PDF(Pubmed)
Abstract：
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.
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.
摘要：
■伯基特淋巴瘤（BL）是儿童非霍奇金淋巴瘤（NHL）中最常见的肿瘤，约占40%的病例。虽然不同的联合短程化疗取得了良好的效果，难治性/复发性BL预后不良，治愈率低于30％。嵌合抗原受体T细胞(CAR-T)治疗急性淋巴细胞白血病(ALL)近年来发展迅速,取得了良好的疗效。然而,在某些情况下,由于T细胞功能异常，不能产生自体CAR-T细胞。在这种情况下,必须考虑同种异体CAR-T疗法。
一名17岁的II期BL男孩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来修饰来自HLA相同匹配的无关供体的T细胞。流式细胞术用于评估细胞因子分析和外周血中CAR-T细胞的持久性，通过qPCR枚举为每ugDNA的拷贝。从患者及其法定监护人获得自体/同种异体CAR-T疗法的知情同意书。
■在用环磷酰胺和氟达拉滨进行淋巴吸收化疗后，输注HLA匹配的同种异体CD20和CD22CAR-T细胞。患者经历了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进入完全缓解（CR）。由于持续的全血细胞减少症和完全供体嵌合体，在CAR-T后55天成功移植了同一供体的无调理外周血干细胞。中性粒细胞在+11天移植，血小板在+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,积极的抗排斥治疗仍在进行中。
■未完成的HLA匹配的同种异体CAR-T细胞疗法可能是一种创新，有效,对无明显急性GVHD的难治/复发BL患儿的安全治疗。来自同一供体的无条件异基因造血干细胞移植（HSCT）对于同种异体CAR-T后具有完全供体T细胞嵌合的患者是可行的。不能忽视的是，HSCT后需要密切的GVHD监测。
一名17岁的II期BL男孩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来修饰来自HLA相同匹配的无关供体的T细胞。流式细胞术用于评估细胞因子分析和外周血中CAR-T细胞的持久性，通过qPCR枚举为每ugDNA的拷贝。从患者及其法定监护人获得自体/同种异体CAR-T疗法的知情同意书。
■在用环磷酰胺和氟达拉滨进行淋巴吸收化疗后，输注HLA匹配的同种异体CD20和CD22CAR-T细胞。患者经历了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进入完全缓解（CR）。由于持续的全血细胞减少症和完全供体嵌合体，在CAR-T后55天成功移植了同一供体的无调理外周血干细胞。中性粒细胞在+11天移植，血小板在+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,积极的抗排斥治疗仍在进行中。
■未完成的HLA匹配的同种异体CAR-T细胞疗法可能是一种创新，有效,对无明显急性GVHD的难治/复发BL患儿的安全治疗。来自同一供体的无条件异基因造血干细胞移植（HSCT）对于同种异体CAR-T后具有完全供体T细胞嵌合的患者是可行的。不能忽视的是，HSCT后需要密切的GVHD监测。
