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PBPK modeling of T cell distribution in cancer patients
EP38567
Poster Title: PBPK modeling of T cell distribution in cancer patients
Submitted on 04 Apr 2022
Author(s): Dmitry Shchelokov 1, Oleg Demin Jr 1, Sara Brett 2 , Stefan Zajic 3, Lourdes Cucurull-Sanchez 2
Affiliations: 1 InSysBio, Moscow, Russia; 2 GlaxoSmithKline, Stevenage, Hertfordshire, UK; 3 GlaxoSmithKline, Upper Providence, PA, USA
This poster was presented at ACoP12
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Poster Information
Abstract: Objectives: Limitation in migration of engineered T cells into the solid tumor tissue is one of the differences between the application of T cell therapies in the treatment of solid and liquid tumors. The aim of this work is to develop a PBPK model of T cell distribution and to predict the percentage of injected dose infiltrated into the tumor tissue of cancer patients.
Methods: A PBPK model of T cell distribution was developed. There are five compartments in the model: blood, tumor, tumor-draining lymph nodes (TDLN), normal tissues, and lymph nodes (LN). The model describes various subsets of T cells and specific features of their migration: CD4 vs CD8, memory (CCR7+) vs effector (CCR7-). The following composition of infused cells was taken into account: percentage of CCR7+ cells, CD4/CD8 ratio, and percentage of CCR3+ cells. Parameters were identified on the basis of in vivo and clinical data on both healthy subjects and cancer patients including (1) CD4/CD8 ratio, percentage of CCR7+ CD4 and CD8 T cells in the blood, tissues, and LN of healthy subjects; (2) CD4/CD8 ratio, percentage of CCR7+ CD4 and CD8 T cells in blood, tumor, and TDLN of cancer patients; (3) data on intravenous administration of labeled lymphocytes in healthy subjects and cancer patients pretreated or not pretreated with cyclophosphamide [1,2].
Results: The model successfully described the dynamics of labeled T cells in blood, tissues, LN, and tumor after intravenous administration, including the observed difference between administered tumor infiltrated lymphocytes and peripheral blood lymphocytes. T cells rapidly disappeared from the circulation within one day and persisted at a level of ~ 3.5% of the injected dose. Approximately 0.2% of the administered dose is infiltrated into the tumor tissue. Administration of 25 mg/kg cyclophosphamide 24-36 hours before T cell infusion resulted in a 3-fold increase of the rate constant of T cell migration into the tumor (95% confidence intervals: 2.14 – 3.86).
Conclusions: The data collected was sufficient to estimate all model parameters and calculate 95% confidence intervals for fitted parameters. The model predicts the kinetics and distribution of T cells
after intravenous administration in healthy subjects and cancer patients. It can be further applied to optimize T cell product composition and other conditions to increase tumor infiltration of engineered T
cell therapies.
Summary: The data collected was sufficient to estimate all model parameters and calculate 95% confidence intervals for fitted parameters. The model predicts the kinetics and distribution of T cells
after intravenous administration in healthy subjects and cancer patients. It can be further applied to optimize T cell product composition and other conditions to increase tumor infiltration of engineered T
cell therapies.
References: [1] Read EJ, Keenan AM, Carter CS, Yolles PS, Davey RJ (1990) In vivo traffic of indium-111-oxine labeled human lymphocytes collected by automated apheresis. J Nucl Med Jun;31(6):999-1006.
[2] Pockaj BA, Sherry RM, Wei JP, Yannelli JR, Carter CS, Leitman SF, Carasquillo JA, Steinberg SM, Rosenberg SA, Yang JC (1994) Localization of 111indium-labeled tumor infiltrating lymphocytes to tumor in patients receiving adoptive immunotherapy. Augmentation with cyclophosphamide and correlation with response. Cancer Mar 15;73(6):1731-7.
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