Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas.
Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas.
复制标题
DOI：
10.1038/s41591-020-1061-7
复制
发表时间：
2020-12
期刊：
影响因子：
82.9
通讯作者：
Green MR
中科院分区：
文献类型：
--
作者：
Deng Q;Han G;Puebla-Osorio N;Ma MCJ;Strati P;Chasen B;Dai E;Dang M;Jain N;Yang H;Wang Y;Zhang S;Wang R;Chen R;Showell J;Ghosh S;Patchva S;Zhang Q;Sun R;Hagemeister F;Fayad L;Samaniego F;Lee HC;Nastoupil LJ;Fowler N;Eric Davis R;Westin J;Neelapu SS;Wang L;Green MR
靶向CD 19的自体嵌合抗原受体（CAR）T细胞疗法在大B细胞淋巴瘤（LBCL）中具有很高的疗效，但在不到一半的患者中观察到长期缓解，并且治疗相关的不良事件（如免疫效应细胞相关神经毒性综合征（ICANS））是一项临床挑战。我们对自体axicabtagene ciloleucel（axi-cel）抗CD 19 CAR T细胞输注产品进行了单细胞RNA测序和基于捕获的细胞鉴定，以鉴定与24例LBCL患者的疗效和毒性相关的转录组学特征。在3个月随访时通过PET/CT获得完全缓解的患者，与部分缓解或疾病进展的患者相比，表达记忆特征的CD 8 T细胞频率高3倍。输注后第7天通过无细胞DNA（cfDNA）测序测量的分子应答与临床应答显著相关（p=0.008），CD 8 T细胞耗竭特征与分子应答差相关（q=2.8×10−149）。此外，具有单核细胞样转录特征的罕见细胞群与高级别ICANS相关（p=0.0002）。我们的研究结果表明，CAR T细胞输注产品的细胞和分子特征的异质性导致了LBCL中Axi-cel治疗后疗效和毒性的变化，并且第7天的分子应答可以作为CAR T细胞疗效的早期预测因子。
Autologous chimeric antigen receptor (CAR) T-cell therapies targeting CD19 have high efficacy in large B-cell lymphomas (LBCL), but long-term remissions are observed in less than half the patients and treatment-associated adverse events such as immune effector cell-associated neurotoxicity syndrome (ICANS) are a clinical challenge. We performed single-cell RNA-sequencing with capture-based cell identification on autologous axicabtagene ciloleucel (axi-cel) anti-CD19 CAR T-cell infusion products to identify transcriptomic features associated with efficacy and toxicity in 24 patients with LBCL. Patients that achieved a complete response by PET/CT at their 3-month follow-up had 3-fold higher frequencies of CD8 T-cells expressing memory signatures compared to patients with partial response or progressive disease. Molecular response measured by cell-free DNA (cfDNA) sequencing at day 7 post-infusion was significantly associated with clinical response (p=0.008), and a signature of CD8 T-cell exhaustion was associated (q=2.8×10−149) with a poor molecular response. Furthermore, a rare cell population with monocyte-like transcriptional features was associated (p=0.0002) with high-grade ICANS. Our results suggest that heterogeneity in the cellular and molecular features of CAR T-cell infusion products contribute to variation in efficacy and toxicity after axi-cel therapy in LBCL, and that day 7 molecular response may serve as an early predictor of CAR T-cell efficacy.
登录
查看更多内容
影响因子：
28.2
作者：
Gust J;Hay KA;Hanafi LA;Li D;Myerson D;Gonzalez-Cuyar LF;Yeung C;Liles WC;Wurfel M;Lopez JA;Chen J;Chung D;Harju-Baker S;Özpolat T;Fink KR;Riddell SR;Maloney DG;Turtle CJ
通讯作者：
Turtle CJ
DOI：
10.1097/cji.0b013e3181ac6138
发表时间：
2009-09
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Kochenderfer JN;Feldman SA;Zhao Y;Xu H;Black MA;Morgan RA;Wilson WH;Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
30.5
作者：
Blackburn, Shawn D.;Shin, Haina;Haining, W. Nicholas;Zou, Tao;Workman, Creg J.;Polley, Antonio;Betts, Michael R.;Freeman, Gordon J.;Vignali, Dario A. A.;Wherry, E. John
通讯作者：
Wherry, E. John
影响因子：
15.9
作者：
Finney, Olivia C.;Brakke, Hannah;Jensen, Michael C.
通讯作者：
Jensen, Michael C.
影响因子：
3.8
作者：
KAZAZI, F;MATHIJS, JM;CUNNINGHAM, AL
通讯作者：
CUNNINGHAM, AL