The First-week Proliferative Response of Peripheral Blood PD-1+CD8+ T Cells Predicts the Response to Anti-PD-1 Therapy in Solid Tumors
The First-week Proliferative Response of Peripheral Blood PD-1+CD8+ T Cells Predicts the Response to Anti-PD-1 Therapy in Solid Tumors
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DOI：
10.1158/1078-0432.ccr-18-1449
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发表时间：
2019-04-01
影响因子：
11.5
通讯作者：
Shin, Eui-Cheol
中科院分区：
文献类型：
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作者：
Kim, Kyung Hwan;Cho, Jinhyun;Shin, Eui-Cheol
目的：研究基于血液的动态生物标记物预测实体瘤中抗程序性细胞死亡蛋白1(PD-1)治疗的反应。实验设计：作为II期临床试验(NCT02607631)的一部分，对接受培溴利珠单抗治疗的转移性或难治性胸腺上皮性肿瘤(TETS；n=31)患者进行预先计划的生物标记物分析。该生物标记物在接受培溴利珠单抗或nivolumab治疗的转移性非小细胞肺癌(NSCLC)患者的独立队列中进一步测试(1；n=33)，并在NSCLC患者的独立队列中验证(NSCLC队列2；n=46)。结果：首剂治疗后7d，PD-1(+)CD8(+)T细胞中Ki-67(+)细胞比例的倍增(Ki-67(D7/D0))显著预示着TETS患者的持久临床获益(Dcb；P<；0.001)和延长无进展生存期(PFS；P=0.027)。在NSCLC队列1中，Ki-67(D7/D0)和Gt；=2.8也与较好的DCB、PFS和总生存期(OS)相关(均P<；0.05)。Ki-67(D7/D0)和Ki-67(D7/D0)和Gt；=2.8显著预测DCB(P=0.001)、PFS(P=0.002)和OS(P=0.037)。Ki-67(D7/D0)与肿瘤PD-L1表达的相关性较低，两者联合应用并不能提高Ki-67(D7/D0)的预测能力。结论：外周血PD-1(+)CD8(+)T细胞的增殖反应，以治疗7d后Ki-67(+)细胞百分率的倍数变化(Ki67(D7/D0))为指标，可作为实体瘤抗PD-1治疗反应和预后的替代指标。
Purpose: To investigate blood-based dynamic biomarkers that predict responses to anti-programmed cell death protein 1 (PD-1) therapy in solid tumors.Experimental Design: Preplanned biomarker analysis was performed as part of a phase II clinical trial (NCT02607631) in patients with metastatic or refractory thymic epithelial tumors (TETs; n = 31) who received pembrolizumab. The biomarker was further tested in an independent cohort of prospectively recruited patients with metastatic non-small cell lung cancer (NSCLC) who received pembrolizumab or nivolumab (NSCLC cohort 1; n = 33) and validated in an independent cohort of patients with NSCLC (NSCLC cohort 2; n = 46). Peripheral blood samples were obtained immediately before treatment (D0) and 7 days after the first dose (D7) and analyzed using multi-color flow cytometry.Results: A higher fold-change in the percentage of Ki-67(+) cells among PD-1(+)CD8(+) T cells 7 days after the first dose (Ki-67(D7/D0)) significantly predicted durable clinical benefit (DCB; P < 0.001) and prolonged progression-free survival (PFS; P = 0.027) in patients with TETs. Ki-67(D7/D0) >= 2.8 was also associated with better DCB, PFS, and overall survival (OS) in NSCLC cohort 1 (all P < 0.05). Ki-67(D7/D0) was subsequently validated in NSCLC cohort 2, and Ki-67(D7/D0) >= 2.8 significantly predicted better DCB (P = 0.001), PFS (P = 0.002), and OS (P = 0.037). Ki-67(D7/D0) had a low correlation with tumor PD-L1 expression and combining both factors did not improve the predictive power of Ki-67(D7/D0).Conclusions: The proliferative response of peripheral blood PD-1(+)CD8(+) T cells, measured as the fold-change in the percentage of Ki-67(+) cells 7 days after treatment (Ki67(D7/D0)), may be a useful surrogate biomarker for predicting the response and prognosis to anti-PD-1 therapy in solid tumors.