不适合移植的大 B 细胞淋巴瘤二线使用 axicabtagene ciloleucel：ALYCANTE 最终分析
Second-line axicabtagene ciloleucel in large B-cell lymphoma ineligible for transplantation: ALYCANTE final analysis.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
大 B 细胞淋巴瘤中靶向 CD19 工程化 T 细胞治疗耐药的决定因素
英文原题：Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas.
查看英文原题
Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas.
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中文摘要
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。为了表征耐药的决定因素，我们对来自两个独立队列（n = 65和n = 73）接受axicabtagene ciloleucel治疗的r/rLBCL患者的700多份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，使得能够整合肿瘤以及工程化和非工程化T细胞效应介导的因素，用于评估治疗失败和预测结局。多类基因的改变与耐药相关，包括B细胞身份基因（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治疗，包括CAR19 T细胞扩增、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相互作用。我们设想这些发现将促进改进的嵌合抗原受体（CAR）T细胞和个性化治疗方法的开发。
展开英文摘要原文
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.
论文信息
- 作者
- Sworder BJ、Kurtz DM、Alig SK、Frank MJ、Shukla N、Garofalo A、Macaulay CW、Shahrokh Esfahani M
- 第一作者单位
- Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA.United States
- 通讯作者单位
- Division of Oncology, Department of Medicine, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA; Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: arasha@stanford.edu.United States
- 文献类型
- 美国 NIH 资助研究 · 非美国政府资助研究
- 期刊
- Cancer cell2023 Jan 9
- 原文标识
- PubMed 36584673 · DOI 10.1016/j.ccell.2022.12.005
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