Developing Targeted Immunotherapy Against Pediatric Acute Myeloid Leukemia
Despite significant improvements in outcomes for children with acute myeloid leukemia (AML), today's therapies can cause toxic side effects, and too many young AML patients still relapse and die from the disease. There is an urgent need for less toxic, more effective therapies.
One type of therapy that has shown great promise harnesses a patient's immune system to fight their cancer by using gene-modified, cancer-specific T cells. Unfortunately, this approach has not been fully developed in AML, largely because molecules that are targeted by T cells (antigens) and leukemia-specific (not found on essential normal tissues) have not yet been discovered. Both are critical requirements for safe and effective immunotherapy. T cells can be engineered with one of a huge diversity of natural, antigen-specific T cell receptors (TCRs), each recognizing one antigen. Common AML-specific gene variants can produce abnormal antigens ("neoepitopes") that specific TCRs might recognize.
To develop new T cell therapy for pediatric AML, we propose to identify AML-specific neoepitopes by merging state-of-the-art gene sequencing of leukemia-specific variants with established HLA-binding prediction algorithms and a high-throughput immune-reactivity screen. We have already identified 166 neoepitopes created by 16 common genetic anomalies and isolated T-cell clones recognizing five HLA-restricted neoepitopes from recurrent AML abnormalities. One of these T cells was able to kill AML in vitro. Our method of interrogating AML-specific mutations will reveal T cell targets with which we will develop novel immunotherapies with TCR-engineered T cells that will likely provide a valuable important new therapy option for children with high-risk AML.
"I am delighted that the Alex's Lemonade Stand Foundation for Childhood Cancer has chosen to fund this project. This award provides critical support that will help enable us to move towards the long-term goal of developing new targeted, less toxic immune therapies for childhood acute myeloid leukemia." - Melinda Biernacki, MD