A Multi-Omics Approach to Overcome Resistance in Infant Leukemia by Identifying Immune Therapy Failure Mechanisms
Abstract
FY18 PRCRP Topic Area(s): (1) Blood cancers, (2) Immunotherapy, (3) Cancer in children, adolescents, and young adults Scientific Objective and Rationale: Most children with acute lymphoblastic leukemia, a cancer of the blood, can be treated successfully with standard chemotherapy; however, a very high-risk group of children that do much more poorly are infants under one year of age with a particular kind of leukemia known as MLLr. Most of these small infants will die, as standard chemotherapy and even several novel specifically targeted new drugs have failed to improve outcomes. An exciting new type of therapy, known as chimeric antigen receptor (CAR) T cells, has proven very effective against leukemias that are resistant to standard drugs. CAR T cells, however, must be made from the immune cells of the patient and, unfortunately, we have not been successful in making CAR T cells from infants. Prior research has revealed that T cells from infants who have received therapy are very poorly suited to become CAR T cells, much more so than T cells from older children, although the reason for this is not clear. Furthermore, even when CAR T cell therapy works, older children who also have the high-risk MLLr type of leukemia experience relapse more often than those who do not, largely because the leukemia figures out how to hide from the CAR T cells. This proposal will focus on using new and highly detailed techniques to study both the MLLr leukemias from infants and simultaneously study the T cell function from the same patients. Our twin goals are to understand how best to target the MLLr leukemias of infants with CAR T cells (to prevent relapse) and how to make the T cells from these infants into effective CAR T cells (to maximize response). Our team is uniquely qualified to do this, representing clinicians who have run the largest clinical trials for infants with leukemia, researchers who have developed the sensitive sequencing techniques proposed, and scientists who originally developed CAR T cell therapy for children with leukemia. Collectively, our prior laboratory studies have been swiftly translated into active clinical trials, testing new targeted therapies in patients with high-risk leukemias, including infants. We anticipate that results from the current studies will transform the care of infants with leukemia, dramatically improving outcomes once our findings are rapidly translated to active clinical trials, as we have done before. FY18 PRCRP Military Relevance Focus Area(s): Infant leukemia (iALL) represents one of the most difficult to treat leukemias of childhood, with long term survival less than 20% as opposed to greater than 85% in older children with leukemia. The burden of an infant with leukemia is a years-long ordeal that currently most often ends in tragedy, directly and severely impacting active military personal and veterans with a baby with cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010357
Entities
People
- Kathrin M. Bernt
Organizations
- United States Army