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研究揭示大B细胞淋巴瘤中以CD19为靶点的工程化T细胞疗法的抗性决定因素
作者：小柯机器人 发布时间：2022/12/31 23:22:56

美国斯坦福大学Ash A. Alizadeh研究组揭示大B细胞淋巴瘤中以CD19为靶点的工程化T细胞疗法的抗性决定因素。2022年12月29日，《癌细胞》杂志在线发表了这项成果。

研究人员表示，大多数接受抗CD19嵌合抗原受体（CAR19）T细胞治疗的复发/难治性大B细胞淋巴瘤（r/rLBCL）患者会复发。
 
为了确定耐药性的决定因素，研究人员对来自两个独立队列（n=65和n=73）的接受axicabtagene ciloleucel治疗r/rLBCL患者的700多个纵向标本进行了分析。一种同时分析循环肿瘤DNA（ctDNA）、无细胞CAR19（cfCAR19）逆转录病毒片段和无细胞T细胞受体重排（cfTCR）的方法使肿瘤和工程化及非工程化T细胞效应器介导的因素得以整合，从而可评估治疗失败和预测结果。
 
多类基因的改变与耐药性有关，包括B细胞特性（PAX5和IRF8）、免疫检查点（CD274），以及影响微环境的基因（TMEM30A）。体细胞肿瘤改变在多个层面影响CAR19疗法，包括CAR19 T细胞的扩增、持久性和肿瘤微环境。此外，CAR19 T细胞在塑造肿瘤基因型和表型方面发挥着相互作用。研究人员认为这些发现将有助于改进嵌合抗原受体（CAR）T细胞和个性化的治疗方法。
 
附：英文原文

Title: Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas

Author: Brian J. Sworder, David M. Kurtz, Stefan K. Alig, Matthew J. Frank, Navika Shukla, Andrea Garofalo, Charles W.M. Macaulay, Mohammad Shahrokh Esfahani, Mari N. Olsen, James Hamilton, Hitomi Hosoya, Mark Hamilton, Jay Y. Spiegel, John H. Baird, Takeshi Sugio, Mia Carleton, Alexander F.M. Craig, Sheren F. Younes, Bita Sahaf, Natasha D. Sheybani, Joseph G. Schroers-Martin, Chih Long Liu, Jean S. Oak, Michael C. Jin, Sara Beygi, Andreas Hüttmann, Christine Hanoun, Ulrich Dührsen, Jason R. Westin, Michael S. Khodadoust, Yasodha Natkunam, Robbie G. Majzner, Crystal L. Mackall, Maximilian Diehn, David B. Miklos, Ash A. Alizadeh

Issue&Volume: 2022-12-29

Abstract: Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants ofresistance, we profiled over 700 longitudinal specimens from two independent cohorts(n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A methodfor simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19)retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabledintegration of tumor and both engineered and non-engineered T cell effector-mediatedfactors for assessing treatment failure and predicting outcomes. Alterations in multipleclasses of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cellsplay a reciprocal role in shaping tumor genotype and phenotype. We envision thesefindings will facilitate improved chimeric antigen receptor (CAR) T cells and personalizedtherapeutic approaches.

DOI: 10.1016/j.ccell.2022.12.005

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00591-8

期刊信息

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
官方网址：https://www.cell.com/cancer-cell/home
投稿链接：https://www.editorialmanager.com/cancer-cell/default.aspx