Novel Immunotherapy Options for Pediatric Acute Myeloid Leukemia
Abstract
Acute myeloid leukemia (AML) remains the type of pediatric leukemia with poorest outcome. Despite undergoing intensive therapies, including chemotherapy and stem cell transplants, approximately 20% of patients cannot be cured and must face severe side effects. Novel targeted therapies that are more effective and less toxic need to be developed in order to improve survival in pediatric AML patients. Immunotherapy, wherein the patient s immune system is activated to identify and kill cancer cells, is an emerging treatment option. In a previous study, we compared the normal cell genome with the AML cell genome, and identified mesothelin as a potential actor in AML. Mesothelin was expressed in 30% of the AML patient samples but not expressed in normal bone marrow cells. Therefore, we can use mesothelin as a novel immunotherapy drug target to flag AML cells, so that they can be neutralized by the body s own T cells. This can be achieved by using bispecific T cell engaging antibodies that both recognize AML cells based on mesothelin expression and vitalize T cells to attack these malignancies. Because normal blood cells are not affected by this drug, the potential side-effects are likely to be limited. The proposed project addresses two FY21 Rare Cancers Research Program Focus Areas - Therapy - Validation of this new therapy using mouse models will lay the foundation for use in children with AML. Therapy resistance, in which cancer cells escape treatment and fail to die, is a critical barrier in cancer treatment. We will attempt to overcome therapy resistance by combining this novel therapy with a second form of immunotherapy that removes the brakes from the body s defense system. This proposal also aims to understand other mechanisms by which therapy resistance may occur, with the hopes of devising methods to prevent leukemia cells from escaping treatment. Research Model - Developing research models for the different subtypes of pediatric AML is one of the goals of this proposal. There are a very limited number of mouse models for a specific AML subtype. We have been successful in generating two such models (and have more in the pipeline). We will leverage these models and models of other subtypes to determine if a certain level of mesothelin is necessary for the efficacy of this new therapy. Upon successful completion of the project, we will be able to carefully choose pediatric AML patients who may benefit from this new treatment option that specifically attacks the leukemic cells. Thus, pediatric AML patients whose cancers have mesothelin will benefit from the development of this novel immunotherapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210981
Entities
People
- Sonali Barwe
Organizations
- Nemours Children's Hospital, Delaware
- United States Army