Enhancing Natural Killer Cell Mediated Targeting and Responses to Myeloid Leukemias
Abstract
As people age, they accumulate mutations and become more susceptible to certain types of cancers. One group of cancers that represents a growing problem in our aging population is myeloid leukemias. Although treatment of these leukemias has advanced considerably over the past couple of decades, most of these myeloid leukemias still have poor prognosis, particularly in the elderly, and require hematopoietic cell transplants to fully kill the tumor. These transplants are costly, risky, and quite harsh on the patient, especially if the patient is older and frail. A great deal of excitement has recently been placed on cellular therapies to treat tumors. Rather than eradicating the tumors through chemicals and radiation, cellular therapies enhance immune function in the patients so the immune cells themselves can kill the tumors. One type of immune cells whose role is to find and kill tumors is the Natural Killer (NK) cell. Upon clinical diagnosis of myeloid leukemia, the NK cells require help in being targeted to the tumor and overcoming inhibitory signals that help the tumor escape recognition and killing. Our group has recently described small bivalent molecules (termed BiKEs) that target NK cells to myeloid tumors and induce NK cell-mediated tumor killing. Though these molecules show promise, the work scope proposed here builds on them through incorporation of signals that will maximize NK cell function. This will be achieved by creating trivalent molecules (termed TriKEs) that target and activate NK cells but also block inhibitory signals provided by the tumor cells, further enhance the activating signals provided by the BiKE, or drive expansion and maintenance of the NK cells killing the tumor cells. Dr. Felices is a trained immunologist with expertise on signal transduction in his first year as an assistant professor at the University of Minnesota. Signal transduction is the study of how triggering of certain receptors on the surface of cells changes the way they function. Dr. Felices ultimate career goal in cancer research is to integrate his signal transduction knowledge into the generation of molecules that improve NK cell-mediated killing of tumors. His main focus, and the focus of this proposal, is on NK cell functions against myeloid tumors, covered in the Fiscal Year 2015 Topic Area Myeloproliferative disorders. This award would provide protected time and resources to allow Dr. Felices to carry out this research, which will be the foundation he will build on in order to translate his efforts into the clinic and cement his career in the cellular immunotherapy field. Dr. Felices finds himself in an outstanding translational environment at the Masonic Cancer Center in the University of Minnesota, filled with clinical partners (including his mentor) and resources meant to move research from the bench side to the bedside; however, the groundwork needs to be laid through generation and testing of these molecules in order to achieve this goal. Besides the protected time for research, this award will also provide Dr. Felices the chance to attend meetings, both clinical and basic in nature, in order to increase his translational knowledge base and his exposure in the field. Dr. Felices will also utilize some of the protected time to attend courses on basic immunology, molecule design, clinical translation, and grant writing in order to help progress his career as an independent researcher. Altogether, the protected time and resources provided by the award will allow Dr. Felices to expand his knowledge on the field and establish himself. The research proposed here is meant to help patients diagnosed with myeloid leukemias, particularly acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and chronic myeloid leukemia (CML). Although the molecules proposed here have the potential to help every patient diagnosed with myeloid leukemias, elderly patients will particularly benefit from this researc
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610380
Entities
People
- Martin Felices
Organizations
- United States Army
- University of Minnesota