肿瘤细胞治疗研究
英文原题：Enrichment of CD7(+)CXCR3(+) CAR T-cells in infusion products is associated with durable remission in relapsed or refractory diffuse large B-cell lymphoma.
R 中 CD7 + CXCR3 + CAR-T 细胞富集并伴 NKG2D 表达升高，而 NR 中 LAG3 与 CD71 较高，这些可能成为治疗结局的稳健相关因素。
背景：CAR-T 细胞疗法是复发或难治性（R/R）弥漫大 B 细胞淋巴瘤（DLBCL）的标准治疗，但超过半数患者无法获得持久缓解。识别 CAR-T 输注产品（IP）中的预测性生物标志物，可能有助于指导改善临床结局的策略。患者与方法：这项单中心观察性研究在瑞士洛桑大学医院（CHUV）开展，分析了 13 例接受标准 CAR-T 治疗的 R/R DLBCL 患者输注产品。研究使用包含 39 种标志物的质谱流式面板，比较长期应答者（R）和未应答者（NR）的表型及功能标志物。对输注产品数据采用无监督和有监督分析方法，并在输注后 30 天内纵向采集外周血样本，追踪 CAR-T 亚群动态。结果：中位随访 13.5 个月时，R 组（n = 8）的 PFS 中位数为 13.3 个月［95% 置信区间（CI）9.7–24.3］，NR 组（n = 5）为 3.5 个月（95% CI 0.5–5.4）（风险比 56.67，95% CI 7.3–439.3，P = 0.0001）。CD3⁺CXCR3⁺CD7⁺ CAR-T 亚群在 CD4⁺ 和 CD8⁺ 区室中均可见，并在 R 组显著富集。这些细胞穿孔素、颗粒酶 B 和 NKG2D 表达升高（NKG2D 升高限于 CD8⁺ 细胞）。相反，NR 组 CXCR3⁺CD7⁺LAG3⁺ CAR-T 细胞频率较高。R 组 CD3、CD7、CXCR3 和 NKG2D 表面表达更高，NR 组则 LAG3、Ki67 和 CD71 水平升高。预测截断比值为 CD3⁺CXCR3⁺CD7⁺LAG3⁺CAR⁺ T 细胞 <0.83，且 CD3⁺CXCR3⁺CD7⁺NKG2D⁺CAR⁺ T 细胞 >1.034 时，预测准确率为 0.92。两组血清 CXCL9 和 CXCL10 浓度无差异。结论：R 组 CD7⁺CXCR3⁺ CAR-T 细胞富集且 NKG2D 表达升高，而 NR 组 LAG3 和 CD71 较高；这些特征可能是较稳健的治疗结局相关指标。尽管结果来自样本量较小、旨在生成假设的队列，但提示针对输注产品组成开展分析，可能有助于开发生物标志物驱动的策略，优化 CAR-T 产品并提高 R/R DLBCL 患者获得持久缓解的可能性。
BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy is the standard of care for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, more than half of patients fail to achieve durable remission. Identifying predictive biomarkers within the CAR T-cell infusion product (IP) may guide strategies to improve clinical outcomes. PATIENTS AND METHODS: This single-center observational study, conducted at Lausanne University Hospital (CHUV), Switzerland, analyzed IPs from 13 patients with R/R DLBCL who underwent standard-of-care CAR T-cell therapy. A 39-marker mass cytometry panel was used to compare phenotypic and functional markers between long-term responders (R) and nonresponders (NR). Unsupervised and supervised analytic approaches were applied to IP data, and longitudinal peripheral blood samples were collected over 30 days after infusion to track CAR T-cell subpopulation dynamics. RESULTS: At a median follow-up of 13.5 months, median progression-free survival (PFS) was 13.3 months [95% confidence interval (CI) 9.7-24.3 months] in R (n = 8) versus 3.5 months (95% CI 0.5-5.4 months) in NR (n = 5) (hazard ratio 56.67, 95% CI 7.3-439.3, P = 0.0001). A CD3 + CXCR3 + CD7 + CAR T-cell subpopulation-found in both CD4 + and CD8 + compartments-was significantly enriched in R. These cells showed increased expression of perforin, granzyme B, and NKG2D (restricted to CD8 + cells). In contrast, NR had a higher frequency of CXCR3 + CD7 + LAG3 + CAR T-cells. Surface expression of CD3, CD7, CXCR3, and NKG2D were higher in R, whereas LAG3, Ki67, and CD71 were elevated in NR. A predictive cut-off ratio of CD3 + CXCR3 + CD7 + LAG3 + CAR + T-cells <0.83 and CD3 + CXCR3 + CD7 + NKG2D + CAR + T-cells >1.034 yielded a predictive accuracy of 0.92. Serum CXCL9 and CXCL10 concentrations did not differ between groups. CONCLUSIONS: Enrichment of CD7 + CXCR3 + CAR T-cells alongside elevated NKG2D expression in R, in contrast to higher LAG3 and CD71 in NR, emerged as potentially robust correlates of therapeutic outcome. Although derived from a small, hypothesis-generating cohort, these findings suggest that targeted analysis of IP composition may inform the development of biomarker-driven strategies to optimize CAR T-cell products and improve the likelihood of durable remission in R/R DLBCL.
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