Host metabolome predicts the severity and onset of acute toxicities induced by CAR T-cell therapy.
Host metabolome predicts the severity and onset of acute toxicities induced by CAR T-cell therapy.
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DOI：
10.1182/bloodadvances.2022007456
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发表时间：
2023-09-12
期刊：
影响因子：
7.5
通讯作者：
Gupta, Neetu
中科院分区：
文献类型：
--
作者：
Jalota, Akansha;Hershberger, Courtney E.;Patel, Manishkumar S.;Mian, Agrima;Faruqi, Aiman;Khademi, Gholamreza;Rotroff, Daniel M.;Hill, Brian T.;Gupta, Neetu
较高的治疗前血糖、较低的胆固醇和氨基酸与CRS的较差和较快发病相关。较低的治疗前谷氨酰胺和羟脯氨酸与较差和较快的ICAN发病有关。抗CD19嵌合抗原受体(CAR)T细胞治疗是复发/难治性大B细胞淋巴瘤患者的一种高效治疗选择。然而，临床上显著的急性炎症毒性的发展阻碍了其广泛应用，包括细胞因子释放综合征(CRS)和免疫效应细胞相关神经毒性综合征(ICANS)，这些毒性会导致显著的发病率，需要密切监测。识别预测CRS和ICAN的严重程度和发病时间的宿主生化特征可能有助于患者分层，以实现及时的缓解策略。在这里，我们报告了与Axicabagene cilleucel或组织凝集素治疗诱导的CRS和ICAN相关的预处理宿主代谢物。非靶向代谢组学分析和使用靶向分析的验证都表明，特定的预处理生化实体的丰度与临床上有意义的CRS(Q和lt；.1)和ICAN(Q和lt；25)的风险和/或发病之间存在显著关联。治疗前较高的血糖水平以及较低的胆固醇和谷氨酸水平与CRS的较快发病相关。相反，基础水平较低的氨基酸、脯氨酸和甘氨酸以及次级胆汁酸异去氧胆酸与临床上显著的CRS显著相关。较低浓度的氨基酸羟脯氨酸与较高的ICANs分级和较快的发病时间相关，而较低的谷氨酰胺浓度与较快的ICANs发展呈负相关。总体而言，我们的数据表明，预处理宿主代谢组在确定具有临床意义的CRS和ICAN的风险方面具有生物标志物潜力，并可能在抗CD19 CAR T细胞治疗前患者的风险分层中有用。
Higher pretreatment glucose and lower cholesterol and amino acids correlate with worse and faster onset of CRS. Lower pretreatment glutamine and hydroxyproline correlate with worse and faster onset of ICANS. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a highly effective treatment option for patients with relapsed/refractory large B-cell lymphoma. However, widespread use is deterred by the development of clinically significant acute inflammatory toxicities, including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), that induce significant morbidity and require close monitoring. Identification of host biochemical signatures that predict the severity and time-to-onset of CRS and ICANS may assist patient stratification to enable timely mitigation strategies. Here, we report pretreatment host metabolites that are associated with CRS and ICANS induced by axicabtagene ciloleucel or tisagenlecleucel therapy. Both untargeted metabolomics analysis and validation using targeted assays revealed a significant association between the abundance of specific pretreatment biochemical entities and an increased risk and/or onset of clinically significant CRS (q < .1) and ICANS (q < .25). Higher pretreatment levels of plasma glucose and lower levels of cholesterol and glutamate were associated with a faster onset of CRS. In contrast, low baseline levels of the amino acids proline and glycine and the secondary bile acid isoursodeoxycholate were significantly correlated with clinically significant CRS. Lower concentration of the amino acid hydroxyproline was associated with higher grade and faster onset of ICANS, whereas low glutamine was negatively correlated with faster development of ICANS. Overall, our data indicate that the pretreatment host metabolome has biomarker potential in determining the risk of clinically significant CRS and ICANS, and may be useful in risk stratification of patients before anti-CD19 CAR T-cell therapy.
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影响因子：
4.3
作者：
Mertens KL;Kalsbeek A;Soeters MR;Eggink HM
通讯作者：
Eggink HM
影响因子：
5.6
作者：
Mazzei, Joseph C.;Zhou, Hui;Brayfield, Bradley P.;Hontecillas, Raquel;Bassaganya-Riera, Josep;Schmelz, Eva M.
通讯作者：
Schmelz, Eva M.
影响因子：
6.7
作者：
Kaddurah-Daouk R;Weinshilboum R;Pharmacometabolomics Research Network
通讯作者：
Pharmacometabolomics Research Network
DOI：
10.1056/nejmoa1707447
发表时间：
2017-12-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Neelapu SS;Locke FL;Bartlett NL;Lekakis LJ;Miklos DB;Jacobson CA;Braunschweig I;Oluwole OO;Siddiqi T;Lin Y;Timmerman JM;Stiff PJ;Friedberg JW;Flinn IW;Goy A;Hill BT;Smith MR;Deol A;Farooq U;McSweeney P;Munoz J;Avivi I;Castro JE;Westin JR;Chavez JC;Ghobadi A;Komanduri KV;Levy R;Jacobsen ED;Witzig TE;Reagan P;Bot A;Rossi J;Navale L;Jiang Y;Aycock J;Elias M;Chang D;Wiezorek J;Go WY
通讯作者：
Go WY
影响因子：
7.5
作者：
Pennisi, Martina;Jain, Tania;Perales, Miguel-Angel
通讯作者：
Perales, Miguel-Angel