肿瘤细胞治疗研究
英文原题：Successful autologous T cell apheresis in pediatric patients with hematologic malignancies, solid tumors, and brain tumors.
我们报告，auto-MNC 采集标准可应用于一系列儿童肿瘤适应证，从而实现高度成功的采集及后续生产，且各疾病组之间无显著差异。
背景：嵌合抗原受体（CAR）T细胞疗法正用于治疗多种儿童癌症。起始细胞材料对成功制备CAR T细胞至关重要，通常通过自体单个核细胞（auto-MNC）单采获得。虽然B细胞急性淋巴细胞白血病（B-ALL）患者的单采策略已有确立，但这些方法尚未标准化，关于其在其他疾病人群中的适用性数据有限。本文报告我们在多种儿童癌症诊断中开展CAR T细胞生产单采的经验。 方法：我们对单中心自体MNC单采事件进行回顾性分析。单采适合性参数包括外周血绝对淋巴细胞计数（ALC）≥300个/μL和CD3+细胞≥150个/μL。达到单采目标定义为处理后产量达到目标值的90%以内（总有核细胞［TNC］2×10^9个，CD3+细胞1×10^9个）。多日采集视为单次单采事件。比较不同疾病组的基线和采集特征，并使用单变量及多变量Logistic回归模型，校正基线协变量后探索基线因素与成功单采之间的关联。 结果：我们评估了138例患者的151次auto-MNC单采，其中诊断为ALL（n=80）、AML（n=23）、淋巴瘤（n=2）、实体瘤（n=16）或脑肿瘤（n=17）。单采时年龄中位数为11.7岁（范围1.4–23.5岁）；处理血量中位数为1.9个总血容量（TBV；范围0.8–8.2），不同疾病组的TBV处理量无显著差异（P=0.218）。总体而言，87%的患者同时达到TNC和CD3+目标，单变量或多变量分析均未发现不同疾病组之间存在显著差异。白血病患者外周血原始细胞负荷未影响采集效率。多变量分析显示，年龄增加与成功单采的优势升高相关（OR=1.17，95% CI 1.06–1.32），而基线白细胞计数增加与成功采集的优势降低相关（OR=0.92，95% CI 0.81–0.99）。随后129次CAR T细胞生产中有127次成功（98.4%）。 结论：我们的结果表明，自体MNC单采标准可适用于多种儿科肿瘤适应证，并可获得高度成功的单采和后续生产，不同疾病组间无显著差异。年龄和基线白细胞计数可能影响单采成功，但总体失败率较低，限制了当前风险因素分析。
BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy is being used to target a range of pediatric cancers. Starting materials are critical for successful CAR T cell manufacturing, most often obtained via autologous mononuclear cell (auto-MNC) apheresis. While apheresis strategies are established for patients with B cell acute lymphoblastic leukemia (B-ALL), these approaches are not standardized and there are limited data on how these practices apply across other disease groups. Here, we report our experience with apheresis for CAR T cell production across various pediatric cancer diagnoses. METHODS: We performed a single-center retrospective analysis of auto-MNC apheresis events. Parameters for apheresis suitability included peripheral blood absolute lymphocyte count (ALC) 300 cells/ L and CD3+ 150 cells/ L. Meeting apheresis goal was defined as postprocessing yield within 90% of target (2 10 9 total nucleated cells [TNC] and 1 10 9 CD3+ cells). Multi-day collections were considered single apheresis events. Baseline and collection characteristics were compared across disease groups, and univariable and multivariable logistic regression models were applied to explore the associations between baseline factors and successful apheresis collection, adjusting for baseline covariates. RESULTS: We evaluated 151 auto-MNC apheresis collections from 138 unique patients diagnosed with ALL (n = 80), AML (n = 23), lymphoma (n = 2), solid tumor (n = 16), or brain tumor (n = 17). The median age at time of apheresis collection was 11.7 years (range 1.4-23.5), and the median amount of blood processed was 1.9 (range 0.8-8.2) total blood volumes (TBV), with no statistically significant difference in TBV processed between disease groups (P = 0.218). Overall, 87% of patients met both total nucleated cell (TNC) and CD3+ goals, with no statistically significant differences across disease groups in univariate or multivariate analyses. Collection efficiency was not impacted by burden of peripheral blasts among patients with leukemia. In multivariate analysis, increasing age was associated with increased odds of successful apheresis (OR: 1.17, 95% CI: 1.06-1.32), while odds of successful collection decreased with increasing baseline white blood cell count (OR: 0.92, 95% CI: 0.81-0.99). Subsequent CAR T cell manufacturing was successful in 127 of 129 procedures (98.4%). CONCLUSIONS: We report that auto-MNC apheresis collection criteria can be applied across an array of pediatric oncologic indications, resulting in highly successful apheresis and subsequent manufacturing campaigns without significant differences between disease groups. Age and baseline WBC count may influence successful apheresis, but overall low failure rates limit current risk factor analysis.
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