Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.
Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
Cancer Cell. 2023 Jan 9;41(1):210-225.e5. doi: 10.1016/j.ccell.2022.12.005. Epub 2022 Dec 29.
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.
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) 患者都会复发。为了明确耐药的决定因素，我们对两个独立队列（n=65 和 n=73）的 r/rLBCL 患者的 700 多个纵向样本进行了分析，这些患者接受了 axicabtagene ciloleucel 治疗。一种同时对循环肿瘤 DNA (ctDNA)、游离 CAR19 (cfCAR19) 逆转录病毒片段和游离 T 细胞受体重排 (cfTCR) 进行分析的方法，可整合肿瘤以及两种工程化和非工程化 T 细胞效应因子，用于评估治疗失败和预测结局。多种类别的基因改变与耐药性相关，包括 B 细胞特征 (PAX5 和 IRF8)、免疫检查点 (CD274) 和影响微环境的基因 (TMEM30A)。体细胞肿瘤改变在多个层面影响 CAR19 治疗，包括 CAR19 T 细胞扩增、持续存在和肿瘤微环境。此外，CAR19 T 细胞在塑造肿瘤基因型和表型方面也发挥着相互作用。我们设想这些发现将促进改良嵌合抗原受体 (CAR) T 细胞和个性化治疗方法的发展。
