Treatment-Related Adverse Events of Chimeric Antigen Receptor T-Cell (CAR T) in Clinical Trials: A Systematic Review and Meta-Analysis.
Treatment-Related Adverse Events of Chimeric Antigen Receptor T-Cell (CAR T) in Clinical Trials: A Systematic Review and Meta-Analysis.
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嵌合抗原受体 T 细胞 (CAR T) 在临床试验中的治疗相关不良事件：系统评价和荟萃分析。
DOI：
10.3390/cancers13153912
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发表时间：
2021-08-03
期刊：
影响因子：
5.2
通讯作者：
Qian W
中科院分区：
文献类型：
--
作者：
Lei W;Xie M;Jiang Q;Xu N;Li P;Liang A;Young KH;Qian W
嵌合抗原受体T （CAR-T）细胞成功治疗恶性血液病已经引起了广泛的临床应用和开发新的CAR-T疗法的热情。然而，它也挑战了医生和研究人员认识和处理治疗相关的毒性。我们对84项符合条件的研究共2592例患者进行了系统回顾和meta分析，以确定CRS和神经系统症状（NS）的综合发生率和严重程度，以及各种癌症类型、CAR-T靶点等因素对ae的潜在差异，从而为其未来的应用和研究提供重要意义。嵌合抗原受体T （CAR-T）细胞治疗癌症是一个快速发展的领域。它已被证明对血液系统恶性肿瘤非常有效，FDA的批准大大增加了广泛临床应用和开发新型CAR-T疗法的热情。然而，它也挑战了医生和研究人员认识和处理治疗相关的毒性。从PubMed、de、美国血液学学会和Cochrane图书馆的数据库中系统检索和回顾了84项符合条件的研究，共纳入了2592名患者。采用贝叶斯logistic回归模型进行meta分析和亚组分析，评估细胞因子释放综合征（CRS）和神经系统症状（NS）等治疗相关毒性的发生率，并分析不同靶点和肿瘤类型之间的差异。合并全分级CRS率和≥3级CRS率分别为77%和29%，其中血液恶性肿瘤（全分级：81%，分级≥3级：29%）的发生率明显高于实体肿瘤（全分级：37%，分级≥3级：19%）。来自单项研究的合并估计NS率在所有分级中为40%，在≥3级中为28%。血液学亚组也高于实体瘤组。肿瘤类型亚组分析显示，抗cd19 CAR-T治疗ALL和NHL、抗bcma CAR-T治疗MM和抗cea CAR-T治疗实体瘤≥3级CRS发生率较高，在24-36%之间，而≥3级NS发生率较高的主要是CD19-ALL/NHL（23-37%）和BCMA-MM（12%）。重要的是，抗cd19 CAR-T研究的亚组分析显示，年轻患者（相对于成年患者）、异体T细胞来源（相对于自体来源）、γ逆转录病毒载体和更高剂量的CAR-T细胞与高级别CRS相关。另一方面，接受更高剂量CAR-T治疗的NHL患者（与ALL患者相比）和成年患者（与年轻患者相比）≥3级NS事件的发生率增加。这项研究提供了治疗相关毒性的全面总结，并将指导未来的临床试验和研究CAR - T细胞疗法的治疗设计。
Successful treatment of hematological malignancies with chimeric antigen receptors T (CAR-T) cells has led to much enthusiasm for the wide clinical usage and development of novel CAR-T therapies. However, it also challenges physicians and investigators to recognize and deal with treatment-associated toxicities. We conducted a systematic review and meta-analysis from 84 eligible study and a total of 2592 patients to identify the comprehensive incidences and severity of CRS and neurological symptoms (NS) as well as the potential differences in AEs across a variety of cancer types, CAR-T targets, and other factors, thereby offering a significant implication on its future application and research. Chimeric antigen receptors T (CAR-T) cell therapy of cancer is a rapidly evolving field. It has been shown to be remarkably effective in cases of hematological malignancies, and its approval by the FDA has significantly increased the enthusiasm for wide clinical usage and development of novel CAR-T therapies. However, it has also challenged physicians and investigators to recognize and deal with treatment-associated toxicities. A total of 2592 patients were included from 84 eligible studies that were systematically searched and reviewed from the databases of PubMed, de, the American Society of Hematology and the Cochrane Library. The meta-analysis and subgroup analysis by a Bayesian logistic regression model were used to evaluate the incidences of therapy-related toxicities such as cytokine release syndrome (CRS) and neurological symptoms (NS), and the differences between different targets and cancer types were analyzed. The pooled all-grade CRS rate and grade ≥ 3 CRS rate was 77% and 29%, respectively, with a significantly higher incidence in the hematologic malignancies (all-grade: 81%; grade ≥ 3: 29%) than in solid tumors (all-grade: 37%; grade ≥ 3: 19%). The pooled estimate NS rate from the individual studies were 40% for all-grade and 28% for grade ≥ 3. It was also higher in the hematologic subgroup than in the solid tumors group. The subgroup analysis by cancer type showed that higher incidences of grade ≥ 3 CRS were observed in anti-CD19 CAR-T therapy for ALL and NHL, anti-BCMA CAR-T for MM, and anti-CEA CAR-T for solid tumors, which were between 24–36%, while higher incidences of grade ≥ 3 NS were mainly observed in CD19-ALL/NHL (23–37%) and BCMA-MM (12%). Importantly, subgroup analysis on anti-CD19 CAR-T studies showed that young patients (vs. adult patients), allologous T cell origin (vs. autologous origin), gamma retrovirus vector, and higher doses of CAR-T cells were associated with high-grade CRS. On the other hand, the patients with NHL (vs ALL), administered with higher dose of CAR-T, and adult patients (vs. young patients) had an increased incidence of grade ≥ 3 NS events. This study offers a comprehensive summary of treatment-related toxicity and will guide future clinical trials and therapeutic designs investigating CAR T cell therapy.
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影响因子：
12.4
作者：
Haas, Andrew R.;Tanyi, Janos L.;Beatty, Gregory L.
通讯作者：
Beatty, Gregory L.
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影响因子：
21.1
作者：
Feng K;Liu Y;Guo Y;Qiu J;Wu Z;Dai H;Yang Q;Wang Y;Han W
通讯作者：
Han W
影响因子：
8.8
作者：
Fitzgerald JC;Weiss SL;Maude SL;Barrett DM;Lacey SF;Melenhorst JJ;Shaw P;Berg RA;June CH;Porter DL;Frey NV;Grupp SA;Teachey DT
通讯作者：
Teachey DT
影响因子：
17.1
作者：
Brentjens RJ;Davila ML;Riviere I;Park J;Wang X;Cowell LG;Bartido S;Stefanski J;Taylor C;Olszewska M;Borquez-Ojeda O;Qu J;Wasielewska T;He Q;Bernal Y;Rijo IV;Hedvat C;Kobos R;Curran K;Steinherz P;Jurcic J;Rosenblat T;Maslak P;Frattini M;Sadelain M
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Sadelain M
影响因子：
20.3
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通讯作者：
Jensen, Michael C.