A cellular platform enables targeted brain delivery of T cells

      The development of effective cell therapy for central nervous system (CNS) malignancies is hindered by poor cellular homing to brain tumors. Lessons learnt from inflammatory brain diseases can give insight into how to overcome the blood brain barrier (BBB) blockade created by cancer. Activated Leukocyte Cell Adhesion Molecule (ALCAM) is a pathological adhesion molecule upregulated in endothelium of a number of inflammatory CNS diseases. We studied the dynamic signature of adhesion molecules in the “anergic” brain tumor endothelium and that of infiltrative brain conditions . ALCAM is highly expressed on primary glioblastoma (GBM) endothelium, while the ubiquitous adhesion molecules ICAM-1 and VCAM-1 are paradoxically downregulated. We saw a significant induction of ALCAM but not VCAM and ICAM expression when GBM endothelium was cultured in supernatants from primary GBM cells. We concluded that GBM endothelium fails to launch the second wave of adhesion molecules needed for T leukocyte capture and BBB transmigration. Hence, we mapped the ALCAM minimal binding region to domain 3 (D3) of CD6 and created an artificial molecules; successfully expressed on the surface of T cells. D3 crosslinked to endothelial ALCAM in proximity ligation assays (PLA; <40 nm) during Transendothelial migration (TEM). Under shear stress, D3 T cells showed a global improved ALCAM specific trafficking kinetics: higher capture on ALCAM+ endothelium, more rolling with slower velocity, arrest and eventually better TEM. This was not seen on ALCAM (-) normal endothelialium or with non-transduced (NT) T cells.In an ex vivo model of BBB, D3 T cells had higher transmigratory ability over (NT) T cells. Signaling through the D3 phosphorylated pZAp70 recruiting Talin that enables LFA-1 (ICAM-ligand) open confirmation, mediating TEM. Structurally, D3 T cells had higher F-actin/FAK colocalization using TIRF microscopy at its interface with ALCAM; indicating better mechanical stabilization and migration process. Lastly, in an orthotopic model of GBM, D3 T cells homed more and accumulated at the tumor site compared to NT controls. This was confirmed by the detection of D3 T cells in brain explants on pathological examination. In conclusion, we created a platform adroit at targeted brain delivery of T cells. This platform serves as a gateway to the effective cellular therapeutics for brain malignancies but potentially as a delivery system for complex biologics for other pathological conditions.
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