以WT1为靶点的T细胞受体基因治疗可预防移植后急性髓系白血病复发，这一成果由美国弗雷德·哈钦森癌症研究中心Philip D. Greenberg研究团队取得。 该研究于2019年7月发表于国际一流学术期刊《自然—医学》上。

由于移植物T细胞尚未被选为白血病特异性细胞，且常常能识别许多正常宿主组织表达的蛋白，移植物抗白血病效应往往伴随着移植物抗宿主疾病的发病率和死亡率。因此，针对选定的AML抗原的T细胞表达受体(TCRs)可能更有效地降低AML复发风险。研究人员因此从HLA-A2⁺正常供体中分离出高特异性的Wilms肿瘤抗原1特异性TCR(TCRC4)，将分离出的TCRC4插入EpsteinBar病毒特异性供体CD8⁺T细胞(TTCR-C4)，可以使移植物抗宿主病的风险降到最低，并且提高转移T细胞生存。将这些预防性post-HCT细胞注入到12例病人体内。输注后中位44个月无复发生存率为100%，而同期比较组88例相似风险AML患者无复发生存率为54% (P=0.002)。TTCR-C4维持TCRC4表达，并且长期持续，具有多功能性。这一策略对于预防HCT后复发风险增加个体的AML复发似乎很有希望。

据悉，异基因造血细胞移植(HCT)后复发是急性髓系白血病(AML)患者进入HCT后死亡的主要原因，具有低风险特征。当HCT确实能延长无复发生存期时，它通常反映了供体T细胞对白血病细胞抗原反应介导的移植物抗白血病效应。

附：英文原文

Title: T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant

Author: Aude G. Chapuis, Daniel N. Egan, Merav Bar, Thomas M. Schmitt, Megan S. McAfee, Kelly G. Paulson, Valentin Voillet, Raphael Gottardo, Gunnar B. Ragnarsson, Marie Bleakley, Cecilia C. Yeung, Petri Muhlhauser, Hieu N. Nguyen, Lara A. Kropp, Luca Castelli, Felecia Wagener, Daniel Hunter, Marcus Lindberg, Kristen Cohen, Aaron Seese, M. Juliana McElrath, Natalie Duerkopp, Ted A. Gooley, Philip D. Greenberg

Issue&Volume: Volume 25 Issue 7, July 2019

Abstract: Relapse after allogeneic hematopoietic cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) entering HCT with poor-risk features. When HCT does produce prolonged relapse-free survival, it commonly reflects graft-versus-leukemia effects mediated by donor T cells reactive with antigens on leukemic cells. As graft T cells have not been selected for leukemia specificity and frequently recognize proteins expressed by many normal host tissues, graft-versus-leukemia effects are often accompanied by morbidity and mortality from graft-versus-host disease. Thus, AML relapse risk might be more effectively reduced with T cells expressing receptors (TCRs) that target selected AML antigens. We therefore isolated a high-affinity Wilms Tumor Antigen 1-specific TCR (TCRC4) from HLA-A2+ normal donor repertoires, inserted TCRC4 into EpsteinBar virus-specific donor CD8+ T cells (TTCR-C4) to minimize graft-versus-host disease risk and enhance transferred T cell survival, and infused these cells prophylactically post-HCT into 12 patients. Relapse-free survival was 100% at a median of 44months following infusion, while a concurrent comparative group of 88 patients with similar risk AML had 54% relapse-free survival (P=0.002). TTCR-C4 maintained TCRC4 expression, persisted long-term and were polyfunctional. This strategy appears promising for preventing AML recurrence in individuals at increased risk of post-HCT relapse.

DOI: 10.1038/s41591-019-0472-9

Source:https://www.nature.com/articles/s41591-019-0472-9