Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo (A.K., V.A.T., D.K.S.) and Center for Immunotherapy, Roswell Park Cancer Institute (S.M., R.C.K.), Buffalo, New York.
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo (A.K., V.A.T., D.K.S.) and Center for Immunotherapy, Roswell Park Cancer Institute (S.M., R.C.K.), Buffalo, New York
J Pharmacol Exp Ther. 2019 Mar;368(3):503-513. doi: 10.1124/jpet.118.252858. Epub 2019 Jan 8.
Here we have investigated whole-body pharmacokinetics (PK) of exogenously administered T cells in a mouse model of melanoma and have developed a physiologically based pharmacokinetic (PBPK) model to quantitatively characterize the data. T cells were isolated from the spleen of tumor-bearing mice, activated, and labeled with chromium-51 to facilitate the quantification. Labeled T cells were injected in the tumor-bearing mice, and PK was measured in 19 different tissues. It was found that T cells disappear from the blood rapidly after administration and accumulate in the tissues to various extents. Spleen, liver, lung, kidney, bone, and lymph nodes accounted for more than 90% of T cells in the body. The distribution of T cells in solid tumors was found to be very low, hovering below 1%ID/g (percent of injected dose per gram of tissue) during the entire study. However, this observation may differ for targeted TCR-T and CAR-T cells. Observed PK profiles also suggest that T-cell-based therapies may be more successful in treating cancers of the lymphatic system and bone marrow metastases compared to solid tumors. A PBPK model was developed to characterize the whole-body PK of T cells, which incorporated key processes such as extravasation, elimination, and recirculation of T cells via lymph flow. Retention factors were incorporated into the spleen, liver, and kidney compartment to adequately capture the PK profiles. The model was able to characterize observed PK profiles reasonably well, and parameters were estimated with good confidence. The PK data and PBPK model presented here provide unprecedented insight into the biodistribution of exogenously administered T cells.
我们研究了黑色素瘤小鼠模型中过继输注 T 细胞的全身药代动力学（PK），并开发了一种基于生理学的药代动力学（PBPK）模型来定量描述数据。从荷瘤小鼠的脾脏中分离出 T 细胞，进行激活，并标记铬-51 以方便定量。将标记的 T 细胞注射到荷瘤小鼠中，在 19 种不同组织中测量 PK。结果发现，T 细胞给药后迅速从血液中消失，并在不同程度上在组织中积累。脾脏、肝脏、肺、肾脏、骨骼和淋巴结占体内 T 细胞的 90%以上。发现 T 细胞在实体瘤中的分布非常低，在整个研究过程中，其浓度徘徊在 1%ID/g（组织中注射剂量的百分比）以下。然而，对于靶向 TCR-T 和 CAR-T 细胞，这种观察结果可能会有所不同。观察到的 PK 谱还表明，与实体瘤相比，基于 T 细胞的疗法可能更成功地治疗淋巴系统癌症和骨髓转移。开发了一种 PBPK 模型来描述 T 细胞的全身 PK，该模型纳入了 T 细胞通过淋巴流动外渗、消除和再循环等关键过程。将保留因子纳入脾脏、肝脏和肾脏隔室，以充分捕捉 PK 谱。该模型能够很好地描述观察到的 PK 谱，并且参数的估计具有很好的可信度。本文提供的 PK 数据和 PBPK 模型为过继输注的 T 细胞的生物分布提供了前所未有的见解。
