Department of Hematology/Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Pediatric Intensive Care Unit, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Immunol. 2023 Sep 6;14:1219872. doi: 10.3389/fimmu.2023.1219872. eCollection 2023.
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.
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-ζ (20CAR) and anti-CD22-BB-ζ (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.
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.
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.
伯基特淋巴瘤（BL）是非霍奇金淋巴瘤（NHL）中最常见的肿瘤，约占病例的 40%。尽管不同的联合短程化疗取得了良好的效果，但难治/复发的 BL 预后较差，治愈率低于 30%。嵌合抗原受体 T 细胞（CAR-T）疗法近年来发展迅速，在急性淋巴细胞白血病（ALL）中取得了优异的效果。然而，在某些情况下，由于 T 细胞功能障碍，无法产生自体 CAR-T 细胞。在这种情况下，必须考虑同种异体 CAR-T 治疗。
一名 17 岁男孩患有 II 期 BL，对广泛化疗和序贯自体 CAR-T 治疗无反应。使用含有抗 CD20-BB-ζ（20CAR）和抗 CD22-BB-ζ（22CAR）转基因的慢病毒载体修饰来自 HLA 匹配的无关供体的 T 细胞。通过流式细胞术评估细胞因子分析和外周血中的 CAR-T 细胞持久性，通过 qPCR 作为每 ug DNA 的拷贝数进行计数。已从患者及其法定监护人处获得自体/同种异体 CAR-T 治疗的知情同意。
在环磷酰胺和氟达拉滨的淋巴细胞耗竭化疗后输注未经编辑的 HLA 匹配同种异体 CD20 和 CD22 CAR-T 细胞。该患者出现 IV 级细胞因子释放综合征（CRS），并在包括托珠单抗在内的抗炎治疗后完全缓解（CR）。由于持续全血细胞减少和完全供者嵌合，在 CAR-T 后 55 天成功移植了同一供体的无预处理外周血造血干细胞。中性粒细胞在第+11 天植入，血小板在第+47 天重建，无明显急性移植物抗宿主病（GVHD），但皮肤和眼睛有轻度慢性 GVHD。目前，仍在进行积极的抗排斥治疗。
未经编辑的 HLA 匹配同种异体 CAR-T 细胞疗法可为难治/复发 BL 患儿提供一种创新、有效且安全的治疗方法，且无明显急性 GVHD。对于同种异体 CAR-T 后完全供者 T 细胞嵌合的患者，来自同一供体的无预处理同种异体造血干细胞移植（HSCT）是可行的。不能忽视的是，HSCT 后需要密切监测 GVHD。
