Physiologically based kinetic model of effector cell biodistribution in mammals: implications for adoptive...

The goal of the present investigation was to develop a physiologically based kinetic model to describe the biodistribution of immunologically active effector cells in normal and neoplastic tissues of mammals based on the current understanding of lymphocyte trafficking pathways and signals. The model was used to extrapolate biodistribution among different animal species and to identify differences among different effector populations and between intra-arterial and systemic injections. Most importantly, the model was used to discern critical parameters for improving the delivery of effector cells. In the model, the mammalian body was divided into 12 organ compartments, interconnected in anatomic fashion. Each compartment was characterized by blood flow rate, organ volume and lymphatic flow rate, and other physiological and immunological parameters. The resulting set of 45 differential equations was solved numerically. The model was used to simulate the following biodistribution data: (a) nonactivated T lymphocytes in rats; (b) interleukin 2-activated tumor-infiltrating lymphocytes in humans; (c) nonactivated natural killer (NK) cells in rats; and (d) interleukin 2-activated adherent NK cells in mice. Comparisons between simulations and data demonstrated the feasibility of the model and the scaling scheme. The similarities as well as differences in biodistribution of different lymphocyte populations were revealed as results of their trafficking properties. The importance of lymphocyte infiltration from surrounding normal tissues into tumor tissue was found to depend on lymphocyte migration rate, tumor size, and host organ. The study confirmed that treatment with effector cells has not been as impressive as originally promised, due, in part, to the biodistribution problems. The model simulations demonstrated that low effector concentrations in the systemic circulation greatly limited their delivery to tumor. This was due to high retention in normal tissues, especially in the lung. Reducing normal tissue retention through decreasing attachment rate or adhesion site density in the lung by 50% could increase the tumor uptake by approximately 40% for tumor-infiltrating lymphocytes and by approximately 60% for adherent NK cells. Our analysis suggested the following strategies to improve effector cell delivery to tumor: (a) bypassing the initial lung entrapment with administration to the arterial supply of tumor; (b) reducing normal tissue retention using effector cells with high deformability or blocking lymphocyte adhesion to normal vessels; and (c) enhancing tumor-specific capture and arrest by modifying the tumor microenvironment.