研究揭示抗CD19 CAR T細胞輸注產品與大B細胞淋巴瘤患者的功效和毒性相關的特徵
作者：
小柯機器人發布時間：2020/10/11 21:34:29
近日，美國德克薩斯大學MD安德森癌症中心Michael R. Green等研究人員，合作揭示抗CD19 CAR T細胞輸注產品與大B細胞淋巴瘤患者的功效和毒性相關的特徵。該項研究成果於2020年10月5日在線發表在《自然—醫學》雜誌上。
據研究人員介紹，靶向CD19的自體嵌合抗原受體（CAR）T細胞療法在大B細胞淋巴瘤（LBCL）中具有很高的療效，但在不到一半的患者中觀察到長期緩解，並且存在與治療相關的不良事件，例如免疫效應細胞相關神經毒性綜合症（ICANS）是一項臨床挑戰。
研究人員對自體的axicabtagene ciloleucel (axi-cel)抗CD19 CAR T細胞輸注產品通過基於捕獲的細胞鑑定進行了單細胞RNA測序，從而鑑定與24例LBCL患者的療效和毒性相關的轉錄組特徵。在3個月的隨訪中通過正電子發射斷層掃描/計算機斷層掃描獲得完全緩解的患者，與具有部分緩解或進行性疾病的患者相比，表達記憶信號的CD8 T細胞的頻率高三倍。
輸注後第7天通過無細胞DNA測序測量的分子反應與臨床反應顯著相關（P=0.008），CD8 T細胞耗竭的特徵與不良的分子反應相關（q=2.8×10-149） 。此外，具有單核細胞樣轉錄特徵的稀有細胞群與高級ICANS相關（P=0.0002）。這些結果表明，CAR T細胞輸注產品的細胞和分子特徵異質性有助於在LBCL中進行axi-cel治療後功效和毒性的變化，並且第7天的分子反應可能是CAR T細胞功效的早期預測指標。
附：英文原文
Title: Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas
Author: Qing Deng, Guangchun Han, Nahum Puebla-Osorio, Man Chun John Ma, Paolo Strati, Beth Chasen, Enyu Dai, Minghao Dang, Neeraj Jain, Haopeng Yang, Yuanxin Wang, Shaojun Zhang, Ruiping Wang, Runzhe Chen, Jordan Showell, Sreejoyee Ghosh, Sridevi Patchva, Qi Zhang, Ryan Sun, Frederick Hagemeister, Luis Fayad, Felipe Samaniego, Hans C. Lee, Loretta J. Nastoupil, Nathan Fowler, R. Eric Davis, Jason Westin, Sattva S. Neelapu, Linghua Wang, Michael R. Green
Issue&Volume: 2020-10-05
Abstract: Autologous chimeric antigen receptor (CAR) T cell therapies targeting CD19 have high efficacy in large B cell lymphomas (LBCLs), but long-term remissions are observed in less than half of 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 who achieved a complete response by positron emission tomography/computed tomography at their 3-month follow-up had three-fold higher frequencies of CD8 T cells expressing memory signatures than patients with partial response or progressive disease. Molecular response measured by cell-free DNA sequencing at day 7 after 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 contributes to variation in efficacy and toxicity after axi-cel therapy in LBCL, and that day 7 molecular response might serve as an early predictor of CAR T cell efficacy. Single-cell transcriptomics reveals that the heterogeneity of anti-CD19 CAR T cell infusion products contributes to variability in clinical response, early molecular response and development of immune effector cell-associated neurotoxicity syndrome in patients with large B cell lymphomas.
DOI: 10.1038/s41591-020-1061-7
Source: https://www.nature.com/articles/s41591-020-1061-7