) The ability to engineer cells and return them to the body to carry out specific therapeutic tasks is an important objective that has become increasingly feasible in recent years as the technologies for cell harvesting, expansion and manipulation have become more sophisticated. However it has been repeatedly found that the majority of cells reinfused after ex vivo manipulation become trapped in the lungs, liver and spleen. We propose to improve the availability of reinfused cells through a variety of approaches. Our research plan is guided by three principal hypotheses. We assume that the principal factor in lung entrapment of lymphocytes is mechanical - i.e., that it is due to both lymphocyte size and local regulation of pulmonary microvascular circulation. The latter takes into account the capacity of the lung to exhibit dynamic flow relaxation under conditions of varying oxygen tension. We assume that the principal factor in liver and spleen entrapment is the macrophage foreign body reaction and the hepatocyte asialoglycoprotein receptor recycling pathway. Finally, we assume that the most significant factor for the persistence of the T cells that survive these challenges is their ability to endure the absence of interleukin 2 (IL-2). We hypothesize that if T cells can be endowed with an ability to evade growth factor withdrawal they can begin to form a more generally applicable cellular platform for tumor therapy, and in this context, we propose to explore different approaches to enhance their capacity to adhere to and extravasate through tumor microvascular endothelium.
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