Safe and potent anti-CD19 CAR T-cells with shRNA-IL-6 gene silencing element in patients with refractory or relapsed B-cell acute lymphoblastic leukemia

IF 7.6 2区 医学 Q1 HEMATOLOGY HemaSphere Pub Date : 2024-10-07 DOI:10.1002/hem3.70007
Jin-Feng Ma, Jia-Wei Yan, Mei-Jing Liu, Chun-Long Yan, Xiao-Wen Tang, Hui-Ying Qiu, Miao Miao, Yue Han, Li-Min Li, Li-Qing Kang, Nan Xu, Zhou Yu, Jing-Wen Tan, Hong-Jia Zhu, Xu Jia, Zhi-Zhi Zhang, Miao Wang, Hai-Ping Dai, Lei Yu, Sheng-Li Xue, De-Pei Wu, Wen-Jie Gong
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Abstract

Severe cytokine release syndrome (sCRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) have limited the widespread use of chimeric antigen receptor T (CAR T)-cell therapy. We designed a novel anti-CD19 CAR (ssCART-19) with a small hairpin RNA (shRNA) element to silence the interleukin-6 (IL-6) gene, hypothesizing it could reduce sCRS and ICANS by alleviating monocyte activation and proinflammatory cytokine release. In a post hoc analysis of two clinical trials, we compared ssCART-19 with common CAR T-cells (cCART-19) in relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Among 87 patients, 47 received ssCART-19 and 40 received cCART-19. Grade ≥3 CRS occurred in 14.89% (7/47) of the ssCART-19 group versus 37.5% (15/40) in the cCART-19 group (p = 0.036). ICANS occurred in 4.26% (2/47) of the ssCART-19 group (all grade 1) compared to 15% (2/40) of the cCART-19 group. Patients in the ssCART-19 group showed comparable rates of treatment response (calculated with rates of complete remission and incomplete hematological recovery) were 91.49% (43/47) for ssCART-19 and 85% (34/40) for cCART-19 (p = 0.999). With a median follow-up of 21.9 months, cumulative nonrelapse mortality was 10.4% for ssCART-19 and 13.6% for cCART-19 (p = 0.33). Median overall survival was 37.17 months for ssCART-19 and 32.93 months for cCART-19 (p = 0.40). Median progression-free survival was 24.17 months for ssCART-19 and 9.33 months for cCART-19 (p = 0.23). These data support the safety and efficacy of ssCART-19 for r/r B-ALL, suggesting its potential as a promising therapy.

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带有 shRNA-IL-6 基因沉默元件的安全有效的抗 CD19 CAR T 细胞用于难治或复发 B 细胞急性淋巴细胞白血病患者。
严重细胞因子释放综合征(sCRS)和免疫效应细胞相关神经毒性综合征(ICANS)限制了嵌合抗原受体T(CAR T)细胞疗法的广泛应用。我们设计了一种新型抗 CD19 CAR(ssCART-19),它带有小发夹 RNA(shRNA)元件以沉默白细胞介素-6(IL-6)基因,并假设它可以通过减轻单核细胞活化和促炎细胞因子释放来减轻 sCRS 和 ICANS。在对两项临床试验进行的事后分析中,我们对复发/难治性 B 细胞急性淋巴细胞白血病(r/r B-ALL)的 ssCART-19 和普通 CAR T 细胞(cCART-19)进行了比较。在87名患者中,47人接受了ssCART-19治疗,40人接受了cCART-19治疗。ssCART-19组有14.89%(7/47)发生≥3级CRS,而cCART-19组为37.5%(15/40)(p = 0.036)。ssCART-19组有4.26%(2/47)的患者发生ICANS(均为1级),而cCART-19组为15%(2/40)。ssCART-19组患者的治疗反应率(以完全缓解率和不完全血液学恢复率计算)相当,ssCART-19组为91.49%(43/47),cCART-19组为85%(34/40)(P = 0.999)。中位随访时间为 21.9 个月,ssCART-19 的累积非复发死亡率为 10.4%,cCART-19 为 13.6%(p = 0.33)。ssCART-19的中位总生存期为37.17个月,cCART-19为32.93个月(p = 0.40)。ssCART-19 的中位无进展生存期为 24.17 个月,cCART-19 为 9.33 个月(p = 0.23)。这些数据支持ssCART-19治疗r/r B-ALL的安全性和有效性,表明它有可能成为一种前景广阔的疗法。
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来源期刊
HemaSphere
HemaSphere Medicine-Hematology
CiteScore
6.10
自引率
4.50%
发文量
2776
审稿时长
7 weeks
期刊介绍: HemaSphere, as a publication, is dedicated to disseminating the outcomes of profoundly pertinent basic, translational, and clinical research endeavors within the field of hematology. The journal actively seeks robust studies that unveil novel discoveries with significant ramifications for hematology. In addition to original research, HemaSphere features review articles and guideline articles that furnish lucid synopses and discussions of emerging developments, along with recommendations for patient care. Positioned as the foremost resource in hematology, HemaSphere augments its offerings with specialized sections like HemaTopics and HemaPolicy. These segments engender insightful dialogues covering a spectrum of hematology-related topics, including digestible summaries of pivotal articles, updates on new therapies, deliberations on European policy matters, and other noteworthy news items within the field. Steering the course of HemaSphere are Editor in Chief Jan Cools and Deputy Editor in Chief Claire Harrison, alongside the guidance of an esteemed Editorial Board comprising international luminaries in both research and clinical realms, each representing diverse areas of hematologic expertise.
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