Modeling of Proliferating CD4 and CD8 T‐Cell Changes to Tremelimumab Exposure in Patients with Unresectable Hepatocellular Carcinoma

作者：Xuyang Song, Robin Kate Kelley, Michelle Green, Nathan Standifer, KyoungSoo Lim, Diansong Zhou, James Dunyak, Alejandra Negro, John F. Kurland, Song Ren, Anis A. Khan, Megan Gibbs, Ghassan K. Abou‐Alfa · 发表于：Clinical Pharmacology & Therapeutics · 年份：2023 · DOI：10.1002/cpt.2992 · 被引用次数：7 · 研究领域：Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses、Immune Cell Function and Interaction

The STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen of single‐dose tremelimumab 300 mg, plus durvalumab 1,500 mg every 4 weeks demonstrated potential for long‐term survival in studies of unresectable hepatocellular carcinoma (uHCC; Study 22 and HIMALAYA). The aim of this analysis was to investigate changes in proliferating CD4+ Ki67+ and CD8+ Ki67+ T cells and their relationship with tremelimumab exposure in patients with uHCC. Median cell count, change from baseline, and percent change from baseline in CD4+ and CD8+ T cells peaked around 14 days after STRIDE. A model of CD4+ and CD8+ T cell response to tremelimumab exposure was developed. Patients with lower baseline T cell counts had a greater percent change from baseline in T cell response to tremelimumab, and baseline T‐cell count was included in the final model. With the full covariate model, the half‐maximal effective concentration (EC50) of tremelimumab was 6.10 μg/mL (standard error = 1.07 μg/mL); > 98.0% of patients were predicted to have a minimum plasma concentration greater than EC50 with tremelimumab 300 or 750 mg. For EC75 (9.82 μg/mL), 69.5% and 98.2% of patients were predicted to exceed the EC75 with tremelimumab 300 and 750 mg, respectively. This analysis supports the clinical hypothesis that combination anti‐cytotoxic T‐lymphocyte‐associated antigen 4 (anti‐CTLA‐4) and anti‐programmed cell death ligand‐1 (anti‐PD‐L1) therapy primes an immune response that may then be sustained by anti‐PD‐L1 ...