Leveraging Low-Oxygen Environments for Improved Natural Killer Cell Immunotherapy
Abstract
This application is designed to transition my career to a setting where I can directly drive change for cancer patients. My field of expertise is the immune system, specifically, natural killer (NK) cells. These are white blood cells that exist in people and spontaneously kill cancerous and pre-cancerous cells. When cancer develops, it means that the NK cells are exhausted, or the cancer has found a way to escape detection and destruction by NK cells. In 2005, my career guide, Prof. Jeffrey Miller, found that if he gave NK cells from healthy donors to patients with leukemia, he increased the patients’ chances of remission. Twenty-six percent of patients whose cancers were resistant to many other therapies went into remission, making them eligible for curative stem cell therapy. Since then, he and others have refined this therapy through bench research and clinical trials. The latest efforts treating lymphoma involved what is called “chimeric antigen receptors” - genetic alterations that are designed to enhance the ability of NK cells to detect and kill cancerous cells. In this trial, 7 of 11 patients went into complete remission. An important advance has been the development of “off-the-shelf” NK cells where thousands of patients can be treated from a single donation of these genetically altered cells. Our group has developed a method for generating off-the-shelf NK cells from skin cells that are reprogrammed into stem cells and then developed into NK cells for clinical trials. We call these “iNK.” iNK with various genetic alterations are currently in clinical trials for the treatment of leukemia, lymphoma, and solid tumors. In the past, solid tumors have resisted other NK cell therapies; we think this is because the oxygen-starved environment and non-cancerous cells in the tumor may stop NK cells from killing the cancer. My preliminary research shows that oxygen levels found within the body (with a range of 12%-1% oxygen) change NK cell behavior. However, research on NK cells and maturation of NK cells from stem cells for clinical trials is performed at atmospheric (20%) oxygen levels. My data suggests that NK cells matured from stem cells at 5% oxygen (the conditions found in bone marrow where NK cells normally develop from stem cells) will be better at killing cancer cells than NK cells matured at 20% oxygen. My data also shows that NK cells in 1% oxygen (conditions found in tumors) are unable to kill, but I have identified a genetic alteration that I think could reverse this defect. This led me to two aims for this project. Firstly, to test if iNK matured in 5% oxygen can kill leukemia better than iNK produced in 20% oxygen. Secondly, to test if iNK with a genetic alteration can stop the spread of colorectal cancer - a solid tumor where NK cells are not yet an effective treatment. Specifically, this genetic alteration is a novel chimeric antigen receptor that I think will increase iNK detection of colorectal cancer cells and make iNK resistant to the effects of low oxygen. I want to lead a research group focused on NK cell therapy, extending the range of cancer types that can be treated by this new, safe therapy that has few side effects. To achieve this, I need to integrate cancer research and clinical trials into my research portfolio to expand and strengthen my position as an expert immunologist. This application would enable that experience, allowing me to run important projects on novel therapies that could, in time, directly contribute to clinical trials. All this would be under the expert direction of my career guides who have proven records of getting therapies into the clinic from the bench in a matter of years. One of the most exciting elements of this proposal is that if I find that maturation of iNK at 5% oxygen improves treatment of leukemia, we could incorporate this change into ongoing clinical trials of treatment of leukemia and lymphoma within 2 years. Similarly, my industry partners, Fate Therapeu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110255
Entities
People
- Philippa Slinger
Organizations
- United States Army
- University of Minnesota