Lesion-Level Response Dynamics to Programmed Cell Death Protein (PD-1) Blockade
Lesion-Level Response Dynamics to Programmed Cell Death Protein (PD-1) Blockade
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DOI：
10.1200/jco.19.00709
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发表时间：
2019-12-20
影响因子：
45.3
通讯作者：
Hellmann, Matthew D.
中科院分区：
文献类型：
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作者：
Osorio, Juan C.;Arbour, Kathryn C.;Hellmann, Matthew D.
对程序性细胞死亡蛋白1（PD-1）阻断的反应通常被认为是肿瘤浸润淋巴细胞复苏的结果。然而，从外周募集的抗肿瘤免疫也可能是应答的重要因素。个体转移的反应动力学的详细评估可以提供洞察介导的反应和抵抗immunotherapy.MATERIALS和方法转移性非小细胞肺癌（NSCLC）或错配修复缺陷（MMRD）癌症与PD-1单药治疗的患者的全身和局部功能进行了独立评估。使用RECIST在每次计算机断层扫描时量化每个靶病变的绝对变化和百分比变化。进展模式被预先定义为系统性或混合性，并与临床outcomes.Results共761个单独的病变从214例NSCLC和290个病变从78例MMRD癌进行了检查。个体靶病灶缓解与每例患者的最佳总体缓解一致（部分缓解/完全缓解患者中85%的NSCLC和93%的MMRD病灶缓解）。在缓解患者中，缓解的时间是一致的（73%的NSCLC和76%的MMRD病变同步缓解），更深的缓解与延长的无进展生存期和总生存期相关。相比之下，在进展时，混合进展很常见（45%的NSCLC和53%的MMRD），与发生系统性进展的患者相比，混合进展与生存期改善相关（NSCLC风险比[HR]，0.58; P = 0.001; MMRD HR，0.40; P = 0.07）。器官部位有不同的反应，淋巴结和肝转移之间的最多和最少的responsible，respectively.CONCLUSION的时间-空间模式的响应跨个人转移往往是统一的，有利于外周，克隆定向抗肿瘤免疫的作用作为一个关键的调解人的PD-1封锁的反应。相比之下，进展是更异质性，潜在地揭示了局部特征和肿瘤间异质性的临床重要性。
PURPOSE Response to programmed cell death protein 1 (PD-1) blockade is often conceptualized as resulting from reinvigoration of tumor-infiltrating lymphocytes. However, recruited antitumor immunity from the periphery may also be an important contributor to response. A detailed assessment of the response dynamics of individual metastasis could provide insight to the systemic and local features that mediate response and resistance to immunotherapy.MATERIALS AND METHODS Patients with metastatic non-small-cell lung cancer (NSCLC) or mismatch repair deficiency (MMRD) carcinoma treated with PD-1 monotherapy were evaluated independently. Absolute and percent change of each target lesion were quantified at each computed tomography scan using RECIST. Patterns of progression were predefined as systemic or mixed and were correlated with clinical outcomes.RESULTS A total of 761 individual lesions from 214 patients with NSCLC and 290 lesions from 78 patients with MMRD carcinoma were examined. Individual target lesion responses aligned with best overall response of each patient (85% NSCLC and 93% MMRD lesions responded in patients with partial response/complete response). In responding patients, timing of response was uniform (73% NSCLC and 76% MMRD lesions responded synchronously), and deeper responses were associated with prolonged progression-free survival and overall survival. By contrast, at progression, mixed progression was common (45% of NSCLC and 53% of MMRD) and associated with improved survival compared with those who experienced systemic progression (NSCLC hazard ratio [HR], 0.58; P = .001; MMRD HR, 0.40; P = .07). Organ sites had differential responses, with lymph node and liver metastasis among the most and least responsive, respectively.CONCLUSION Temporal-spatial patterns of response across individual metastases tend to be uniform, favoring the role of peripheral, clonally directed antitumor immunity as a key mediator of response to PD-1 blockade. In contrast, progression is more heterogeneous, potentially revealing the clinical importance of local features and intertumoral heterogeneity.