<br>表达诱导型 IL-7 和 CCL19 的抗 CD19 CAR T 细胞在复发或难治性大 B 细胞淋巴瘤患者中的安全性和可行性,Cell Discovery

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表达诱导型 IL-7 和 CCL19 的抗 CD19 CAR T 细胞在复发或难治性大 B 细胞淋巴瘤患者中的安全性和可行性
Cell Discovery ( IF 13.0 ) Pub Date : 2024-01-09 , DOI: 10.1038/s41421-023-00625-0
Wen Lei _{1,

2} , Ai Zhao _{3,

4} , Hui Liu _{1,

2} , Chunmei Yang ₂ , Cheng Wei ₃ , Shanshan Guo ₁ , Zhilu Chen ₅ , Qunyi Guo ₆ , Linjie Li ₇ , Mingzhe Zhao ₈ , Gongqiang Wu ₉ , Guifang Ouyang ₁₀ , Ming Liu ₁₁ , Jinyi Zhang ₁₁ , Jimin Gao _{3,

12} , Wenbin Qian _{1,

2}

Affiliation

Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Geriatrics, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang, China.
Department of Hematology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China.
Department of Hematology, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China.
Department of Hematology, Lishui Municipal Central Hospital, Lishui, Zhejiang, China.
Department of Hematology, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, China.
Department of Hematology, Dongyang People's Hospital, Wenzhou Medical University, Dongyang, Zhejiang, China.
Ningbo Clinical Research Center for Hematological Tumor Diseases, Department of hematology, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China.
Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Hangzhou Qilan Biomedical Technology Co., Ltd, Hangzhou, Zhejiang, China.

尽管 CD19 特异性嵌合抗原受体 (CAR) T 细胞可以治愈复发或难治性大 B 细胞淋巴瘤 (R/R LBCL) 患者，但肿瘤抗原阳性的疾病复发仍然是一个挑战。表达细胞因子/趋化因子的 CAR-T 细胞可以克服抑制环境，但这种 CAR-T 疗法的临床安全性和有效性仍不清楚。在此，我们报告了 CD19 特异性 CAR-T 细胞的临床前开发，该细胞能够在 CD19 接合后表达白细胞介素 (IL)-7 和趋化因子（CC 基序）配体 (CCL)-19（称为 7 × 19 CAR-T 细胞）以及针对 R/R LBCL 患者进行 7 × 19 CAR-T 细胞疗法的 1 期和扩展期试验的结果 (NCT03258047)。在剂量递增阶段，没有观察到剂量限制性毒性。 39 名 R/R LBCL 患者接受了 7 × 19 CAR-T，剂量范围为每公斤体重 0.5 × 10 ⁶ –4.0 × 10 ^{6 个}细胞。 5 名患者（12.8%）发生 3 级细胞因子释放综合征，4 名患者（10.3%）发生 ≥ 3 级神经毒性。单次输注后 3 个月的总体缓解率为 79.5%（完全缓解，56.4%；部分缓解，23.1%）。中位随访时间为 32 个月，中位无进展生存期为 13 个月，中位总生存期尚未达到，两年时估计率为 53.8%（95% CI，40.3% 至 72.0%）。总之，来自多中心临床研究的这些长期随访数据表明，7 × 19 CAR-T 细胞可以诱导持久反应，中位总生存期超过 2 年，并且在 R/ 患者中具有可控的安全性。 R LBCL。

"点击查看英文标题和摘要"

Safety and feasibility of anti-CD19 CAR T cells expressing inducible IL-7 and CCL19 in patients with relapsed or refractory large B-cell lymphoma

Although CD19-specific chimeric antigen receptor (CAR) T cells are curative for patients with relapsed or refractory large B-cell lymphoma (R/R LBCL), disease relapse with tumor antigen-positive remains a challenge. Cytokine/chemokine-expressing CAR-T cells could overcome a suppressive milieu, but the clinical safety and efficacy of this CAR-T therapy remain unclear. Here we report the preclinical development of CD19-specific CAR-T cells capable of expressing interleukin (IL)-7 and chemokine (C-C motif) ligand (CCL)-19 upon CD19 engagement (referred to as 7 × 19 CAR-T cells) and results from a phase 1 and expansion phase trial of 7 × 19 CAR-T cell therapy in patients with R/R LBCL (NCT03258047). In dose-escalation phase, there were no dose-limiting toxicities observed. 39 patients with R/R LBCL received 7 × 19 CAR-T with doses ranged from 0.5 × 10⁶–4.0 × 10⁶ cells per kg body weight. Grade 3 cytokine release syndrome occurred in 5 (12.8%) patients and ≥ grade 3 neurotoxicity in 4 (10.3%) patients. The overall response rate at 3 months post-single infusion was 79.5% (complete remission, 56.4%; partial response, 23.1%). With a median follow-up of 32 months, the median progression-free survival was 13 months, and median overall survival was not reached, with an estimated rate of 53.8% (95% CI, 40.3% to 72.0%) at two years. Together, these long-term follow-up data from the multicenter clinical study suggest that 7 × 19 CAR-T cells can induce durable responses with a median overall survival of greater than 2 years, and have a manageable safety profile in patients with R/R LBCL.

更新日期：2024-01-09

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