Development of Novel Chemokine Beacons to Drive Targeted Migration of Natural Killer Cells Toward Colorectal Cancer
Abstract
Colorectal Cancer greatly impacts healthcare burden, with around 140,000 new cases and 60,000 deaths in the United States yearly. About 80% of colorectal cancers are classified as “sporadic” and infectious agents, which military personnel are exposed to at higher levels during deployment, have been shown to be drivers for this category putting military personnel at a higher risk. Early detection of colorectal cancer results in 90% survival, while delayed detection results in 40% survival. Though the US Department of Veterans Affairs has an outstanding colon cancer-screening program for Veterans, it is impossible to detect all cases early. Current therapeutic approaches to advanced cases of metastatic colorectal cancer result in low survival rates and must be improved. Immunotherapies, or therapies that enhance the ability of the body’s own cells to kill tumors, are surging in all forms of cancer therapy, including colorectal cancer. While it might sound simplistic, in order for an immunotherapy to work there needs to be tumor killing cells at the site of the tumor. This has been a major stumbling block in recent immunotherapies, in which tumors remain “cold,” because the tumor killing cells do not enter the tumor. Our objective is to improve survival of patients with metastatic colorectal cancer through methodologies to induce better migration of tumor killing cells, called Natural Killer cells, to the site of the tumor while also preventing exhaustion of these cells so they can perpetuate tumor killing. This addresses the colorectal cancer and immunotherapy Fiscal Year 2019 Peer Reviewed Cancer Research Program (PRCRP) Topic Areas and the “gaps in treatment and survivorship” Focus Area. To increase migration of the Natural Killer cells into colorectal tumors, we will subvert a known tumor escape mechanism. Tumors can escape Natural Killer cells by cutting off from their surface proteins that can be identified by a receptor on the Natural Killer cells. This not only prevents the Natural Killer cell from finding the tumor cell, but the proteins cut off from the tumor cell also bind to circulating Natural Killer cells and shut them down. In fact, it has been shown that presence of these proteins in the blood can be used as a prognostic of poor survival in colorectal cancer. We will create molecules, called chemokine beacons, that have one arm that binds and blocks these soluble tumor-derived proteins attached to another arm that has a protein (known as a chemokine) that tells the Natural Killer cells to move in the direction that the soluble tumor proteins are coming from. As the tumor cells shed these proteins to try to escape the Natural Killer cells, the chemokine beacons will form a gradient that the Natural Killer cells follow in order to find and kill the tumor. My laboratory has expertise in development of these types of biologic molecules to improve Natural Killer cell functionality. One of my other molecules, partly funded by a previous PRCRP Career Development Award, will enter the clinic this month (September of 2019) to treat acute myeloid leukemia, demonstrating the translational potential of these types of approaches to immunotherapy. We will test the chemokine beacons with state of the art systems to evaluate how they drive directed migration of the Natural Killer cells to colorectal tumors. The main deliverable of this proposal is generation and validation of first-in-class molecules to increase immune infiltration into colorectal cancer tumor sites. Since the mechanism of escape is similar in many other types of tumors, these molecules could be applied in other tumor settings. Besides driving migration of Natural Killer cells, it is also possible that these molecules will also drive migration of cytotoxic T cells, another subset of tumor killing cells. Should we succeed, we have a facility at the University of Minnesota capable of producing a batch of chemokine beacon drug that can be tested on metastati
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010535
Entities
People
- Martin Felices
Organizations
- United States Army
- University of Minnesota