细胞模型，研究其作用机制，完成本研究不仅为EBV-T/NK-LPD的治疗提供新思路，同时探索更适用于胞内靶点的细胞模型，有利于拓展细胞疗法在其他病毒相关肿瘤及实体瘤中的应用，提供更广阔的靶点和细胞模型选择性。

Majority of the Epstein Barr virus associated T/NK cell lymphoproliferative disorders (EBV-T/NK-LPD) have poor prognosis, and the current treatments are extremely limited. In most cases, EBV-T/NK-LPD only express latent antigens of EBV, which are in the form of either intracellular or transmembrane proteins, thus difficult to be targeted by traditional antibodies or CAR-T cells. We intend to develope a TCR mimic abTCR-T cell model targeting intracellular antigens of EBV, by using TCR mimic antibodies that recognize MHC-presented peptides. We aim to confirm its anti-tumor effect through ex vivo and in vivo assays, and to explore the differences in activities and molecular mechanisms between abTCR-T and CAR-T cells. This project provides not only new sights of treating EBV-T/NK-LPD, but also broader possibilities of selecting targets and cell models for other virus-related malignancies and solid tumors.