Kim Se Jin, Mugundu Ganesh M, Singh Aman P
Oncology Cell Therapy and Therapeutic Area Unit, Cell Therapy Clinical Pharmacology and Modeling, Precision and Translational Medicine, Takeda Pharmaceuticals, Cambridge, Massachusetts, USA.
Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York, USA.
Clin Transl Sci. 2024 Dec;17(12):e70101. doi: 10.1111/cts.70101.
Autologous chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable response rates, yet its widespread implementation is hindered by logistical, financial, and physical constraints. Additionally, challenges such as poor persistence and allorejection are associated with allogeneic cell therapies. An innovative approach involves in vivo transduction of endogenous T-cells through the administration of CAR mRNA encapsulated in polymeric nanoparticles (NPs), resulting in transient CAR surface expression on circulating T-cells. This method presents a promising alternative, although the dose-exposure-response relationship of in vivo CAR-Ts remains poorly elucidated. The transient nature of CAR expression may necessitate repeated dosing, potentially introducing additional hurdles like cost and patient compliance. To address this issue, we have devised a translational pharmacokinetic-pharmacodynamic (PK-PD) model that characterizes the transient surface CAR expression following mRNA-encapsulated NP administration, leveraging in vitro and in vivo data alongside critical binding kinetic parameters sourced from literature. Our model adequately captures the transient surface CAR expression in both settings, while incorporating known physiological parameter values and exhibiting precise estimation of unknown parameters (coefficient of variation < 30%). Global sensitivity analyses underscore the significance of intracellular mRNA stability, highlighting the sensitivity of parameters linked to free intracellular mRNA concentration. Model-based simulations indicate that optimizing dose and dosing frequency can achieve sustained CAR expression, despite the transient protein expression characteristic of mRNA-based therapies. This mechanistic PK-PD model holds potential for integration into physiologically-based pharmacokinetic models, facilitating the translation of in vivo CAR-T-cell therapies from preclinical studies to human applications.
自体嵌合抗原受体（CAR）T细胞疗法已显示出显著的应答率，但其广泛应用受到后勤、财务和物理限制的阻碍。此外，诸如持久性差和同种异体排斥等挑战与同种异体细胞疗法相关。一种创新方法涉及通过施用封装在聚合物纳米颗粒（NP）中的CAR mRNA对内源性T细胞进行体内转导，从而在循环T细胞上产生瞬时CAR表面表达。尽管体内CAR-T细胞的剂量-暴露-反应关系仍未得到充分阐明，但该方法提供了一种有前景的替代方案。CAR表达的瞬时性质可能需要重复给药，这可能会带来成本和患者依从性等额外障碍。为了解决这个问题，我们设计了一个转化药代动力学-药效学（PK-PD）模型，该模型通过利用体外和体内数据以及从文献中获取的关键结合动力学参数，来表征mRNA封装的NP给药后瞬时表面CAR的表达。我们的模型能够充分捕捉两种情况下的瞬时表面CAR表达，同时纳入已知的生理参数值，并对未知参数进行精确估计（变异系数<30%）。全局敏感性分析强调了细胞内mRNA稳定性的重要性，突出了与游离细胞内mRNA浓度相关参数的敏感性。基于模型的模拟表明，尽管基于mRNA的疗法具有瞬时蛋白表达特性，但优化剂量和给药频率可以实现持续的CAR表达。这种机制性PK-PD模型具有整合到基于生理的药代动力学模型中的潜力，有助于将体内CAR-T细胞疗法从临床前研究转化为人体应用。
