PHYSIOLOGICALLY-BASED KINETIC-MODEL OF EFFECTOR CELL BIODISTRIBUTION IN MAMMALS - IMPLICATIONS FOR ADOPTIVE IMMUNOTHERAPY

The goal of the present investigation was to develop a physiologically based kinetic model to describe the biodistribution of immunologicall y active effector cells in normal and neoplastic tissues of mammals ba sed on the current understanding of lymphocyte trafficking pathways an d signals. The model was used to extrapolate biodistribution among dif ferent animal species and to identify differences among different effe ctor populations and between intra-arterial and systemic: injections, Most importantly, the model was used to discern critical parameters fo r improving the delivery of effector cells. In the model, the mammalia n body was divided into 12 organ compartments, interconnected in anato mic fashion, Each compartment was characterized by blood flow rate, or gan volume and lymphatic flow rate, and other physiological and immuno logical parameters. The resulting set of 45 differential equations was solved numerically. The model was used to simulate the following biod istribution data: (a) nonactivated T lymphocytes in rats; (b) interleu kin 2-activated tumor-infiltrating lymphocytes in humans; (c) nonactiv ated natural killer (NK) cells in rats; and (d) interleukin 2-activate d 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 ly mphocyte populations were revealed as results of their trafficking pro perties. The importance of lymphocyte infiltration from surrounding no rmal tissues into tumor tissue was found to depend on lymphocyte migra tion rate, tumor size, and host organ. The study confirmed that treatm ent with effector cells has not been as impressive as originally promi sed, due, in part, to the biodistribution problems. The model simulati ons demonstrated that low effector concentrations in the systemic circ ulation greatly limited their delivery to tumor, This was due to high retention in normal tissues, especially in the lung. Reducing normal t issue retention through decreasing attachment rate or adhesion site de nsity in the lung by 50% could increase the tumor uptake by similar to 40% for tumor-infiltrating lymphocytes and by similar to 60% for adhe rent NK cells. Our analysis suggested the following strategies to impr ove effector cell delivery to tumor: (a) bypassing the initial lung en trapment with administration to the arterial supply of tumor; (b) redu cing normal tissue retention using effector cells with high deformabil ity or blocking lymphocyte adhesion to normal vessels; and (c) enhanci ng tumor-specific capture and arrest by modifying the tumor microenvir onment.