TRAIL Coated Genetically Engineered Immunotherapeutic Nano‐Ghosts Vesicles Target Human Melanoma‐Avoiding the Need for High Effective Therapeutic Concentration of TRAIL

Abstract

Cancer cell therapy using cytotoxic T lymphocytes (CTL) or mesenchymal stem cells (MSC) possesses hurdles due to the cells, susceptibility to host induced changes. Here, versatile inanimate broadly applicable nanovesicles, termed immunotherapeutic-nano-ghosts (iNGs), are armed with inherent surface-associated targeting and therapeutic capabilities in which the promise and benefits of MSC therapy and T cell immunotherapy are combined into one powerful off-the-shelf approach for treating malignant diseases. To mimic the cytotoxic or immunosuppressive functions of T cells, iNG are produced from MSC that were genetically engineered (GE) or metabolically manipulated to express additional membrane-bound proteins, endowing the NGs derived therefrom with additional surface-associated functions such as tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). iNGs from GE-MSCs (GE-iNGs) show superior TRAIL retention and induce apoptosis in different cancer cell lines in vitro. In vivo studies on a human melanoma model demonstrate that a systemic, three-day frequency, administration of GE-iNGs result in tumor inhibition comparable to a six orders of magnitude higher concentration of soluble TRAIL. The iNGs are therefore a promising nanovesicle platform that can affect tumors in a non-immunogenic manner while avoiding the need for a highly effective therapeutic concentration.