Engineering Next-Generation CAR T Cells to Treat Pediatric AML: Enhancing Safety Through Dynamic Control and Specificity
Abstract
The Topic Areas and Military Relevance Focus Area: This proposal will address at least two focus areas specified in the application guidelines: Immunotherapy and Cancer in Children, Adolescents, and Young Adults. This proposal will generate novel approaches to harness the immune system to target and kill cancer cells. This approach is expected to be more effective and have less associated toxicities. Patient Population: Leukemia is the most common cause of cancer and cancer related death in children, adolescents, and young adults. Of the various forms of leukemia, a subtype of leukemia termed “acute myeloid leukemia” (AML) is particularly aggressive. The cause of AML in children is unknown; however, potential exposures to radiation or chemical mutagens during times of conflict may pose increased threats to families who are serving overseas. Unfortunately, approximately a 50% of children who develop AML will die of this disease. Furthermore, the current chemotherapy that is used to treat AML is particularly toxic, leading to a multitude of immediate and long-term side effects that, in and of themselves, can lead to pain, organ failure, and even death. The work being proposed is also generalizable to an older population—myeloid cancers are a vexing disease in older adults with an urgent need to improve outcomes. Patients who develop AML are in desperate need of more effective and less toxic therapies. Rationale: Over the past few decades, extensive research has been carried out to develop methods of harnessing the immune system to target and kill cancer cells. These “living drugs” are particularly effective and lack many of the toxicities that accompany traditional chemotherapy because they are a natural part of one’s immune system. One approach to harnessing the immune system that has been particularly successful is termed a “chimeric antigen receptor (CAR) T cell.” This approach capitalizes on an immune cell’s natural ability to kill infected cells. A CAR T cell is generated by engineering immune T cells from a patient to selectively target and kill cancer cells instead of infected cells. This approach has had outstanding success in curing children and adults with certain types of leukemia. However, it has been incredibly challenging to develop T cell immunotherapy to treat AML because AML cells look very similar to certain types of healthy blood cells that are critical for life. Current CAR T cell approaches are unable to distinguish between AML cells and healthy cells. Goal of Research Proposal: We have engineered a variety of tools that will enable us to develop next-generation immunotherapies that we believe will be able to effectively kill AML cells without significant toxicity to normal, healthy blood cells. Specifically, in the Lim lab, we have developed two receptors that can be used to (1) switch ON and OFF the killing activity of T cells and (2) distinguish with exquisite specificity between AML cells and normal healthy blood cells. Our first receptor is termed an ON/OFF switch receptor. It is regulated by a small molecule drug. With addition of the small molecule, the T cell is turned ON; with removal of the small molecule, the T cell is turned OFF; with moderate amounts of the small molecule, moderate amounts of T cell killing can be achieved. Our second receptor is termed a synthetic Notch receptor. It allows T cells to discriminate AML cells from healthy blood cells by recognizing and killing only cells that express certain combinations of cell-surface markers. Although these types of new receptors have been developed and extensively studied in the lab, they have never been applied to the treatment of AML. Using these receptors, our goal is to develop two novel forms of immunotherapy to treat patients with AML. We will test these therapies against AML cells in the lab to confirm that they can effectively kill AML cells. For our first receptor, we will test the ability to cont
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810202
Entities
People
- Wendell Lim
Organizations
- United States Army
- University of California, San Francisco