Leslie S. Kean
A5027478389- Hematopoietic Stem Cell Transplantation
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- CAR-T cell therapy research
- Renal Transplantation Outcomes and Treatments
- Immunotherapy and Immune Responses
- Cytomegalovirus and herpesvirus research
- Single-cell and spatial transcriptomics
- Immunodeficiency and Autoimmune Disorders
- Hemoglobinopathies and Related Disorders
- Blood groups and transfusion
- Acute Lymphoblastic Leukemia research
- Virus-based gene therapy research
- Inflammatory Bowel Disease
- Polyomavirus and related diseases
- Chronic Lymphocytic Leukemia Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Acute Myeloid Leukemia Research
- Childhood Cancer Survivors' Quality of Life
- Transplantation: Methods and Outcomes
- RNA Interference and Gene Delivery
- Erythrocyte Function and Pathophysiology
- Immune Response and Inflammation
- CRISPR and Genetic Engineering
- Neuroscience and Neural Engineering
Harvard University
2018-2025
Dana-Farber/Boston Children's Cancer and Blood Disorders Center
2019-2025
Dana-Farber Cancer Institute
2019-2025
Boston Children's Hospital
2018-2025
Boston Children's Museum
2018-2025
Boston University
2023
Dana-Farber Brigham Cancer Center
2021
Brigham and Women's Hospital
2021
Translational Research Institute
2021
Seattle Children's Hospital
2013-2020
There is pressing urgency to understand the pathogenesis of severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme (ACE2), and in concert with host proteases, principally transmembrane serine protease (TMPRSS2), promotes cellular entry. The cell subsets targeted by tissues factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, mouse...
In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been standard prophylaxis against graft-versus-host disease (GVHD). A phase 2 study indicated the potential superiority of post-transplantation regimen cyclophosphamide, tacrolimus, and mycophenolate mofetil.
Chimeric antigen receptor (CAR) T-cell immunotherapy has revolutionized the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) neurotoxicity. A major barrier to developing therapeutics prevent CAR T cell–mediated neurotoxicity lack clinically relevant models. Accordingly, we developed a rhesus macaque (RM) model via adoptive transfer autologous CD20-specific cells. Following cyclophosphamide lymphodepletion,...
Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need novel therapeutics. ABA2 was phase II trial to rigorously assess safety, efficacy, and immunologic effects adding T-cell costimulation blockade with abatacept calcineurin inhibitor...
Worldwide, each year over 30,000 patients undergo an allogeneic hema-topoietic stem cell transplantation with the intent to cure high-risk hematologic malignancy, immunodeficiency, metabolic disease, or a life-threatening bone marrow failure syndrome. Despite substantial advances in donor selection and conditioning regimens greater availability of allograft sources, transplant recipients still endure morbidity mortality graft-versus-host disease (GVHD). Herein, we identify key aspects acute...
Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for certain hematologic malignancies and nonmalignant diseases. The field of allo-HCT has witnessed significant advances, including broadening indications transplantation, availability alternative donor sources, less toxic preparative regimens, new manipulation techniques, novel GVHD prevention methods, all which have expanded the applicability procedure. These advances led to clinical practice conundrums when...
Despite emergence of novel therapies to treat hematologic malignancies, allogeneic hematopoietic cell transplantation (allo-HCT) remains an essential treatment modality capable curing these diseases. Allo-HCT has been also shown be curative in benign disorders such as aplastic anemia, sickle disease, and thalassemia, among others. Recently, the American Society for Transplantation Cellular Therapy (ASTCT) published standardized definitions recovery, graft rejection, failure, poor function,...
We performed a first-in-disease trial of in vivo CD28:CD80/86 costimulation blockade with abatacept for acute graft-versus-host disease (aGVHD) prevention during unrelated-donor hematopoietic cell transplantation (HCT). All patients received cyclosporine/methotrexate plus 4 doses (10 mg/kg/dose) on days -1, +5, +14, +28 post-HCT. The feasibility adding abatacept, its pharmacokinetics, pharmacodynamics, and impact aGVHD, infection, relapse, transplantation-related mortality (TRM) were...
There is pressing urgency to better understand the pathogenesis of severe acute respiratory syndrome (SARS) coronavirus (CoV) clade SARS-CoV-2. SARS-CoV-2, like SARS-CoV, utilizes ACE2 bind host cells. While initial SARS-CoV-2 cell entry and infection depend on in concert with protease TMPRSS2 for spike (S) protein activation, specific subsets targeted by tissues, factors that regulate expression, remain unknown. Here, we leverage human non-human primate (NHP) single-cell RNA-sequencing...
Abstract Mixed hemopoietic chimerism has the potential to correct genetic hemological diseases (sickle cell anemia, thalassemia) and eliminate chronic immunosuppressive therapy following organ transplantation. To date, most strategies require either recipient conditioning (γ-irradiation, depletion of peripheral immune system) or administration “mega” doses bone marrow facilitate reliable engraftment. Although encouraging, many issues remain that may restrict prevent clinical application such...
Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer chronic infections. In murine bone marrow transplant models, PD-L1 expression on host tissues reduces the incidence of graft-versus-host disease (GVHD). also expressed cells; however, it unclear whether this population influences function. Here, we examined effects modulation function in GVHD. patients severe GVHD, was increased donor cells....
Alloimmunization against red blood cell (RBC) antigens is a cause of morbidity and mortality in transfused patients with sickle disease (SCD). To investigate distinguishing characteristics who develop RBC alloantibodies after transfusion (responders) versus those do not (non-responders), cross-sectional study 90 children SCD on chronic therapy at single institution was conducted which 18 immune parameters (including T B subsets) were tested via flow cytometry, medical records reviewed....
A critical question facing the field of transplantation is how to control effector T cell (Teff) activation while preserving regulatory (Treg) function. Standard calcineurin inhibitor-based strategies can partially Teffs, but breakthrough still occurs, and these agents are antagonistic Treg Conversely, mechanistic target rapamycin (mTOR) inhibition with sirolimus more Treg-compatible inadequate fully Teff activation. In contrast, blockade OX40L signaling has capacity despite maintaining We...
Organ infiltration by donor T cells is critical to the development of acute graft-versus-host disease (aGVHD) in recipients after allogeneic hematopoietic stem cell transplant (allo-HCT). However, deconvoluting transcriptional programs newly recruited from those tissue-resident aGVHD target organs remains a challenge. Here, we combined serial intravascular staining technique with single-cell RNA sequencing dissect tightly connected processes which initially infiltrate tissues and then...
Regulatory T cells (T regs ) make major contributions to immune homeostasis. Because reg dysfunction can lead both allo- and autoimmunity, there is interest in correcting these disorders through adoptive transfer. Two of the central challenges clinically deploying cellular therapies are ensuring phenotypic stability maximizing potency. Here, we describe an approach address issues creation OX40 ligand (OX40L)–specific chimeric antigen receptor (CAR)–T under control a synthetic forkhead box P3...