Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
Pediatric Hematology Oncology, Johns Hopkins, Baltimore, Maryland, USA.
J Immunother Cancer. 2023 May;11(5). doi: 10.1136/jitc-2022-006596.
The expansion and persistence of chimeric antigen receptor (CAR) T-cells in patients are associated with response, toxicity, and long-term efficacy. As such, the tools used to detect CAR T-cells following infusion are fundamental for optimizing this therapeutic approach. Nevertheless, despite the critical value of this essential biomarker, there is significant variability in CAR T-cell detection methods as well as the frequency and intervals of testing. Furthermore, heterogeneity in the reporting of quantitative data adds layers of complexity that limit intertrial and interconstruct comparisons. We sought to assess the heterogeneity of CAR T-cell expansion and persistence data in a scoping review using the PRISMA-ScR checklist. Focusing on 21 clinical trials from the USA, featuring a Food and Drug Administration-approved CAR T-cell construct or one of its predecessors, 105 manuscripts were screened and 60 were selected for analysis, based on the inclusion of CAR T-cell expansion and persistence data. Across the array of CAR T-cell constructs, flow cytometry and quantitative PCR were identified as the two primary techniques for detecting CAR T-cells. However, despite apparent uniformity in detection techniques, the specific methods used were highly variable. Detection time points and the number of evaluated time points also ranged markedly and quantitative data were often not reported. To evaluate whether subsequent manuscripts from a trial resolved these issues, we analyzed all subsequent manuscripts reporting on the 21 clinical trials, recording all expansion and persistence data. While additional detection techniques-including droplet digital PCR, NanoString, and single-cell RNA sequencing-were reported in follow-up publications, inconsistencies with respect to detection time points and frequency remained, with a significant amount of quantitative data still not readily available. Our findings highlight the critical need to establish universal standards for reporting on CAR T-cell detection, especially in early phase studies. The current reporting of non-interconvertible metrics and limited provision of quantitative data make cross-trial and cross-CAR T-cell construct comparisons extremely challenging. Establishing a standardized approach for collecting and reporting data is urgently needed and would represent a substantial advancement in the ability to improve outcomes for patients receiving CAR T-cell therapies.
嵌合抗原受体 (CAR) T 细胞在患者体内的扩增和持续存在与疗效、毒性和长期疗效相关。因此，输注后用于检测 CAR T 细胞的工具对于优化这种治疗方法至关重要。尽管这种重要生物标志物具有关键价值，但 CAR T 细胞检测方法以及检测的频率和间隔存在显著差异。此外，定量数据报告的异质性增加了限制试验间和试验内比较的复杂性。我们试图使用 PRISMA-ScR 清单在范围综述中评估 CAR T 细胞扩增和持久性数据的异质性。我们重点关注来自美国的 21 项临床试验，这些试验均使用了经食品和药物管理局批准的 CAR T 细胞构建体或其前身之一，筛选了 105 篇手稿，并根据 CAR T 细胞扩增和持久性数据的纳入情况选择了 60 篇进行分析。在各种 CAR T 细胞构建体中，流式细胞术和定量聚合酶链反应被确定为检测 CAR T 细胞的两种主要技术。然而，尽管检测技术似乎具有一致性，但具体使用的方法却存在很大差异。检测时间点和评估时间点的数量也有明显差异，并且通常未报告定量数据。为了评估试验的后续手稿是否解决了这些问题，我们分析了报告 21 项临床试验的所有后续手稿，记录了所有的扩增和持久性数据。虽然在后续出版物中报告了其他检测技术，包括液滴数字 PCR、NanoString 和单细胞 RNA 测序，但检测时间点和频率仍存在不一致性，大量定量数据仍然不易获得。我们的研究结果强调了迫切需要为 CAR T 细胞检测报告建立通用标准，特别是在早期研究中。目前对不可转换指标的报告和有限的定量数据提供使得跨试验和跨 CAR T 细胞构建体的比较极具挑战性。建立一种标准化的数据收集和报告方法是迫切需要的，这将极大地提高接受 CAR T 细胞治疗的患者的治疗效果。
