靶向CD19的工程T细胞治疗对大B细胞淋巴瘤的耐受性决定因素。
Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas.
发表日期：2023 Jan 09
作者：
Brian J Sworder, David M Kurtz, Stefan K Alig, Matthew J Frank, Navika Shukla, Andrea Garofalo, Charles W 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
来源：
CANCER CELL
摘要：
大多数复发/难治性大B细胞淋巴瘤（r/rLBCL）患者接受抗CD19嵌合抗原受体（CAR19）T细胞治疗后会出现复发。为了表征耐药性的决定因素，我们对接受axicabtagene ciloleucel治疗的两个独立队列（n = 65和n = 73）的r/rLBCL患者超过700个纵向标本进行了分析。一种同时进行循环肿瘤DNA（ctDNA）、无细胞CAR19（cfCAR19）逆转录片段和无细胞T细胞受体重排（cfTCR）的分析方法，实现了肿瘤和工程和非工程T细胞效应介质的整合，用于评估治疗失败和预测结局。对多种基因类别的改变与耐药性有关，包括B细胞身份（PAX5和IRF8）、免疫检查点（CD274）和影响微环境的基因（TMEM30A）。体细胞瘤突变影响CAR19治疗的多个层面，包括CAR19 T细胞扩增、持久性和肿瘤微环境。此外，CAR19 T细胞在形成肿瘤基因型和表型方面具有相互作用的角色。我们认为这些发现将有助于改善嵌合抗原受体（CAR）T细胞和个性化治疗方法。
Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes 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 CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.Copyright © 2022 Elsevier Inc. All rights reserved.