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A Multi-Omics Approach to Overcome Resistance in Infant Leukemia by Identifying Immune Therapy Failure Mechanisms
[Technical Report, Final Report]
JOHNS HOPKINS UNIV BALTIMORE MD
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Most children with acute lymphoblastic leukemia can be cured 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, though 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 have developed CAR T cell therapy for leukemia.
[A, Approved For Public Release]