CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
重度细胞因子释放综合征与 CD19 CAR-T 细胞治疗后血液学毒性相关
英文原题：Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T-cell therapy.
查看英文原题
Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T-cell therapy.
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中文摘要
CD19靶向嵌合抗原受体（CAR）T细胞疗法在复发/难治性B细胞恶性肿瘤患者中已显示出显著疗效；然而，它与包括细胞因子释放综合征（CRS）、神经毒性以及造血恢复受损在内的毒性相关。后者与需要延长生长因子或输血支持的高级别血细胞减少相关，可能导致感染或出血等额外并发症。迄今为止，与血液学毒性独立相关的因素尚未得到充分表征。为弥补这一不足，我们回顾性分析了173例在1/2期临床试验（https://ClinicalTrials.gov；NCT01865617）中接受既定组成CD19 CAR-T 细胞疗法的患者，主要终点为CAR-T 细胞输注后第28天的中性粒细胞绝对计数和血小板计数。
我们观察到输注后28天中性粒细胞和血小板恢复的累积发生率分别为81%和75%。在相当一部分患者中观察到血液学毒性，末次随访时持续性中性粒细胞减少为9%，血小板减少为14%。使用去偏最小绝对收缩和选择算子回归分析进行高维建模，并考虑患者、疾病和治疗相关变量，我们确定CRS严重程度增加是血小板计数降低的独立预测因素，而淋巴细胞清除前血小板计数较低是CD19 CAR-T 细胞输注后中性粒细胞和血小板计数均降低的独立预测因素。
此外，纳入CRS相关细胞因子的多变量模型发现，较高的白细胞介素-6峰值血清浓度与较低的d28细胞计数相关；相反，较高的转化生长因子-β1血清浓度与较高的细胞计数相关。
我们的研究结果表明，患者筛选和改善CRS管理可能会改善CD19 CAR-T 细胞治疗后的造血恢复。
展开英文摘要原文
CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in patients with relapsed/refractory B-cell malignancies; however, it is associated with toxicities including cytokine release syndrome (CRS), neurotoxicity, and impaired hematopoietic recovery. The latter is associated with high-grade cytopenias requiring extended growth factor or transfusional support, potentially leading to additional complications such as infection or hemorrhage.
To date, the factors independently associated with hematologic toxicity have not been well characterized. To address this deficit, we retrospectively analyzed 173 patients who received defined-composition CD19 CAR T-cell therapy in a phase 1/2 clinical trial (https://clinicaltrials. gov; NCT01865617), with primary end points of absolute neutrophil count and platelet count at day-28 after CAR T-cell infusion.
We observed cumulative incidences of neutrophil and platelet recovery of 81% and 75%, respectively, at 28 days after infusion. Hematologic toxicity was noted in a significant subset of patients, with persistent neutropenia in 9% and thrombocytopenia in 14% at last follow-up.
Using debiased least absolute shrinkage selector and operator regression analysis for high-dimensional modeling and considering patient-, disease-, and treatment-related variables, we identified increased CRS severity as an independent predictor for decreased platelet count and lower prelymphodepletion platelet count as an independent predictor of both decreased neutrophil and platelet counts after CD19 CAR T-cell infusion.
Furthermore, multivariable models including CRS-related cytokines identified associations between higher peak serum concentrations of interleukin-6 and lower day-28 cell counts; in contrast, higher serum concentrations of transforming growth factor- 1 were associated with higher counts.
Our findings suggest that patient selection and improved CRS management may improve hematopoietic recovery after CD19 CAR T-cell therapy.
论文信息
- 作者
- Juluri KR、Wu QV、Voutsinas J、Hou J、Hirayama AV、Mullane E、Miles N、Maloney DG
- 单位
- Clinical Research Division and.
- 文献类型
- 美国 NIH 资助研究
- 期刊
- Blood advances2022 Apr 12
- 原文标识
- PubMed 34666344 · DOI 10.1182/bloodadvances.2020004142
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