CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Molecular Disease Monitoring in Patients With Relapsed/refractory B-Cell Lymphoma Receiving Anti-CD19 CAR T-Cell Therapy.
Molecular Disease Monitoring in Patients With Relapsed/refractory B-Cell Lymphoma Receiving Anti-CD19 CAR T-Cell Therapy.
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监测 MRD 是检测 tisa-cel 治疗反应不佳的一种灵敏而特异的方法。
CAR-T 改善了复发/难治性大B细胞淋巴瘤患者既往较差的结局，但约六成患者治疗后无应答或复发。PET/CT常用于评估疗效；肿瘤细胞释放到外周血的游离循环肿瘤DNA可用于微小残留病监测。
本回顾性试点研究收集10例患者CAR-T 输注前及第14、28、56、90、180和365天样本，以二代测序追踪克隆性VDJ重排，并与第90和365天PET/CT比较。
9例有可追踪序列者纳入研究。中位随访12.7个月时，4例存活；第90天3例影像学完全缓解，6例进展。第14或28天可检出的微小残留病对一年内影像学进展的敏感度为83%、特异度为100%。第28天仍可检出者中位总生存期和无进展生存期分别为6.7和1.3个月。
微小残留病监测可灵敏且特异地识别替沙仑赛疗效不佳者，需进一步研究更频繁监测及其他产品。
Chimeric antigen receptor (CAR) T-cell therapy has improved the historically poor outcomes for relapsed and refractory (R/R) large B-cell non-Hodgkin's lymphoma (LBCL). However, nearly 60% of patients will either fail to respond or relapse after CAR T-cell therapy. Currently, PET/CT scans are used to assess response. Cell-free circulating tumor DNA (ctDNA) is released by tumor cells into the peripheral blood and can be measured for minimal residual disease (MRD) assessment.
In this retrospective, IRB approved pilot study, archived lymphoma tissue and ctDNA from peripheral blood samples on day 0, 14, 28, 56, 90, 180, and 365 after CAR T-cell infusion from 10 patients with R/R NHL were collected for next-generation sequencing (NGS) of clonal variable-diversity-joining (VDJ) rearrangements (Adaptive biotechnologies [Seattle, WA]). Response was assessed by PET/CT on days 90 and 365 and graded according to the Lugano 2014 criteria. The primary endpoint was to determine the feasibility of detecting ctDNA to monitor disease response after anti-CD19 CAR T-cell therapy. The secondary endpoint was to compare the sensitivity/specificity of MRD assessment from ctDNA to PET/CT imaging.
Nine out of 10 patients with a trackable sequence [median age 69 (range: 56-76); 55.6% male; median LDH 224], were included in this study. Each received tisagenlecleucel (tisa-cel) CAR T-cell therapy after median 2 prior treatments (range: 2-4). 7/9 patients had R/R diffuse large B-cell lymphoma (DLBCL), and 2/9 had transformed follicular lymphoma. At a median follow up of 12.7 months (range: 1.5-30 months), 4 patients were alive. By day 90, 3 patients (33.3%) achieved a radiographic complete response (CR) whilst 6 patients (66.6%) had progressive disease (PD). Detectable MRD on day 14 or day 28 had 83% sensitivity and 100% specificity for radiographic progression at any time before 1 year. For patients with PD, the median (interquartile range) MRD at day 0, 14, and 28 were 17.31 (1.01, 96.84), 9.12 (0.30, 18.8), and 23.77 (8.01, 137.53) copies per milliliter (mL), respectively. For patients with detectable MRD at day 28, mOS and mPFS were 6.7 and 1.3 months, respectively.
Monitoring MRD was a sensitive and specific method to detect poor response to tisa-cel. Additional studies evaluating MRD more frequently and with different products are warranted.
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