Targeting cancer-specific non-protein molecular signatures for immunotherapy of pediatric AML
Childhood acute myeloid leukemia (AML) is a lethal blood cancer that remains difficult to treat because a large proportion of patients have disease that does not respond to currently available treatments. Immunotherapy is a type of cancer treatment that exploitsthe immune system to fight cancer cells. Over the past decade,several immunotherapies have emerged as highly effective forms of cancer therapy in the setting of both solid tumors and blood cancersin children. For example, immunotherapy isroutinely employed to treat children with high-risk neuroblastoma, or children with acute lymphoblastic leukemia. However, there are currently no successful forms of immunotherapy for most children with AML. One of the major limitationsto using immunotherapy for AML has been the lack of suitable targets on the surface of AML cells. Almost all currently known surface markers on AML cells are shared by healthy cellssuch as blood forming stem cellsin the bone marrow, raising a safety concern referred to as on-target off-tumor toxicity. Therefore, the identification of suitable targetsis critical to developing safe and effective immunotherapiesfor children suffering from AML. The search for suitable targetsfor AML immunotherapy hasfocused mostly on protein molecules on the surface of AML cells, but it is also important to pay attention to certain sugar and lipid signaturesthat are known to be associated with malignant cells but that do not exist on normal cells.
Project Goal:
Our laboratory recently identified sugar and lipid molecules on AML cellsthat have not been previously recognized as potential AML immunotherapy targets. The goal of this proposal isto develop therapeutic moleculestargeting these cell surface markersthat are uniquely expressed on the surface of AML cells and not on normal blood or blood precursor cells. The therapeutic moleculesthat will be used for this project are designed to bind to immune cellssuch as T lymphocytes and bring those cancer fighting cells close to their target, resulting in cancer cell death. We will utilize well-developed tools and have assembled an expert team to pursue these studies. Our biotech partner Vitruviae is committed to providing proprietary reagents and therapeutic molecules(including moleculesthat will bind to more than one target) that we will test with AML cell lines,samplesfrom children with AML, and AML mouse models. Successful completion of this project will validate previously unknown targetsfor immunotherapy of pediatric AML and generated evidence suggesting that these novel targets can safely be exploited for immunotherapy. We expect that these investigations will also advance our understanding of AML disease biology and ultimately yield promising novel therapeutic approachesfor pediatric AML patients.
