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Principal Investigator: Corey S Cutler
Organization: DANA-FARBER CANCER INST
Fiscal Year: 2024
Award: $2,508,066
Funding agency: National Heart Lung and Blood Institute
Summary
Chronic GVHD (cGVHD) is the major cause of late morbidity, mortality and compromised organ function
after allogeneic hematopoietic stem cell transplant (HCT). It can affect essentially all organs and tissues,
including the lungs, where the disease is termed Bronchiolitis Obliterans Syndrome (BOS). BOS is a
progressive, irreversible, and often fatal lung disease that occurs following HCT. BOS occurs in approximately
5-10% of HCT survivors and is considered the pulmonary manifestation of cGVHD. Approximately 10-15% of
cGVHD patients will develop BOS, and less than 15% of BOS patients survive 5 years. The primary site of
inflammation in BOS is the small airway, eventually leading to fibrosis. cGVHD results from a failure to achieve
immune tolerance after transplant. The mechanisms responsible for the failure of tolerance are complex
and involve multiple cell types, but T cells are central to this process. Resting T cells preferentially use
mitochondrial oxidative phosphorylation as basal energy. In acute GVHD, donor T cells exposed to host
alloantigen in an inflammatory environment rapidly differentiate and proliferate, with bioenergetic and
biosynthetic needs fulfilled by reprogramming metabolism and using multiple energy sources. In cGVHD,
metabolism demands are less well understood, but with the high energy demands of proliferating immune cells
in cGVHD, strategies to specifically block critical metabolic pathways may prove to be a novel treatment strategy.
In this Program, we focus on the critical questions that plague the field of cGVHD. We address shortcomings in
our understanding of the pathogenesis of human cGVHD and our ability to prioritize the next generation of
therapeutic strategies by defining the immune networks that characterize patients who develop cGVHD and
interrogate the mechanisms of both success and failure of cGVHD treatment regimens. We explore the unique
metabolic demands in cGVHD pathogenesis and lung injury repair and focus therapeutics on the most severe
manifestation of cGVHD, BOS. We employ novel organoid cultures and immunogenomics to pinpoint the cellular
and antigenic targets of BOS. We have assembled a collaborative, multidisciplinary team, uniquely poised to
make significant impact in the field.
Terms: <3-D><3-Dimensional><3D><Acute GVHD><Acute Graft Versus Host Disease><Address><Affect><Alloantigen><Allogenic><Alveolar><Antigenic Determinants><Antigens><Assay><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding Determinants><Bioassay><Bioenergetics><Biological Assay><Biological Markers><Biometrics><Biometry><Biostatistics><Blood><Blood Reticuloendothelial System><Body Tissues><Bronchiolitis Obliterans><CRISPR><CRISPR/Cas system><Cell Body><Cell Communication><Cell Interaction><Cell-to-Cell Interaction><Cells><Chronic><Chronic GVHD><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Co-Stimulator><Co-culture><Cocultivation><Coculture><Coculture Techniques><Complex><Costimulator><Coupled><Defect><Disease><Disorder><Dose><Drugs><Energy-Generating Resources><Engineering><Epidermal Thymocyte Activating Factor><Epithelium><Epitopes><Equilibrium><Evolution><Exposure to><Exudative Bronchiolitis><Failure><Fibrosis><Gene Expression><Gene Modified><Germinal Center><Guide RNA><HSC transplantation><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hematopoietic Stem Cell Transplant><Hematopoietic Stem Cell Transplantation><Human><IL-2><IL2 Protein><Image><Immune><Immune Monitoring><Immune Targeting><Immune Tolerance><Immunes><Immunochemical Immunologic><Immunogenetics><Immunogenomics><Immunologic><Immunologic Monitoring><Immunologic Tolerance><Immunological><Immunological Monitoring><Immunologically><Immunologics><Immunomonitoring><In vivo analysis><Individual><Inducer Cells><Inducer T-Lymphocytes><Inflammation><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intermediary Metabolism><Link><Lung><Lung Diseases><Lung Respiratory System><Lung damage><Lung tissue regeneration><Lymphocyte Mitogenic Factor><Mediator><Medication><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Mice><Mice Mammals><Mitochondria><Mitogenic Factor><Modality><Modeling><Modern Man><Monitor><Morbidity><Morbidity - disease rate><Murine><Mus><Organ><Organoids><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Pathogenesis><Pathway interactions><Patients><Pattern><Pharmaceutical Preparations><Population><Prediction of Response to Therapy><Principal Investigator><Process><Proliferating><Proliferative Bronchiolitis><Pulmonary Diseases><Pulmonary Disorder><RNA library><Regulatory T-Lymphocyte><Resistance><Resolution><Rest><Risk><Site><Specificity><Structure of germinal center of lymph node><Syndrome><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell growth factor><T cell infiltration><T cell targeted therapeutics><T cell therapy><T-Cell Growth Factor><T-Cell Stimulating Factor><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><Teff cell><Testing><Therapeutic><Thymocyte Stimulating Factor><Time><Tissue Banks><Tissue Collection><Tissue repository><Tissues><Transplantation><Treatment Protocols><Treatment Regimen><Treatment Schedule><Treg><Writing><acute graft vs host disease><acute graft vs. host disease><adoptive T cell transfer><adoptive T-cell therapy><balance><balance function><bio-markers><biologic marker><biomarker><cell type><cellular targeting><chronic graft versus host disease><chronic graft vs host disease><chronic graft vs. host disease><conditional knock-out><conditional knockout><data management><diagnostic profile><diagnostic signature><disease of the lung><disorder of the lung><drug detection><drug testing><drug/agent><effector T cell><energy source><experiment><experimental research><experimental study><experiments><gRNA><gene modification><genetically modified><global gene expression><global transcription profile><hematopoietic cell transplantation><hematopoietic cellular transplantation><hematopoietic progenitor cell transplantation><imaging><immune system tolerance><immune unresponsiveness><immunogen><immunological paralysis><in vitro regeneration><in vivo evaluation><in vivo testing><inflammatory environment><inflammatory milieu><inhibitor><injury and repair><lung disorder><lung injury><lung regeneration><mitochondrial><mortality><mouse model><multidisciplinary><murine model><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathway><patient profile><phase 2 trial><phase II trial><predict therapeutic response><predict therapy response><profiles in patients><progenitor cell function><progenitor function><programs><pulmonary><pulmonary damage><pulmonary injury><pulmonary regeneration><pulmonary tissue damage><pulmonary tissue injury><regulatory T-cells><resistant><resolutions><responders and non-responders><responders from non-responders><responders or non-responders><responders versus non-responders><responders vs non-responders><responders/nonresponders><response><response to therapy><response to treatment><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell analysis><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><stem and progenitor cell function><stem and progenitor function><stem cell function><success><therapeutic T-cell platform><therapeutic response><therapy prediction><therapy response><three dimensional><thymus derived lymphocyte><transcriptome><transplant><transplant survivor><treatment prediction><treatment response><treatment response prediction><treatment responsiveness><treatment strategy>