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异体来源、供者来源、第二代、针对 CD19 的嵌合抗原受体 T 细胞用于治疗儿科复发/难治性 B 细胞前体急性淋巴细胞白血病。

Allogeneic, donor-derived, second-generation, CD19-directed CAR-T cells for the treatment of pediatric relapsed/refractory BCP-ALL.

机构信息

Department of Hematology/Oncology, Cell and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Bambino Gesù Children's Hospital, Rome, Italy.

Miltenyi Biomedicine, Bergisch Gladbach, Germany.

出版信息

Blood. 2023 Jul 13;142(2):146-157. doi: 10.1182/blood.2023020023.


DOI:10.1182/blood.2023020023
PMID:37172203
Abstract

Autologous CD19-directed chimeric antigen receptor (CAR)-T cells have shown unprecedented efficacy in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, patients either relapsing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or displaying profound lymphopenia and/or rapidly progressing disease often cannot access autologous products. These hurdles may be overcome by allogeneic, donor-derived CAR-T cells. We tested donor-derived T cells transduced with a second-generation (4.1BB) CD19-directed CAR for treatment of patients with BCP-ALL in a hospital-exemption setting. Two constructs were tested: a retroviral construct incorporating the suicide gene inducible caspase-9 (CD19-CAR-Retro_ALLO) first and then a lentiviral construct and an automated, Prodigy-based manufacturing process (CD19-CAR-Lenti_ALLO). Thirteen children/young adults received ALLO-CAR-T cells between March 2021 and October 2022. Doses ranged between 1.0 × 106 and 3.0 × 106 CAR-T cells per kg. The toxicity profile was comparable with that of autologous CAR-T cells, characterized mainly by cytopenia, cytokine release syndrome (maximum grade 1), and grade 2 immune-effector cell-associated neurotoxicity syndrome. One case of acute graft-versus-host disease (GVHD) occurred and was rapidly controlled with steroids and ruxolitinib. None of the other patients, including 3 given ALLO-CAR-T cells from an HLA-haploidentical donor, experienced GVHD. Two patients received ALLO-CAR-T cells before HSCT and showed a significant expansion of CAR-T cells without any sign of GVHD. All patients obtained complete remission (CR) with absence of minimal residual disease in the bone marrow. With a median follow-up of 12 months (range, 5-21), 8 of 13 patients maintained CR. Allogeneic anti-CD19 CAR-T cells can effectively treat highly refractory BCP-ALL relapsing after allo-HSCT without showing increased toxicity as compared with autologous CAR-T cells.

摘要

自体 CD19 导向嵌合抗原受体 (CAR)-T 细胞在复发/难治性 B 细胞前体急性淋巴细胞白血病 (BCP-ALL) 儿童中显示出前所未有的疗效。然而,接受异基因造血干细胞移植 (allo-HSCT) 后复发或表现出严重淋巴细胞减少症和/或疾病迅速进展的患者通常无法获得自体产品。这些障碍可以通过同种异体、供体来源的 CAR-T 细胞来克服。我们在豁免医院的环境下,测试了用第二代 (4.1BB) CD19 导向 CAR 转导的供体 T 细胞治疗 BCP-ALL 患者。测试了两种构建体:一种是包含自杀基因诱导型半胱天冬酶 9 的逆转录病毒构建体(CD19-CAR-Retro_ALLO),然后是一种慢病毒构建体和一种自动化、基于 Prodigy 的制造工艺(CD19-CAR-Lenti_ALLO)。2021 年 3 月至 2022 年 10 月期间,13 名儿童/年轻成年人接受了 ALLO-CAR-T 细胞治疗。剂量范围为每公斤 1.0×106 至 3.0×106 CAR-T 细胞。毒性谱与自体 CAR-T 细胞相似,主要表现为细胞减少症、细胞因子释放综合征(最高 1 级)和 2 级免疫效应细胞相关神经毒性综合征。发生 1 例急性移植物抗宿主病 (GVHD),用类固醇和鲁索利替尼迅速控制。包括 3 名接受 HLA 单倍体不相合供体 ALLO-CAR-T 细胞的患者在内,没有其他患者发生 GVHD。2 名患者在 HSCT 前接受了 ALLO-CAR-T 细胞治疗,CAR-T 细胞显著扩增,没有任何 GVHD 的迹象。所有患者均获得完全缓解 (CR),骨髓中无微小残留病。中位随访时间为 12 个月(范围为 5-21 个月),13 例患者中有 8 例维持 CR。与自体 CAR-T 细胞相比,同种异体抗 CD19 CAR-T 细胞可有效治疗 allo-HSCT 后复发的高度难治性 BCP-ALL,且毒性没有增加。

相似文献

[1]
Allogeneic, donor-derived, second-generation, CD19-directed CAR-T cells for the treatment of pediatric relapsed/refractory BCP-ALL.

Blood. 2023-7-13

[2]
Integrating CAR T-Cell Therapy and Transplantation: Comparisons of Safety and Long-Term Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation After CAR T-Cell or Chemotherapy-Based Complete Remission in B-Cell Acute Lymphoblastic Leukemia.

Front Immunol. 2021

[3]
[Allogeneic donor-derived CD19 CAR-T therapy of relapsed B-cell acute lmphoblastic leukemia after allogeneic hematopoietic stem cell transplantation].

Zhonghua Xue Ye Xue Za Zhi. 2021-5-14

[4]
[Maintenance therapy following CD19 CAR-T treatment for relapsed B-cell acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation].

Zhonghua Xue Ye Xue Za Zhi. 2020-6-14

[5]
Donor-derived CD19 CAR-T Cells versus Chemotherapy Plus Donor Lymphocyte Infusion for Treatment of Recurrent CD19-positive B-ALL After Allogeneic Hematopoietic Stem Cell Transplantation.

Curr Med Sci. 2023-8

[6]
Humanized Anti-CD19 CAR-T Cell Therapy and Sequential Allogeneic Hematopoietic Stem Cell Transplantation Achieved Long-Term Survival in Refractory and Relapsed B Lymphocytic Leukemia: A Retrospective Study of CAR-T Cell Therapy.

Front Immunol. 2021

[7]
Donor-derived stem cell infusion for sustained pancytopenia after CD19 CAR-T therapy for relapsed patients post allogeneic stem cell transplantation.

Eur J Haematol. 2024-1

[8]
Donor-derived CAR-T Cells Serve as a Reduced-intensity Conditioning Regimen for Haploidentical Stem Cell Transplantation in Treatment of Relapsed/Refractory Acute Lymphoblastic Leukemia: Case Report and Review of the Literature.

J Immunother. 2018

[9]
Allogeneic Donor-Derived Anti-CD19 CAR T Cell Is a Promising Therapy for Relapsed/Refractory B-ALL After Allogeneic Hematopoietic Stem-Cell Transplantation.

Clin Lymphoma Myeloma Leuk. 2020-9

[10]
Humanized CD19 CAR-T cells in relapsed/refractory B-ALL patients who relapsed after or failed murine CD19 CAR-T therapy.

BMC Cancer. 2022-4-12

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[2]
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[3]
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Front Immunol. 2025-6-19

[4]
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[6]
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[7]
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Bone Marrow Transplant. 2025-4-9

[8]
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[9]
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[10]
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