Murray Joseph C, Sivapalan Lavanya, Hummelink Karlijn, Balan Archana, White James R, Niknafs Noushin, Rhymee Lamia, Pereira Gavin, Rao Nisha, Phallen Jillian, Leal Alessandro, Bartlett David L, Marrone Kristen A, Naidoo Jarushka, Levy Benjamin, Rosner Samuel, Hann Christine L, Scott Susan C, Feliciano Josephine, Lam Vincent K, Ettinger David S, Li Qing Kay, Illei Peter B, Monkhorst Kim, Zaidi Ali H, Scharpf Robert B, Brahmer Julie R, Velculescu Victor E, Forde Patrick M, Anagnostou Valsamo
bioRxiv. 2023 Jun 26:2023.06.23.546338. doi: 10.1101/2023.06.23.546338.
Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect -especially in the setting of stable disease-call for the development of molecularly-informed real-time minimally invasive predictive biomarkers. In addition to capturing tumor regression, liquid biopsies may be informative in evaluating immune-related adverse events (irAEs).
We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response for each patient. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles.
Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank p=0.0003) and overall survival (log-rank p=0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, peripheral blood T-cell repertoire reshaping, assessed by significant TCR clonotypic expansions and regressions were noted on-treatment.
Molecular responses assist with interpretation of heterogeneous clinical responses especially for patients with stable disease. Our complementary assessment of the tumor and immune compartments by liquid biopsies provides an approach for monitoring of clinical benefit and immune-related toxicities for patients with NSCLC receiving immunotherapy.
Longitudinal dynamic changes in cell-free tumor load and reshaping of the peripheral T-cell repertoire capture clinical outcomes and immune-related toxicities during immunotherapy for patients with non-small cell lung cancer.
尽管免疫疗法是晚期非小细胞肺癌（NSCLC）治疗的主要手段，但仍缺乏强大的临床反应生物标志物。临床反应的异质性以及影像学反应评估在及时准确预测治疗效果方面的有限价值——尤其是在疾病稳定的情况下——促使人们开发基于分子信息的实时微创预测生物标志物。除了捕捉肿瘤消退外，液体活检在评估免疫相关不良事件（irAE）方面可能也具有参考价值。
我们研究了接受基于免疫疗法方案的转移性NSCLC患者循环肿瘤DNA（ctDNA）的纵向变化。通过ctDNA靶向纠错测序以及白细胞和肿瘤组织的匹配测序，我们追踪了无细胞肿瘤负荷（cfTL）的系列变化，并确定了每位患者的分子反应。同时对外周T细胞库动态进行了系列评估，并与血浆蛋白表达谱一起进行了评估。
分子反应定义为cfTL的完全清除，与无进展生存期（对数秩检验p = 0.0003）和总生存期（对数秩检验p = 0.01）显著相关，并且在捕捉影像学稳定疾病患者的不同生存结果方面特别有参考价值。对于发生irAE的患者，在治疗期间通过显著的TCR克隆型扩增和消退评估发现外周血T细胞库重塑。
分子反应有助于解释异质性临床反应，特别是对于疾病稳定的患者。我们通过液体活检对肿瘤和免疫区室进行的补充评估为监测接受免疫疗法的NSCLC患者的临床获益和免疫相关毒性提供了一种方法。
无细胞肿瘤负荷的纵向动态变化以及外周T细胞库的重塑捕捉了非小细胞肺癌患者免疫治疗期间的临床结果和免疫相关毒性。
