UC Irvine

Despite decades of research and advancement in cancer therapeutics, metastases continue to be challenging to treat using traditional highly toxic drugs. Metastases can be too small to identify by the traditional electromagnetic scans used for identifying large tumors, and thus go undiagnosed and untreated until they have spread beyond the ability of drugs to stop them. Cancer bone metastases are especially problematic to treat due to their ability to degrade bone tissue and invade into the damaged bone. The discovery that stem cells may have a propensity to home toward tumors, implies they may be able to identify features of the tumor micro-environment, which traditional small molecule drugs are not specific enough to distinguish from healthy tissue. MSC (mesenchymal stromal/stem cells) are particularly useful because they have far lower immunogenicity than other allogeneic cell or tissue transplants. We developed several systems using MSC as vectors to deliver therapeutics more specifically to the tumor microenvironment, with far lower toxicity than standard chemotherapy. Unfortunately, animal models of bone metastasis leave much to be desired, and a new method using a combination of in vivo selection and intra-arterial delivery of cancer cells, was developed to study our cancer bone metastasis treatment in mice. One novel treatment system we developed and tested involves the multipotent mRNA transfection of MSC with P-selectin glycoprotein ligand-1 and Sialyl-Lewis X to improve homing capabilities of the MSC, osteoprotegerin to reduce bone resorption, and cytosine deaminase to convert injected prodrug to potent anti-cancer drug specifically in the locale of the tumors. This treatment was shown to both reduce tumor growth and to impair the destruction of bone caused by the metastatic invasion of bone tissue. Additionally, MSC are well known to have strong immunomodulatory capabilities. We performed a meta-analysis of preclinical and clinical studies using MSC to treat Rheumatoid arthritis (RA), and found that significant work still needs to be done to evaluate the effects of MSC transplantation on inflammatory diseases, such as RA. Using what was learned from the meta-analysis MSC were evaluated in their ability to treat two prevalent auto-immune diseases: RA and inflammatory bowel disease (IBD). The MSC therapy significantly reduced inflammation in both RA and IBD when given as systemic injections. These studies were the basis of IND applications to the US FDA for a new MSC therapeutic product (BX-U001), which were approved to be further evaluated in clinical trials in the coming years. There are many more possible applications of MSC to treat disease because they have low immunogenicity and minimal safety concerns (considered by many to be the safest allogeneic stem cell transplant option), they can be easily mass produced (despite being primary cells), their ability to be engineered to carry many therapeutics (due to the complexity and modularity of cells), and their innate homing towards sites of inflammation and cancer. The combination of many different tools and abilities, make MSC like the Swiss Army knife of cell therapies, capable of tackling challenges which single target small molecule drugs cannot.