The immunobiology of blinatumomab response and resistance in relapsed pediatric B-ALL
Patrick Brown
MDThe Johns Hopkins University School of Medicine
Project Term: July 1, 2019 - June 30, 2022
Responses to blinatumomab in B-ALL are binary, with some patients having a striking response and deep remission, while others show no response at all, despite the presence of CD19 expression on leukemic cells and adequate numbers of CD3+ T-cells. This project will identify biomarkers to predict which patients will respond to blinatumomab. We have an agreement to use blinatumomab for research and a cohort of pediatric samples from the ongoing Children’s Oncology Group study for relapsed B-ALL.
Pediatric pre-B cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. With current therapies, long-term survivorship reaches nearly 90%. However, despite these advances in therapy, nearly 20% of patients will relapse. In addition, survivors are at higher risk for other medical problems in the future, as a result of the years of intensive chemotherapy needed to effectively treat B-ALL. These issues underscore the need to develop better and more targeted therapies for B-ALL. Blinatumomab is an antibody that targets two types of cells simultaneously – B-ALL leukemia cells and normal T-cells. By bringing T-cells in proximity to B-ALL cells, T-cells are able to activate pathways to result in killing of the leukemia cells. This occurs without significant toxicity to other cells in the body. In order for blinatumomab to be effective, the B-ALL cells must express a protein called CD19 on their cells. In addition, there has to be a sufficient quantity of T-cells, which express the protein CD3. However, even when these criteria are met, some patients have no response to blinatumomab at all. We hypothesize that there are differences in other cells in the bone marrow of responders and nonresponders that lead to this difference. I am the principal investigator for a current study run through the Children’s Oncology Group (COG) for children and young adults with relapsed B-ALL. In this study, patients are randomized to receive either blinatumomab or standard chemotherapy. Prior to this randomization, bone marrow is collected from all patients. For patients who receive blinatumomab, blood samples are collected at various times prior to and during the blinatumomab infusion. All of these samples from across the world are sent to my laboratory, where they undergo processing prior to freezing. We have samples from nearly 500 patients, approximately half of whom go on to receive blinatumomab. This provides us with a robust number of patient samples with which we can test our hypothesis and perform the necessary experiments for validation as well. We also have the knowledge of 1) which patients received blinatumomab and 2) which patients are classified as responders versus nonresponders after blinatumomab exposure. We will investigate the bone marrow of known blinatumomab responders and nonresponders to see if there are any changes in the types of cells that are present. We will also test the peripheral blood that was collected during blinatumomab treatment to see if there are differences in the proteins that are found in blood when we compare responders and nonresponders. We expect that this will allow us to identify patients who are likely to respond to blinatumomab therapy, thereby personalizing therapy for B-ALL patients. Patients who are predicted to respond to blinatumomab may be able to avoid significant toxicity from exposure to chemotherapy.