Combined targeted and immune-therapy of metastatic cancer by MSC-derived Nano-Ghosts

Combination therapies comprised of immunotherapy and targeted therapy, may improve clinical outcomes when treating metastases. Targeted therapies can not only induce direct tumor cell death by selective inhibiting molecular pathways but can also stimulate different components of the immune system. In response, immunotherapy can sensitize tumor cells to immune attack and enhance the cytotoxic response achieved with targeted therapy leading to a long-lasting remission. Effective treatment using such combinations, which often differ in their physicochemical properties and bioavailability, requires them to reach their diverse targets simultaneously.

To address this challenge, we propose to utilize our novel targeted drug and gene delivery system, termed Nano-Ghosts (NGs). These are nano-vesicles reconstructed from the plasma membrane of allogeneic human mesenchymal stem cells (MSCs). The NGs’ retention of MSC membrane proteins ensures their safety and allogenic tolerability and furnishes them with the ability to home in on multiple tumors and sites of inflammation. The ability to entrap different therapeutics in the NGs, along with their multitude of cellular targets makes them uniquely adequate carriers for combination therapies.

The NGs’ selective targeting capabilities were demonstrated in a variety of metastatic cancer cells and have most effectively targeted lung cancer cells. We demonstrated that the NGs have selectively accumulated in the lungs of metastases-bearing mice, while rapidly clearing from all other blood-filtering organs. Furthermore, NGs loaded with a pDNA encoding a cancer-toxic gene, dramatically inhibited established metastases in a metastatic orthotopic NSCLC. We seek to explore the NGs’ ability to target the primary tumor and its metastatic lesions. NGs will be loaded with different combination of genetic payloads and highly immunogenic proteins, for synergistically triggering cell apoptosis and sensitizing cancer cells to an intense cytotoxic immune response. The engineered NGs will be evaluated at different stages of a metastatic NSCLC model to produce both immediate and long-lasting synergistic effects.