Role of the AML "Immunome" in response and failure of chimeric antigen receptor T cell therapy
Saar Gill
MD PhDPerelman School of Medicine at the University of Pennsylvania
Project Term: October 1, 2022 - September 30, 2025
Most patients with acute myeloid leukemia (AML) are not cured with chemotherapy alone, and most long-term survivors of AML have undergone an allogeneic stem cell transplant (also known as bone marrow transplant). The outlook is quite grim for patients whose AML relapses after transplant. We have developed a new type of treatment for AML called chimeric antigen receptor (CAR) T cells for these patients. The goal of this project is to investigate how to improve CAR T cells for AML.
Acute myeloid leukemia (AML) is a cancer of the blood-forming stem cells in the bone marrow. Adults with AML have a long-term survival of approximately 30%, due to relapse (inadequately effective treatment) or complications of treatment. Chimeric antigen receptor (CAR) T cells are a form of immune-based treatment that has been shown to be very effective in hematologic malignancies such as B-cell leukemia or lymphoma. T cells are a normal component of the immune system, and have a demonstrated ability to kill leukemia if only they can be “shown” which cells to attack. The CAR T cell technology uses the tools of genetic engineering to convey this information to the patient’s T cells, directing them to attack target cells by placing in them a receptor (“sensor”) for certain molecules that are present in cancer cells. We have recently concluded a clinical trial of CAR T cells for AML, where we found encouraging evidence of strong anti-leukemia response in some patients. The goal of this project is to discover why only some patients were successfully treated, which will allow us to improve upon this treatment in future. One possible explanation could be that AML cells (called blasts) exert a suppressive effect on the immune system. Since blasts arise from normal cells that do have a function in the immune system, it is at least conceivable that blasts retain some of the ability to interact with other components of the immune system (such as T cells). Since we know that the same technology is very successful in a related blood cancer called B-cell acute lymphoid leukemia (B-ALL), we intend to carefully compare the behavior of CART cells directed against the B-cell antigen CD19 with those directed against the myeloid antigen CD123.
To achieve our goal of understanding how to improve CAR T cell therapy for AML we will utilize patient specimens, mouse models, and the latest analytics to work out whether the problem lies in the T cells, the AML blasts, or the surrounding immune system.