Novel immunotherapeutic strategies in infants with high risk AML
Soheil Meshinchi
PhD, MDFred Hutchinson Cancer Research Center
Project Term: July 1, 2019 - June 30, 2022
Treatment of AML in infants is especially challenging given unique genetic make-up of the disease as well as specific susceptibilities of the host. We will leverage the RNA Seq data from over 2000 patients to discover and validate novel targets (cell surface proteins), and in collaboration with Dr. Correnti (Protein Scientist) and Dr. Fry (CART development expert) generate and test novel antibodies, ADCs, BiTEs and CARTs directed against leukemia-specific targets in infants.
Acute Myeloid Leukemia (AML) is a particularly devastating disease in infants, where therapies that are intended to cure leukemia frequently fail to cure the disease as well as lead to significant life limiting or life ending complications. Leukemia-specific, targeted therapies are critical, especially in these most vulnerable patients in order to cure the disease without causing irreversible damage to the growing body. Through the largest and most detailed genetic sequencing studies, we have identified two genetic abnormalities (chromosome translocations) that are only seen in babies younger than 5 years of age, and cause lack of response to all available therapies, and more than 80% of babies with these abnormalities die of leukemia despite intensive chemotherapy. In our initial analysis of this sequencing data we discovered that leukemic cells in the babies with one of these abnormalities (CBF/GLIS) express a protein called CD56 at high levels. Expression of this protein on the leukemia provides an opportunity for targeting the leukemic cells with immunotherapy. Our initial studies have shown great promise that targeting CD56 with available drugs bound to CD56 antibody allowed killing of leukemic cells that express CD56. In collaboration with Dr. Correnti (director of protein science lab, FHCRC) and Dr. Fry (Denver Children’s Hospital), we will make new immunotherapies directed at CD56. In addition, we intend to use the genomic sequencing data we have generated from 2000 children with AML to discover novel immunotherapeutic targets and generate new antibodies to generate three different immunotherapies including antibody-drug conjugates (ADCs), Bispecific T-cell engagers (BiTEs), and chimeric antibody T-cells (CARTs). Our initial interrogation of the sequencing data has identified a large number of potential targets and made us highly optimistic that we will be able to identify and validate potential targets and rapidly move into therapeutic development in the first two years of this grant, followed by testing of these immunotherapies for their efficacy in the laboratory.