Transcription Control of Exhaustion Program in CAR T-Cell Therapy
Abstract
Our objective is to improve treatments for patients with solid tumors, especially pancreatic cancer. Remarkable advances in the recent years have proven beyond doubt that white blood cells called T cells are able to kill cancer cells, sometimes to the point of delivering complete cures. This has been shown to be true even for patients with advanced solid tumors that are resistant to all other modes of treatment. One of the most promising of these immunotherapies involves taking T cells out of a patients body, genetically modifying them with a targeting agent that binds to cancer cells and injecting them once again into the patients blood stream where they bind to and kill cancer cells. This approach has been remarkably effective in patients with advanced blood cancers; however, it has shown limited effectiveness so far in trials for patients with solid tumors. One reason for this lack of success is that T cells become exhausted, losing function after a week or two. Our research seeks to discover novel genetic modifications that will prevent T cells from becoming exhausted so they will continue fighting cancer until it is cleared. To do so, we have performed computational analyses on large amounts of data comparing exhausted T cells to functional T cells. What weve found is that certain genes are on in exhausted T cells across all conditions we analyzed. We believe that preventing these genes from turning on is the key to preventing exhaustion. To do so, we will specifically modify a subset of genes called transcription factors that are known to regulate the on or off state of other genes. By doing so, we will attack exhaustion at its roots: the master regulators that control the whole program. Already in pilot studies we have had remarkable success with this approach. With this funding, we will build on those studies to bring exhaustion-free T cells to patients. This research will ultimately create a treatment option that is useful across all solid tumors. All T cells become exhausted. Currently, any therapy that uses T cells has a limited window in which it needs to clear the cancer or else it will fail when the T cells become exhausted. Our research will lead to methods to expand that window, allowing T cell therapies to function in tumors for longer, increasing the chances that each patient has a remission or cure. We will focus our studies on pancreatic cancer, one of the most lethal cancers and one to which military personnel are at especially high risk. This heightened risk is due in part to heightened exposure to stressors more frequent in the high-intensity environment military personnel face. Currently, T cell immunotherapies are not effective in improving survival for patients with pancreatic cancer. When we test the efficacy of our modified T cells, we will do so against pancreatic cancer cell lines and mice that develop pancreatic tumors. If our research is successful, it will likely be first applied in clinical trials for patients with pancreatic cancer. These clinical trials are not far away, as the University of Texas M.D. Anderson Cancer Center is a leading center for testing of novel T cell therapies, and the Mazur Lab is well acquainted with the doctors who run these trials. It is feasible that, by the end of the 3-year grant period, we will have specific modifications that enhance T cell efficacy and sufficient data to warrant testing in humans. This means that patients could start to benefit in as few as 3 years. These human trials, if successful, could eventually lead to improved treatment options for this terrible disease to which military personnel are especially prone. The Department of Defense (DoD) Career Development Award would provide me with resources that will allow me to successfully develop my research goals and give me ideal conditions to establish my lab in the new field of study and at the front line of new therapeutic discovery for this fatal disease. Science is my lifel
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910761
Entities
People
- Pawel K Mazur
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army