Early changes in the circulating T cells are associated with clinical outcomes after PD-L1 blockade by durvalumab in advanced NSCLC patients.
Early changes in the circulating T cells are associated with clinical outcomes after PD-L1 blockade by durvalumab in advanced NSCLC patients.
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DOI：
10.1007/s00262-020-02833-z
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Naidus E;Bouquet J;Oh DY;Looney TJ;Yang H;Fong L;Standifer NE;Zhang L
免疫检查点抑制剂（ICI）旨在激活耗尽的肿瘤反应性T细胞，从而导致肿瘤消退。Durvalumab是一种与程序性死亡配体-1（PD-L1）分子结合的ICI，被批准作为治疗III期不可切除的非小细胞肺癌（NSCLC）患者的巩固治疗。循环免疫细胞的免疫表型分析显示，durvalumab治疗后早期循环增殖性CD 4+和CD 8 + T细胞增加。为了检查durvalumab的作用机制并鉴定潜在的预测性生物标志物，我们评估了在I期试验（NCT 01693562，2012年9月14日）中招募的接受durvalumab的71名NSCLC患者的循环T细胞表型和TCR基因。在基线和第15天对这些NSCLC患者的外周血样品进行TCR库的下一代测序。尽管患者的TCR库多样性显示出对治疗的混合反应，但在第15天表现出多样性增加的患者获得了显著更长的总生存期（OS）（未达到中位OS，而多样性降低的患者为17.2个月，p = 0.015）。我们应用网络分析来评估指示抗原驱动的免疫应答的会聚T细胞克隆型。TCR簇较大的患者OS改善（未达到中位OS，TCR簇较小的患者为13.1个月，p = 0.013）。durvalumab治疗NSCLC后早期TCR库多样化可能预示生存期延长，并为durvalumab药效学活性提供机制基础。在线版本包含补充材料，可通过10.1007/s 00262 -020-02833-z获得。
Immune checkpoint inhibitors (ICI) are designed to activate exhausted tumor-reactive T cells thereby leading to tumor regression. Durvalumab, an ICI that binds to the programmed death ligand-1 (PD-L1) molecule, is approved as a consolidation therapy for treatment of patients with stage III, unresectable, non-small cell lung cancer (NSCLC). Immunophenotypic analysis of circulating immune cells revealed increases in circulating proliferating CD4 + and CD8 + T cells earlier after durvalumab treatment. To examine durvalumab’s mechanism of action and identify potential predictive biomarkers, we assessed the circulating T cells phenotypes and TCR genes of 71 NSCLC patients receiving durvalumab enrolled in a Phase I trial (NCT01693562, September 14, 2012). Next-generation sequencing of TCR repertoire was performed on these NSCLC patients’ peripheral blood samples at baseline and day 15. Though patients’ TCR repertoire diversity showed mixed responses to the treatment, patients exhibiting increased diversity on day 15 attained significantly longer overall survival (OS) (median OS was not reached vs 17.2 months for those with decreased diversity, p = 0.015). We applied network analysis to assess convergent T cell clonotypes indicative of an antigen-driven immune response. Patients with larger TCR clusters had improved OS (median OS was not reached vs 13.1 months for patients with smaller TCR clusters, p = 0.013). Early TCR repertoire diversification after durvalumab therapy for NSCLC may be predictive of increased survival and provides a mechanistic basis for durvalumab pharmacodynamic activity. The online version contains supplementary material available at 10.1007/s00262-020-02833-z.
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影响因子：
6.4
作者：
Liu, Yang-Yang;Yang, Qi-Fan;Liu, Li
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DOI：
10.1073/pnas.1705327114
发表时间：
2017-05-09
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影响因子：
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DOI：
10.1056/nejmoa1504627
发表时间：
2015-07-09
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brahmer J;Reckamp KL;Baas P;Crinò L;Eberhardt WE;Poddubskaya E;Antonia S;Pluzanski A;Vokes EE;Holgado E;Waterhouse D;Ready N;Gainor J;Arén Frontera O;Havel L;Steins M;Garassino MC;Aerts JG;Domine M;Paz-Ares L;Reck M;Baudelet C;Harbison CT;Lestini B;Spigel DR
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Spigel DR
影响因子：
50.3
作者：
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