Systemic Distribution and Tumor Localization of Adoptively Transferred Lymphocytes in Mice: Comparison with Physiologically Based Pharmacokinetic Model

Abstract

The mechanisms by which tumors are able to evade cellular immune responses are still largely unknown. It is likely, however, that the initial recruitment of lymphocytes to tumor vessels is limited by cell retention in normal tissue, which results in a low flux of these cells into the tumor vasculature. We grew MCaIV. (20mouse mammary carcinoma) tumors in the leg of SCID mice and injected ¹¹¹In-oxine-labeled, primed T lymphocytes directed against the tumor intravenously. The systemic distribution of cells in normal organs was similar between mice injected with primed and control lymphocyte populations, except for a delayed clearance of primed lymphocytes from the lungs. Kinetics of lymphocyte localization to the tumor were identical between the primed and control lymphocyte populations. Splenectomy before the injection of primed lymphocytes increased delivery of cells to the lungs and liver after 1 hour with no significant improvement in tumor localization. Within 24 to 168 hours after injection, localization of cells in the liver of splenectomized mice was higher than in the control group. However, no significant difference in tumor localization was observed between groups. A physiologically based compartmental model of lymphocyte distribution predicted the compartmental sequestration and identified model parameters critical for experimental planning and therapeutic optimization.