Correlating TCR diversity to immune reconstitution after cord blood transplant

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DESCRIPTION (provided by applicant): Many patients requiring stem cell transplantation for hematological malignancies are unable to find a suitable HLA-matched sibling or unrelated donor. Transplants using stem cells from umbilical cord blood provide an alternative for these patients, allowing transplantation to proceed with less stringent HLA-matching requirements. Unfortunately, in addition to the risk of relapsed disease, patients undergoing cord blood transplants have a high risk of death from infections due to slow reconstitution of their immune system. In this clinical observational study, we propose to use high-throughput DNA sequencing of T- Cell Receptor (TCR) and Immunoglobulin heavy chain (IgH) genes from peripheral blood to study the reconstitution of the adaptive immune system following cord blood transplant. We will use high-throughput sequencing to estimate the diversity of T- and B-cell receptors in each of approximately 240 patients at defined time-points following transplant, and demonstrate a correlation between our measure of adaptive immune receptor diversity and subsequent morbidity and mortality from infectious complications. Further development of this technique would lead to a Phase III application with a clinical intervention study in which this assay would provide a diagnostic method to identify patients at high risk for infectious complications soon after transplant. Clinical care would be administered for an increased-intensity regimen of antimicrobial prophylaxis to high-risk patients. We expect that early identification of high-risk patients, combined with more aggressive prophylaxis for these patients, will reduce the high treatment-related mortality present in cord blood transplants.