Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria.
Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
Front Immunol. 2023 Jan 9;13:1004703. doi: 10.3389/fimmu.2022.1004703. eCollection 2022.
BACKGROUND: Chimeric antigen receptor T (CART) cell therapy targeting the B cell specific differentiation antigen CD19 has shown clinical efficacy in a subset of relapsed/refractory (r/r) diffuse large B cell lymphoma (DLBCL) patients. Despite this heterogeneous response, blood pre-infusion biomarkers predicting responsiveness to CART cell therapy are currently understudied. METHODS: Blood cell and serum markers, along with clinical data of DLBCL patients who were scheduled for CART cell therapy were evaluated to search for biomarkers predicting CART cell responsiveness. FINDINGS: Compared to healthy controls (n=24), DLBCL patients (n=33) showed significant lymphopenia, due to low CD3CD4 T helper and CD3CD56 NK cell counts, while cytotoxic CD3CD8 T cell counts were similar. Although lymphopenic, DLBCL patients had significantly more activated HLA-DR (P=0.005) blood T cells and a higher frequency of differentiated CD3CD27CD28 (28.7 ± 19.0% versus 6.6 ± 5.8%; P<0.001) T cells. Twenty-six patients were infused with CART cells (median 81 days after leukapheresis) and were analyzed for the overall response (OR) 3 months later. Univariate and multivariate regression analyses showed that low levels of differentiated CD3CD27CD28 T cells (23.3 ± 19.3% versus 35.1 ± 18.0%) were independently associated with OR. This association was even more pronounced when patients were stratified for complete remission (CR versus non-CR: 13.7 ± 11.7% versus 37.7 ± 17.4%, P=0.001). A cut-off value of ≤ 18% of CD3CD27CD28 T cells predicted CR at 12 months with high accuracy (P<0.001). , CD3CD8CD27CD28 compared to CD3CD8CD27CD28 CART cells displayed similar CD19 target cell-specific cytotoxicity, but were hypoproliferative and produced less cytotoxic cytokines (IFN-γ and TNF-α). CD3CD8 T cells outperformed CD3CD4 T cells 3- to 6-fold in terms of their ability to kill CD19 target cells. INTERPRETATION: Low frequency of differentiated CD3CD27CD28 T cells at leukapheresis represents a novel pre-infusion blood biomarker predicting a favorable response to CART cell treatment in r/r DLBCL patients.
背景：嵌合抗原受体 T（CART）细胞疗法针对 B 细胞特异性分化抗原 CD19，在部分复发/难治性（r/r）弥漫性大 B 细胞淋巴瘤（DLBCL）患者中显示出临床疗效。尽管存在这种异质性反应，但目前对预测 CART 细胞治疗反应的血液预输注生物标志物研究较少。
方法：评估计划接受 CART 细胞治疗的 DLBCL 患者的血细胞和血清标志物以及临床数据，以寻找预测 CART 细胞反应性的生物标志物。
结果：与健康对照者（n=24）相比，DLBCL 患者（n=33）表现出明显的淋巴细胞减少症，这是由于 CD3CD4 T 辅助细胞和 CD3CD56 NK 细胞计数低所致，而细胞毒性 CD3CD8 T 细胞计数相似。尽管淋巴细胞减少症，DLBCL 患者的血液 T 细胞中 HLA-DR 表达显著增加（P=0.005），并且分化的 CD3CD27CD28（28.7±19.0%对 6.6±5.8%；P<0.001）T 细胞的频率更高。26 名患者接受了 CART 细胞输注（白细胞分离后中位数 81 天），并在 3 个月后分析其总体反应（OR）。单变量和多变量回归分析显示，分化的 CD3CD27CD28 T 细胞水平较低（23.3±19.3%对 35.1±18.0%）与 OR 独立相关。当患者根据完全缓解（CR 与非 CR：13.7±11.7%对 37.7±17.4%，P=0.001）进行分层时，这种相关性更加明显。CD3CD27CD28 细胞≤18%的截值可在 12 个月时以高准确性（P<0.001）预测 CR。此外，与 CD3CD8CD27CD28 CART 细胞相比，CD3CD8CD27CD28 CART 细胞显示出相似的 CD19 靶细胞特异性细胞毒性，但增殖能力较低，产生的细胞毒性细胞因子（IFN-γ 和 TNF-α）较少。CD3CD8 T 细胞在杀伤 CD19 靶细胞方面的能力比 CD3CD4 T 细胞高 3-6 倍。
解释：白细胞分离时分化的 CD3CD27CD28 T 细胞频率较低代表一种新的预输注血液生物标志物，可预测 r/r DLBCL 患者对 CART 细胞治疗的有利反应。
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