Targeting the cell surface U5 snRNP complex as a novel immunotherapy for AML
Bingyi Chen
PhDMemorial Sloan Kettering Cancer Center
Project Term: July 1, 2024 - June 30, 2027
A major limitation of immunotherapy approaches for AML has been the lack of known targetable cell surface antigens specific to AML cells. This project characterizes the pathologic and biologic effects of a novel cell surface antigen complex uniquely present on AML cells but not normal hematopoietic precursors, known as the U5 snRNP complex. Furthermore, we will interrogates U5 snRNP complex components as novel AML-associated antigens and CAR T cells targets for AML treatment.
Despite several recent advances in U.S. FDA approved therapies for patients with acute myeloid leukemia (AML), the overall survival for most patients diagnosed with AML is <20%. In a considerable portion of patients, the only potentially curative treatment available is allogeneic hematopoietic stem cell transplantation (HSCT), which is fraught by high levels of short- and long-term toxicities. Furthermore, curative therapeutic options are limited for those unfit to receive cytotoxic chemotherapy or undergo allogeneic hematopoietic stem cell transplant. These challenges clearly illustrate the need for new, effective therapeutic strategies. Of immense current interest to accomplish this goal is immunotherapy, that is, stimulating the immune system to scavenge and attack cancer cells, including chimeric antigen receptor (CAR) T cell therapy. CAR T cell therapy aims to redirect the cytotoxic activity of T lymphocytes toward specific antigens of cancer cells. However, the lack of known targetable cell surface antigens which discriminate malignant cells from vital normal hematopoietic precursor cells limits the immunotherapy approaches for AML.
In order to capture AML-associated antigens as well as immune effector cells and the distribution of activating and inhibitory Fc receptors in AML patient bone marrow, we systematically performed high-density immunophenotyping by spectral flow cytometry coupled with proteogenomics and found that an RNA helicase and conserved spliceosome component, known as U5 snRNP200, expressed on the surface of AML cells. U5 snRNP200 is present on the cell surface of malignant cells in ~50% of AML patients but not on normal hematopoietic precursors. This finding highlights U5 snRNP200 as an attractive therapeutic target in AML. Following the above findings, we generated CAR T cells targeting U5 snRNP200 and demonstrated that these CAR T cells effectively eliminated both human AML cell lines in vitro and in vivo. In addition, we generate armored CAR T cells targeting U5 snRNP200 and aim to test the efficacy and safety of armored CAR T cells on human and syngeneic mouse models of AML. Furthermore, we aim to identify the mechanistic basis for cell surface U5 snRNP200 localization. Our proposal will define novel pathologic contributions of U5 snRNP200 aberrantly localized to the surface of AML cells and develop multiple novel CAR T cells targeting U5 snRNP200 for therapeutic targeting of AML.