肿瘤细胞治疗研究
英文原题：Case Report: Unedited allogeneic chimeric antigen receptor T cell bridging to conditioning-free hematopoietic stem cell transplantation for a child with refractory Burkitt lymphoma.
未经编辑的 HLA 配型相合异体 CAR-T 细胞疗法可能是复发/难治性 BL 患儿的一种创新、有效且安全的治疗选择，且未出现明显急性 GVHD。
目的：伯基特淋巴瘤（BL）是儿童最常见的非霍奇金淋巴瘤（NHL），约占病例的40%。不同短疗程联合化疗虽取得良好疗效，但复发或难治性BL预后差，治愈率低于30%。近年来，CAR-T 细胞疗法快速发展，并在急性淋巴细胞白血病中取得优异疗效。然而，部分病例因T细胞功能障碍无法制备自体CAR-T细胞，此时需考虑异基因CAR-T治疗。方法：一名17岁II期BL男孩对多轮强化化疗及序贯自体CAR-T治疗均无应答。研究采用携带抗CD20-BB-（20CAR）和抗CD22-BB-（22CAR）转基因的慢病毒载体，改造一名HLA相合同非亲缘供者的T细胞。采用流式细胞术分析细胞因子，并通过qPCR以每微克DNA拷贝数计量外周血CAR-T细胞持续情况。患者及法定监护人均签署自体/异基因CAR-T治疗知情同意书。结果：患者接受环磷酰胺和氟达拉滨淋巴细胞清除化疗后，输注未经基因编辑的HLA匹配异基因CD20和CD22 CAR-T细胞。患者发生4级细胞因子释放综合征（CRS），经包括托珠单抗在内的抗炎治疗后达到完全缓解。由于持续性全血细胞减少且供者嵌合率达100%，CAR-T治疗后第55天成功接受同一供者来源、无需预处理的外周血干细胞移植。第+11天中性粒细胞植入，第+47天血小板恢复，未出现明显急性移植物抗宿主病（GVHD），但皮肤和眼部出现轻度慢性GVHD。目前仍在接受抗排斥治疗。结论：未经基因编辑的HLA匹配异基因CAR-T治疗可为难治或复发BL患儿提供一种创新、有效且安全的方案，且未见明显急性GVHD。异基因CAR-T后供者T细胞完全嵌合者可行同一供者的无预处理异基因造血干细胞移植；但移植后仍须密切监测GVHD。
PURPOSE: Burkitt lymphoma (BL) is the most common tumor of non-Hodgkin's lymphoma (NHL) in children, accounting for about 40% of cases. Although different combined short-course chemotherapies have achieved a good effect, refractory/relapsed BL has a poor prognosis with cure rates less than 30%. Chimeric antigen receptor T cell (CAR-T) therapy has developed rapidly in recent years and achieved excellent results in acute lymphoblastic leukemia (ALL). However, in some cases, there is a failure to produce autologous CAR-T cells because of T-cell dysfunction. In such cases, allogeneic CAR-T therapy has to be considered. METHODS: A 17-year-old boy with stage II BL did not respond to extensive chemotherapy and sequential autologous CAR-T therapy. Lentiviral vectors containing anti-CD20-BB- (20CAR) and anti-CD22-BB- (22CAR) transgenes were used to modify the T cells from an HLA-identical matched unrelated donor. Flow cytometry was used to assess the cytokine analyses and CAR-T cell persistence in peripheral blood, enumerated by qPCR as copies per ug DNA. Informed consent for autologous/allogeneic CAR-T therapy was obtained from the patient and his legal guardian. RESULTS: Unedited HLA-matched allogeneic CD20 and CD22 CAR-T cells were infused after lymphodepletion chemotherapy with cyclophosphamide and fludarabine. The patient experienced Grade IV cytokine release syndrome (CRS) and went into complete remission (CR) after anti-inflammatory treatment including tocilizumab. Because of persistent pancytopenia and full donor chimerism, the same donor's conditioning-free peripheral blood stem cells were successfully transplanted 55 days post CAR-T. Neutrophils were engrafted at day +11 and platelets were rebuilt at day +47 without obvious acute graft-versus-host disease (GVHD), but there was mild chronic GVHD in the skin and eyes. Currently, active anti-rejection therapy is still underway. CONCLUSION: Unedited HLA-matched allogeneic CAR-T cell therapy could be an innovative, effective, and safe treatment for children with refractory/relapse BL without obvious acute GVHD. Conditioning-free allogeneic hematopoietic stem cell transplantation (HSCT) from the same donor is feasible for a patient with full donor T-cell chimerism after allogeneic CAR-T. It cannot be ignored that close GVHD monitoring is needed post HSCT.
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