Yamada Akihiro, Choules Mary P, Brightman Frances A, Takeshita Shigeru, Nakao Shinsuke, Amino Nobuaki, Nakayama Takeshi, Takeuchi Masato, Komatsu Kanji, Ortega Fernando, Mistry Hitesh, Orrell David, Chassagnole Christophe, Bonate Peter L
Astellas Pharma Inc., Tokyo, Japan.
Astellas Pharma Inc., Northbrook, Illinois, USA.
CPT Pharmacometrics Syst Pharmacol. 2025 Mar;14(3):572-582. doi: 10.1002/psp4.13297. Epub 2025 Jan 8.
The antitumor efficacy of an intratumoral injection of a genetically engineered oncolytic vaccinia virus carrying human IL-7 and murine IL-12 genes (hIL-7/mIL-12-VV) was demonstrated in CT26.WT-bearing mice. In the CT26.WT-bearing mouse model, the efficacy of the combination of hIL-7/mIL-12-VV plus the anti-programmed cell death protein (PD)-1 antibody was determined to be correlated with the timing of administration: greater efficacy was observed when hIL-7/mIL-12-VV was administered before the anti-PD-1 agent instead of simultaneous administration. To identify an optimal dosing regimen for first-in-human clinical trials, a multiple model-informed drug-development (MIDD) approach was used through development of a quantitative systems pharmacology (QSP) model and an agent-based model (ABM). All models were built and verified using available literature and preclinical study data. Multiple dosing scenarios were explored using virtual populations by altering the interval between hIL-7/hIL-12-VV and pembrolizumab administration. In contrast with observations from preclinical studies, both the QSP and the ABM models demonstrated no antagonistic effect on the dose-dependent antitumor efficacy of hIL-7/hIL-12-VV by pembrolizumab in simulations of clinical therapy. Based on the MIDD strategy, it was recommended that the highest dose of hIL-7/hIL-12-VV and pembrolizumab should be administered on the same day, but with pembrolizumab administration following hIL-7/hIL-12-VV administration. Multiple different modeling approaches uniquely supported and informed the first-in-human clinical trial design by guiding the optimal dose and regimen selection.
在携带CT26.WT肿瘤的小鼠中证实了瘤内注射携带人IL-7和小鼠IL-12基因的基因工程溶瘤痘苗病毒（hIL-7/mIL-12-VV）的抗肿瘤疗效。在携带CT26.WT肿瘤的小鼠模型中，确定hIL-7/mIL-12-VV联合抗程序性细胞死亡蛋白（PD）-1抗体的疗效与给药时间相关：当hIL-7/mIL-12-VV在抗PD-1药物之前给药而非同时给药时，观察到更高的疗效。为了确定首次人体临床试验的最佳给药方案，通过开发定量系统药理学（QSP）模型和基于主体的模型（ABM），采用了多模型知情药物开发（MIDD）方法。所有模型均使用现有文献和临床前研究数据构建并验证。通过改变hIL-7/hIL-12-VV与派姆单抗给药之间的间隔，使用虚拟人群探索了多种给药方案。与临床前研究的观察结果相反，在临床治疗模拟中，QSP模型和ABM模型均未显示派姆单抗对hIL-7/hIL-12-VV的剂量依赖性抗肿瘤疗效有拮抗作用。基于MIDD策略，建议hIL-7/hIL-12-VV和派姆单抗的最高剂量应在同一天给药，但派姆单抗应在hIL-7/hIL-12-VV给药后给药。多种不同的建模方法通过指导最佳剂量和方案选择，独特地支持并为首次人体临床试验设计提供了信息。
