The First-week Proliferative Response of Peripheral Blood PD-1 + CD8 + T Cells Predicts the Response to Anti-PD-1 Therapy in Solid Tumors

• Published in: Clinical cancer research 2019-04, Vol.25 (7), p.2144-2154
• Main Authors: Kim, Kyung Hwan, Cho, Jinhyun, Ku, Bo Mi, Koh, Jiae, Sun, Jong-Mu, Lee, Se-Hoon, Ahn, Jin Seok, Cheon, Jaekyung, Min, Young Joo, Park, Su-Hyung, Park, Keunchil, Ahn, Myung-Ju, Shin, Eui-Cheol
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers, Tumor; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Proliferation - drug effects; Female; Flow Cytometry; Humans; Lymphocyte Count; Male; Middle Aged; Molecular Targeted Therapy; Neoplasms - blood; Neoplasms - diagnosis; Neoplasms - drug therapy; Neoplasms - mortality; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; ROC Curve; Survival Analysis; Time Factors; Treatment Outcome
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-1449

To investigate blood-based dynamic biomarkers that predict responses to anti-programmed cell death protein 1 (PD-1) therapy in solid tumors. Preplanned biomarker analysis was performed as part of a phase II clinical trial (NCT02607631) in patients with metastatic or refractory thymic epithelial tumors (TETs; = 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; = 33) and validated in an independent cohort of patients with NSCLC (NSCLC cohort 2; = 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. 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 ) significantly predicted durable clinical benefit (DCB; < 0.001) and prolonged progression-free survival (PFS; = 0.027) in patients with TETs. Ki-67 ≥ 2.8 was also associated with better DCB, PFS, and overall survival (OS) in NSCLC cohort 1 (all < 0.05). Ki-67 was subsequently validated in NSCLC cohort 2, and Ki-67 ≥ 2.8 significantly predicted better DCB ( = 0.001), PFS ( = 0.002), and OS ( = 0.037). Ki-67 had a low correlation with tumor PD-L1 expression and combining both factors did not improve the predictive power of Ki-67 . 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 (Ki-67 ), may be a useful surrogate biomarker for predicting the response and prognosis to anti-PD-1 therapy in solid tumors.