Neoadjuvant PD-1 Blockade in Resectable Lung Cancer.
Neoadjuvant PD-1 Blockade in Resectable Lung Cancer.
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DOI：
10.1056/nejmoa1716078
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发表时间：
2018-05-24
期刊：
影响因子：
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通讯作者：
Pardoll DM
中科院分区：
文献类型：
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作者：
Forde PM;Chaft JE;Smith KN;Anagnostou V;Cottrell TR;Hellmann MD;Zahurak M;Yang SC;Jones DR;Broderick S;Battafarano RJ;Velez MJ;Rekhtman N;Olah Z;Naidoo J;Marrone KA;Verde F;Guo H;Zhang J;Caushi JX;Chan HY;Sidhom JW;Scharpf RB;White J;Gabrielson E;Wang H;Rosner GL;Rusch V;Wolchok JD;Merghoub T;Taube JM;Velculescu VE;Topalian SL;Brahmer JR;Pardoll DM
阻断程序性死亡 1 (PD-1) 蛋白的抗体可改善晚期非小细胞肺癌 (NSCLC) 患者的生存率，但尚未在可切除的 NSCLC 中进行测试，这种疾病在过去十年中几乎没有取得任何进展。在这项试点研究中，我们对未经治疗、可手术切除的早期（I、II 或 IIIA 期）NSCLC 成人患者进行了两次术前剂量的 PD-1 抑制剂纳武单抗治疗。纳武单抗（剂量为每公斤体重 3 毫克）每 2 周静脉注射一次，计划在首次给药后约 4 周进行手术。该研究的主要终点是安全性和可行性。我们还评估了肿瘤病理反应、程序性死亡配体 1 (PD-L1) 的表达、突变负荷以及突变相关的新抗原特异性 T 细胞反应。新辅助纳武单抗具有可接受的副作用，并且与手术延迟无关。在切除的 21 个肿瘤中，20 个被完全切除。 20 个切除肿瘤中有 9 个（45%）发生了主要病理反应。 PD-L1 阳性和 PD-L1 阴性肿瘤均出现缓解。病理反应与治疗前肿瘤突变负荷之间存在显着相关性。在接受评估的 9 名患者中，有 8 名患者在 PD-1 阻断后，肿瘤和外周血中发现的 T 细胞克隆数量全身增加。治疗后 2 至 4 周，来自原发性肿瘤的突变相关新抗原特异性 T 细胞克隆在病理评估完全缓解后在外周血中迅速扩增；在施用纳武单抗之前未检测到其中一些克隆。新辅助纳武单抗副作用很少，不会延误手术，并且在 45% 的切除肿瘤中诱导了主要的病理反应。肿瘤突变负荷可预测 PD-1 阻断的病理反应。治疗诱导外周血中突变相关的新抗原特异性 T 细胞克隆的扩增。 （由癌症研究所 - Stand Up 2 Cancer 和其他机构资助；ClinicalTrials.gov 编号，NCT02259621。）
Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non–small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses. Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab. Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood. (Funded by Cancer Research Institute–Stand Up 2 Cancer and others; ClinicalTrials.gov number, NCT02259621.)