Bone Marrow-derived Mesenchymal Stem Cells (MSCs) as a Selective Delivery Vehicle for a PSA-Activated Protoxin for Advanced Prostate Cancer

摘要

Circulating Mesenchymal Stem Cells (MSCs) originating from the bone marrow have the ability to differentiate into cells of the mesoderm lineage and an innate tropism for tumor tissue in response to the inflammatory microenvironment present in malignant lesions. MSCs have been detected in the perivascular space of many tumors, including those of the prostate, and have been shown to be a critical element in oncogenic progression. MSCs are inherently non-immunogenic, which prevents allogeneic MSCs from being rejected by normal host defense mechanisms. This immune-privileged status, together with their oncotropic properties, makes possible the infusion of allogeneic MSCs into patients for therapeutic purposes, such as the delivery of cytotoxic agents to sites of primary and metastatic prostate cancer. PRX302 is a PSA- activated aerolysin-based protoxin that forms membrane pores and leads to necrosis by a proliferation-independent mechanism at low picomolar concentrations. Importantly, PRX302 binds with low nanomolar affinity to GPI- anchor proteins, which are highly expressed on the surface of all mammalian cells. Therefore, MSCs can be genetically manipulated to express the PRX302 transgene endogenously from a safe harbor locus.