TCR-T细胞治疗异基因造血干细胞移植后EB病毒感染相关疾病的研究

With the rapid progress of haploidentical hematopoietic stem cell transplantation and organ transplantation, the number of patients benefited from transplantation is increasing. With the uses of ATG and other immunosuppressive agents, Epstein–Barr virus infection become one of fatal complications after allogeneic hematopoietic stem cell transplantation and need new treatments. . In the previous studies,we found that EBV-specific CTL treatment for patients with poor effect of rituximab existed the problems of timeliness and virus escape.TCR engineered T cells (TCR-T) are expected to be the better method for EBV-associated infections and/or diseases.We used antigen expressed after EBV infection in the body after transplantation as the primary antigen. And we established series of key technique, such as in vitro induction of EBV-specific T cells with HLA-restricted and non-restricted,TCR gene eukaryotic expression vectors and transduced T cells as antigen-specific TCR-T cells.. On this basis,we intend to get HLA molecules of more than 75% of our population,and EB virus-specific T cells with dominant and non-dominant epitopes. In this way, we enable patients to be treated with enough T cells with EB virus identification and killing ability in the short term, which can be effective in the treatment of post-transplant EB virus infection-related diseases. It is important for reducing transplant-related mortality.

EB病毒(EBV)感染是异基因造血干细胞移植和多器官联合移植后常见并且致命性并发症之一，疗效亟待进一步提高。 . 本研究组前期发现，EBV特异性杀伤性T淋巴细胞（EBV-CTL）为代表的免疫细胞治疗美罗华无效患者存在时效性和病毒逃逸问题，而TCR基因修饰的T细胞（TCR-T）有望成为治愈移植后EB病毒感染相关疾病的有效方法，我们以在移植后EBV感染机体表达的潜伏抗原为主要识别抗原，建立了HLA分子限制性和非限制性体外诱导EBV特异性T细胞、TCR基因真核细胞表达载体、转导T细胞成为抗原特异性TCR-T细胞等关键技术，并证实了EBV特异性T细胞的杀伤活性。. 在此基础上，拟获得可以覆盖我国75%以上人群HLA分子、同时针对优势表位和非优势表位的EBV特异性TCR-T细胞，使患者在短期内迅速获得足量的具有EBV识别和杀伤能力的T细胞，有效治疗移植后EBV感染相关疾病。

EB病毒(EBV)感染是异基因造血干细胞移植和多器官联合移植后常见并且致命性并发症之一，疗效亟待进一步提高。本研究组前期发现，EBV特异性杀伤性T淋巴细胞（EBV-CTL）为代表的免疫细胞治疗美罗华无效患者存在时效性和病毒逃逸问题，而TCR基因修饰的T细胞（TCR-T）有望成为治愈移植后EB病毒感染相关疾病的有效方法，我们以在移植后EBV感染机体表达的潜伏抗原为主要识别抗原，建立了单细胞测序筛选TCR特异性基因，TCR基因合成并转导T细胞成为TCR-T细胞等关键技术，并证实了TCR-T细胞的体外杀伤活性。目前已获得可以覆盖我国75%以上人群HLA分子、同时针对优势表位和非优势表位的EBV特异性TCR-T细胞。本研究下一步将进行一项TCR-T细胞治疗移植后EBV感染相关疾病的临床试验，以验证其体内活性。