Development of immunotherapeutic nano-ghosts as a cell-free nanometric system for cancer immunotherapy

Cancer immunotherapy relies on exploiting the therapeutic potential of tumor-specific antibodies and cellular immune effector mechanisms, such as Cytotoxic T lymphocytes (CTLs), for treating cancer. However, this approach faces some critical challenges limiting the applicability and availability of immunotherapy. These include overcoming physiological and biological barriers that limit T cells infiltration and cytotoxic effect as well as directing T cells against multiple malignancies1,2. Mesenchymal Stem cells (MSCs), contrastingly, are equipped with a variety of mechanisms that enable them to target various tumors at different stages. Nonetheless, clinical studies testing this approach have been mostly disappointing, due to MSCs susceptibility to host-induced changes.

We hypothesize that overcoming these challenges can be achieved by combining the safety and tumor-targeting capabilities of MSCs with the tumor-restrictive properties of CTLs in an inanimate platform that can withstand the limiting host influences. Furthermore, using such an inanimate platform will enable the delivery of anti-cancerous factors through their encapsulation or their expression on its surface, thus enhancing the therapeutic effect. The foundations for this platform were established by a novel class of nanovesicles (~200 nm), termed immuno-Nano-Ghosts (iNGs), which are produced from the plasma membranes of human MSCs (hMSCs) and T cell membranes.

The iNGs were shown to retain both T cells and MSCs natural surface moieties and encompass their unique targeting and cytotoxic capabilities towards cancer tumors. Equipped with the membrane proteins of both cell types, iNGs retain MSC active tumor-targeting abilities, while exploiting T cell’s cytotoxic effects. Moreover, their nanometric size allows the iNGs to utilize the enhanced permeability and retention effect of the tumor’s microenvironment for their targeting. To date, our results have established the safety of Nano-Ghosts (NG) derived from MSCs (MSC-NG) and their ability to target multiple tumor models3. Furthermore, we have managed to genetically engineer MSCs to express CTL-inspired membrane protein as well as to develop a protocol for the production of NG from T cells. Such an approach may result in as immunomimetic therapeutic system that allows it to target and selectively eradicate tumors and cancer malignancies.