Optimizing HCT Outcomes: A Multi-omic Investigation

Hematopoietic stem cell transplantation (HCT) is an essential treatment for high-risk non-malignant and malignant hematologic diseases. However, outcomes remain inadequate, with multiple immune-mediated complications contributing to mortality. With 5-yr survival often <60%, there is an urgent need to improve results. We will address this by deciphering the mechanisms driving HCT outcomes by studying the biology of HCT patients at a depth and scale not previously achieved. To accomplish this, we have partnered with the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), the NMDP, and the Pediatric Transplant Consortium (PTCTC) to perform detailed biologic studies on patients with both non-malignant and malignant hematologic diseases enrolled on multicenter HCT trials. Our goal is to leverage the power of systems immunology, genomics, and state-of-the-art microbiome analysis to determine, from patient samples, the underlying mechanisms that drive clinical transplant outcomes. We will do so through the following Aims: Aim 1: The Tradeoff Between T Cell Reconstitution and GVHD: Optimizing Immunomodulation to Optimize Transplant Outcomes. In this Aim, we will test the hypothesis that a GVHD prophylaxis strategy can be identified that improves immune reconstitution compared to PT-Cy (50mg/kg), while still controlling GVHD. Aim 2: The Host:Microbe Dyad and Its Influence on Transplant Outcomes. In this Aim, we will test the hypothesis that microbiome dynamics at the taxonomic and subtaxonomic (strain) level, driven by conditioning regimen and GVHD prophylaxis choice, are predictive of (a) pathogen domination and infectious complications of HCT, (b) gut GVHD, and (c) immune reconstitution. Aim 3: Cellular and Molecular Analysis To Predict Relapse and Graft Failure: In this Aim, we will examine the interface of immune reconstitution and both relapse and graft failure. This proposal seeks to create a new paradigm for transplant trials: an integrated, embedded scientific hub that can efficiently collaborate across multicenter clinical trial organizations to address the most pressing biologic questions linked to patient outcomes. If successful, it will lead to the discovery of biologic mechanisms driving HCT results, such that fully safe and effective transplant approaches can be developed. Project Number: 1R01HL181969-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Leslie Kean (+2 co-PIs) | Institution: BOSTON CHILDREN'S HOSPITAL, BOSTON, MA | Award Amount: $2,024,340 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 IIDB-F (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL18196901