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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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.
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CLINICAL CANCER RESEARCH, v.25, no.7, pp.2144 - 2154

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