document: A limitation of the pharmacyte approach is the one-time nature of the intervention: ACT T-cells can only be loaded once with a cargo of adjuvant drug prior to transfer, and the duration of stimulation is inherently limited by expansion of the cell population in vivo, since cell-bound particles are diluted with each cell division. We hypothesized that a strategy to target supporting drugs to T-cells with nanoparticle drug carriers directly in vivo would enable transferred lymphocytes to be repeatedly stimulated with supporting adjuvant drugs, and thereby provide continuous supporting signals over the prolonged durations that might be necessary for elimination of large tumor burdens. Such “re-arming” of T-cells with supporting drugs could be achieved by repeated administration of targeted particles, allowing adoptively-transferred T-cells to be restimulated multiple times directly in vivo, while the use of internalizing targeting ligands would minimize the likelihood of immune responses against the nanoparticle carrier. To our knowledge, only two prior studies have attempted to target nanoparticles to T-cells in vivo [17,18]. In both of these studies, particles were targeted to T-cells via peptide-MHC ligands that bind to specific T-cell receptors. However, peptide-MHC-functionalized nanoparticles have recently been shown to deliver an anergizing/tolerizing signal to T-cells [18,19] — which is ideal for treating graft rejection or autoimmunity, but runs counter to the goals of cancer immunotherapy.
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