肿瘤细胞治疗研究
英文原题：Novel humanized CD19-CAR-T (Now talicabtagene autoleucel, Tali-cel™) cells in relapsed/ refractory pediatric B-acute lymphoblastic leukemia- an open-label single-arm phase-I/Ib study.
Novel humanized CD19-CAR-T (Now talicabtagene autoleucel, Tali-cel™) cells in relapsed/ refractory pediatric B-acute lymphoblastic leukemia- an open-label single-arm phase-I/Ib study.
我们开发了一种新型人源化 CD19 靶向 CAR-T (HCAR19)，已获批开展 1/1b/2 期试验。
CAR-T（CAR-T）细胞疗法可有效治疗复发/难治性B细胞急性淋巴细胞白血病（r/r B-ALL），但尚未普遍可及。本研究开发了一种新型人源化CD19靶向CAR-T细胞（HCAR19），并获准开展1/1b/2期试验。入组患者年龄3–25岁，患r/r B-ALL且不适合异基因干细胞移植。淋巴细胞清除采用标准剂量氟达拉滨和环磷酰胺。采用3+3设计测试3个剂量范围，以确定2期剂量（P2D）：A剂量每千克1×10^6个HCAR19细胞，B剂量每千克3–5×10^6个，C剂量每千克10–15×10^6个。主要终点为第30天骨髓流式细胞术评估的总缓解率（ORR）。2021年5月至2023年9月共纳入12例患者，中位年龄14岁（范围5–24岁），筛查时骨髓原始细胞中位比例19.5%。10例（83%）发生细胞因子释放综合征，主要为1–2级；1例发生2级免疫效应细胞相关神经毒性综合征（ICANS）。所有患者均出现3级血细胞减少。ORR为91.7%（11/12），包括8例（66.7%）完全缓解（CR）和3例（25%）部分缓解。8例CR患者中7例接受B或C剂量，且缓解均持续至12个月随访。剂量低于每千克3×10^6个或未达到CR的患者出现应答早期丢失或快速进展。HCAR19安全性良好，毒性可管理，且可产生持久缓解；确定的P2D为每千克5–10×10^6个HCAR19细胞。试验注册号：CTRI/2021/05/033348和CTRI/2023/03/050689。
Chimeric Antigen Receptor-T (CAR-T) cell therapy is effective for relapsed/refractory B-acute lymphoblastic leukemia (r/r B-ALL) but is not universally available. We developed a novel humanized CD19-directed CAR-T (HCAR19) approved for Phase 1/1b/2 trials. Patients aged 3-25 years were enrolled with r/r B-ALL and ineligible for allogeneic stem cell transplant. Lymphodepletion utilized standard-dose fludarabine and cyclophosphamide. A 3 + 3 design testing 3 dose-ranges was used to determine Phase-2 Dose (P2D): Dose-A, 1 10 6 HCAR19 cells/kg, Dose-B, 3-5 10 6 /kg, and Dose-C, 10-15 10 6 /kg. Primary endpoint was overall response rate (ORR) at day-30 on bone-marrow flow-cytometry. From May-2021 to September-2023 12 patients [median age-14 (range: 5-24) years] were enrolled with median bone marrow blasts 19.5% at screening. Cytokine release syndrome occurred in 10 (83%) patients, predominantly Grades 1-2, and Grade-2 immune-cell associated neurotoxicity (ICANS) in 1. All patients had Grade-3 cytopenia. ORR was 91.7% (11/12), complete response (CR) in 8 (66.7%) and partial response in 3 (25%). Seven of 8 CRs were at Dose-levels B and C, all of which were sustained till 12 months follow-up. Patients who received dose levels below 3 10 6 /kg, or did not achieve CR, had early loss of response or rapid progression. HCAR19 demonstrated safety, manageable toxicity, and durable remissions. and P2D was determined as 5-10 10 6 HCAR19-cells/kg. CLINICAL TRIAL REGISTRATION: The study is registered in the Clinical Trials Registry- India (CTRI/2021/05/033348 and CTRI/2023/03/050689).
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