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嵌合抗原受体修饰 T 细胞对中国复发/难治性急性淋巴细胞白血病患者 CD19 的强大抗白血病活性。

Potent Anti-leukemia Activities of Chimeric Antigen Receptor-Modified T Cells against CD19 in Chinese Patients with Relapsed/Refractory Acute Lymphocytic Leukemia.

机构信息

Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Innovative Cellular Therapeutics Co., Ltd (formerly SiDanSai Biotechnology Co., Ltd), Shanghai, China.

出版信息

Clin Cancer Res. 2017 Jul 1;23(13):3297-3306. doi: 10.1158/1078-0432.CCR-16-1799. Epub 2016 Dec 30.


DOI:10.1158/1078-0432.CCR-16-1799
PMID:28039267
Abstract

Patients with relapsed/refractory acute lymphocytic leukemia (R/R ALL) have a poor prognosis. Chimeric antigen receptor-modified T cells against CD19 (CART19) have displayed anti-leukemia activities. However, data from systemic trials in Chinese patients are limited. T cells transduced with CD19-directed CAR lentiviral vectors were infused in patients with R/R ALL under fludarabine- and cyclophosphamide-based lymphodepletion. The postinfusion responses, toxicities, expansion, and persistence of CART19s in enrolled patients were observed and monitored. We enrolled 15 patients with R/R ALL. The median transduction efficiency of CART19s was 33%. cytotoxicity assays were conducted and showed prominent antileukemia activities with CART19s. The patients received CART19s infusion at doses of 1.1 × 10/kg to 9.8 × 10/kg. Twelve patients achieved complete remission 1 month after CART19s infusion. CART19s expanded and persisted in peripheral blood and bone marrow. At 150 days, the overall survival rate and leukemia-free survival rate were 65.5% and 37.8%, respectively. The cumulative incidence of relapse and the nonrelapse mortality rate were 54.5% and 7.7%, respectively. Four patients underwent subsequent haploidentical hematopoietic stem cell transplantation. In this trial, 10 patients experienced cytokine release syndrome (CRS). Grade 3 CRS developed in 40% of patients and was associated with a higher disease burden on day -1 and a higher number of previous relapses. This trial demonstrated potent antileukemia activities of CART19s in Chinese patients with R/R ALL. Disease relapse remained the main obstacle. However, patients with a high risk of relapse after CART19s might benefit from subsequent haploidentical hematopoietic stem cell transplantation. .

摘要

复发/难治性急性淋巴细胞白血病(R/R ALL)患者的预后较差。嵌合抗原受体修饰的针对 CD19(CART19)的 T 细胞显示出抗白血病活性。然而,来自中国患者的系统试验数据有限。在氟达拉滨和环磷酰胺为基础的淋巴耗竭下,将靶向 CD19 的 CAR 慢病毒载体转导的 T 细胞输注到 R/R ALL 患者中。观察和监测入组患者的输注后反应、毒性、CART19 的扩增和持续存在。我们入组了 15 例 R/R ALL 患者。CART19 的中位转导效率为 33%。进行了细胞毒性测定,结果显示 CART19 具有明显的抗白血病活性。患者接受了 1.1×10/kg 至 9.8×10/kg 的 CART19 输注剂量。12 例患者在 CART19 输注后 1 个月达到完全缓解。CART19 在外周血和骨髓中扩增和持续存在。在 150 天时,总生存率和无白血病生存率分别为 65.5%和 37.8%。复发累积发生率和非复发死亡率分别为 54.5%和 7.7%。4 例患者随后进行了半相合造血干细胞移植。在这项试验中,10 例患者发生细胞因子释放综合征(CRS)。40%的患者出现 3 级 CRS,与 -1 天疾病负担较高和既往复发次数较多相关。这项试验表明,CART19 在我国 R/R ALL 患者中具有强大的抗白血病活性。疾病复发仍然是主要障碍。然而,CART19 后复发风险较高的患者可能受益于随后的半相合造血干细胞移植。

相似文献

[1]
Potent Anti-leukemia Activities of Chimeric Antigen Receptor-Modified T Cells against CD19 in Chinese Patients with Relapsed/Refractory Acute Lymphocytic Leukemia.

Clin Cancer Res. 2016-12-30

[2]
CD19 targeted CAR-T therapy versus chemotherapy in re-induction treatment of refractory/relapsed acute lymphoblastic leukemia: results of a case-controlled study.

Ann Hematol. 2018-5

[3]
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

[4]
Potent anti-leukemia activities of humanized CD19-targeted Chimeric antigen receptor T (CAR-T) cells in patients with relapsed/refractory acute lymphoblastic leukemia.

Am J Hematol. 2018-4-28

[5]
Durable Responses and Low Toxicity After Fast Off-Rate CD19 Chimeric Antigen Receptor-T Therapy in Adults With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia.

J Clin Oncol. 2021-10-20

[6]
CD4CD25CD127 regulatory T cells associated with the effect of CD19 CAR-T therapy for relapsed/refractory B-cell acute lymphoblastic leukemia.

Int Immunopharmacol. 2021-7

[7]
Chimeric antigen receptor T cells for sustained remissions in leukemia.

N Engl J Med. 2014-10-16

[8]
Co-infusion of haplo-identical CD19-chimeric antigen receptor T cells and stem cells achieved full donor engraftment in refractory acute lymphoblastic leukemia.

J Hematol Oncol. 2016-11-25

[9]
Donor-derived CD19-targeted T cell infusion induces minimal residual disease-negative remission in relapsed B-cell acute lymphoblastic leukaemia with no response to donor lymphocyte infusions after haploidentical haematopoietic stem cell transplantation.

Br J Haematol. 2017-11

[10]
Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia.

Am J Hematol. 2018-9-26

引用本文的文献

[1]
Prominent efficacy and good safety of sequential CD19 and CD22 CAR-T therapy in relapsed/refractory adult B-cell acute lymphoblastic leukemia.

Exp Hematol Oncol. 2025-1-3

[2]
Advancement and Challenges in Monitoring of CAR-T Cell Therapy: A Comprehensive Review of Parameters and Markers in Hematological Malignancies.

Cancers (Basel). 2024-9-29

[3]
Identification of early predictive biomarkers for severe cytokine release syndrome in pediatric patients with chimeric antigen receptor T-cell therapy.

Front Immunol. 2024

[4]
Prediction of First-in-Human Dose of Chimeric Antigen Receptor-T (CAR-T) Cells from Mice.

Eur J Drug Metab Pharmacokinet. 2024-11

[5]
Comparing the Differences in Adverse Events among Chimeric Antigen Receptor T-Cell Therapies: A Real-World Pharmacovigilance Study.

Pharmaceuticals (Basel). 2024-8-5

[6]
CD19 CAR T cells for B cell malignancies: a systematic review and meta-analysis focused on clinical impacts of CAR structural domains, manufacturing conditions, cellular product, doses, patient's age, and tumor types.

BMC Cancer. 2024-8-22

[7]
CD19 chimeric antigen receptor-T cells as bridging therapy to allogeneic hematopoietic cell transplantation improves outcome in patients with refractory/relapsed B-cell acute lymphoblastic leukemia.

Heliyon. 2024-7-1

[8]
PrCRS: a prediction model of severe CRS in CAR-T therapy based on transfer learning.

BMC Bioinformatics. 2024-5-20

[9]
Inhibition of CD38 enzymatic activity enhances CAR-T cell immune-therapeutic efficacy by repressing glycolytic metabolism.

Cell Rep Med. 2024-2-20

[10]
Prediction of severe CRS and determination of biomarkers in B cell-acute lymphoblastic leukemia treated with CAR-T cells.

Front Immunol. 2023

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