肿瘤细胞治疗研究
英文原题：Host immune biomarkers associated with infection risk after CAR T-cell therapy.
纵向免疫分析识别出与感染风险和 CAR-T 相关毒性相关的不同免疫学特征。这些发现提示免疫监测在改善风险分层和指导 CAR-T 治疗后支持治疗方面具有作用。
感染是CAR-T治疗后非复发死亡的主要原因，但个体化风险预测仍具挑战性。本探索性研究评估了接受CAR-T治疗的弥漫性大B细胞淋巴瘤（DLBCL）患者中感染及其他治疗中出现的不良事件的免疫相关性。
20例复发或难治性DLBCL患者接受了axicabtagene ciloleucel（n = 7）或tisagenlecleucel（n = 13）治疗，并在单采时（基线）、淋巴细胞清除后及第30天（D30）进行前瞻性血液采集。在刺激后的外周血单个核细胞中评估细胞因子反应；使用bulk RNA-seq进行转录组分析。感染分为早期（单采-D30）或晚期（D30-D90）。使用多变量回归探讨免疫特征与感染之间的关联。
11例患者（55%）发生了18次感染（13次早期，5次晚期）。早期感染与较高的基线中性粒细胞活化细胞因子（OR=4.35，p=0.047）、刺激后较低的TREM-1水平（每降低500pg/mL，OR=1.37，p=0.004）以及血红素代谢基因上调相关。晚期感染与MCP-1分泌增加（每500pg/mL，OR=1.82，p=0.013）及D30时TNF-α相关通路受抑制相关。至D30时，与Th1（295 vs. 9365pg/mL，p < 0.001）、T细胞（263 vs. 531pg/mL）和B细胞通路（220 vs. 584pg/mL）相关的细胞因子反应较基线显著受抑制（p < 0.001），并伴有免疫活化特征的转录组下调。在毒性方面也观察到不同的免疫模式。CRS（≥2级）与D30时Th1细胞因子受抑制（IL-12：3 vs. 403pg/mL，p < 0.001）及RNASE1过表达相关，而ICANS（≥1级）与Th1细胞因子升高相关（2368 vs. 1361pg/mL，p=0.007），且不依赖于皮质类固醇的使用。
BACKGROUND: Infection is the leading cause of non-relapse mortality after CAR-T therapy, yet individual risk prediction remains challenging. This exploratory study evaluated immune correlates of infection and other treatment-emergent adverse events in patients with diffuse large B-cell lymphoma (DLBCL) receiving CAR-T. METHODS: Twenty patients with relapsed or refractory DLBCL received axicabtagene ciloleucel (n = 7) or tisagenlecleucel (n = 13), with prospective blood collection at apheresis, (baseline), post-lymphodepletion, and day 30 (D30). Cytokine responses were assessed in stimulated peripheral blood mononuclear cells; transcriptomic profiling was performed using bulk RNA-seq. Infections were classified as early (apheresis-D30) or late (D30-D90). Associations between immune features and infection were explored using multivariable regression. RESULTS: Eighteen infections (13 early, 5 late) occurred in 11 patients (55%). Early infections were associated with higher baseline neutrophil activation cytokines (OR=4.35, p=0.047), lower TREM-1 levels following stimulation (OR=1.37 per 500pg/mL decrease, p=0.004), and upregulation of heme metabolism genes. Late infections correlated with increased MCP-1 secretion (OR=1.82 per 500pg/mL, p=0.013) and suppression of TNF-α-related pathways at D30. By D30, cytokine responses associated with Th1 (295 vs. 9365pg/mL, p < 0.001), T-cell (263 vs. 531pg/mL) and B-cell pathways (220 vs. 584pg/mL) were significantly suppressed compared to baseline (p < 0.001) accompanied by transcriptomic downregulation of immune activation signatures. Distinct immune patterns were also observed in toxicity. CRS (grade ≥ 2) was linked to suppressed Th1 cytokines at D30 (IL-12: 3 vs. 403pg/mL, p < 0.001) and RNASE1 overexpression, while ICANS (grade ≥ 1) was associated with increased Th1 cytokines (2368 vs. 1361pg/mL, p=0.007), independent of corticosteroid use. CONCLUSIONS: Longitudinal immune profiling identified distinct immunological signatures linked to infection risk and CAR-T-related toxicities. These findings suggest a role for immune monitoring in improving risk stratification and guiding supportive care after CAR-T therapy.
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