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Principal Investigator: MICHAEL L WHITFIELD
Organization: DARTMOUTH COLLEGE
Fiscal Year: 2024
Award: $1,082,397
Funding agency: National Institute of General Medical Sciences
Dysregulation of normal tissue repair processes can lead to fibrosis, a pathological feature of many diseases,
including chronic inflammatory conditions, autoimmune diseases, and cancer. Excessive accumulation of
extracellular matrix can occur in all tissues, and if progressive, can be fatal. The long-term goal of our group is
to understand the underlying cellular and molecular interactions that contribute to fibrosis, and to use this insight
to develop effective therapeutics to combat this condition, which accounts for up to 45% of all deaths in the
United States each year. Although long assumed to be irreversible, recent evidence from both preclinical studies
and clinical trials demonstrates that fibrosis can be halted and even reversed in vivo. However, there is a
significant gap in the development of safe and effective therapeutic interventions that directly target the mediators
of fibrotic pathogenesis. To address this gap, we have assembled an interdisciplinary team with distinct expertise
to develop and assess the in vivo efficacy of a novel cellular immunotherapy to combat fibrosis.
Fibrosis drives pathology in the chronic autoimmune disease systemic sclerosis (SSc). SSc has the highest case
fatality rate of any systemic autoimmune disease with no validated biomarkers or curative treatments. Multi-
tissue bioinformatic analyses implicate alternatively activated macrophages (MØs) as key drivers of SSc in
multiple end-target organs, suggesting these cells are a common feature across organs and subsets in SSc
patients. Thus, we hypothesize that targeting these pathogenic MØs directly will reduce fibrosis in SSc patients.
To test this hypothesis, we will engineer chimeric antigen receptor (CAR) T cells to secrete anti-fibrotic mediators
and evaluate their therapeutic efficacy in vivo using multi-omic and spatial transcriptomic technologies developed
by the parent award. The development of this therapy, which will target pro-fibrotic MØs that drive fibrosis and
key secreted mediators of fibroblast activation, has potentially significant therapeutic benefit for patients that
suffer from many fibrotic conditions, including cancer. This proposal integrates the diverse expertise of each co-
Project Leader, with Dr. Pioli contributing MØ, fibrosis and SSc expertise, Dr. Huang contributing CAR T cell
therapy engineering expertise, and Dr. Kolling bringing expertise in the development and application of single
cell multi-omics and spatial transcriptomics approaches.
Terms: <Address><Affect><Antigen Targeting><Antigens><Autoimmune Diseases><Award><Binding><Bio-Informatics><Bioinformatics><Biological><Biology><Blood leukocyte><Blood monocyte><Body Tissues><CAR T cell therapy><CAR T cells><CAR T therapy><CAR modified T cells><CAR-T><CAR-Ts><COBRE><Cancer Treatment><Cancers><Case Fatality Rates><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell Therapy><Cell-Extracellular Matrix><Cells><Cellular immunotherapy><Center of Biomedical Research Excellence><Centers of Research Excellence><Cessation of life><Chronic><Cicatrix><Clinical Trials><Co-culture><Cocultivation><Coculture><Coculture Techniques><Cold-Insoluble Globulins><Collagen><Cytolysis><Cytoplasm><Data><Death><Deposit><Deposition><Development><Disease><Disorder><Dose><Dysfunction><ECM><Engineering><Extracellular Matrix><Extracellular Matrix Proteins><FN1><Fibroblasts><Fibronectin 1><Fibronectins><Fibrosis><Functional disorder><Future><Goals><Grant><Heterogeneity><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune mediated therapy><Immunes><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunologically Directed Therapy><Immunotherapy><Inflammation><Inflammatory><Intracellular Communication and Signaling><K Cells><Killer Cells><LETS Proteins><Large External Transformation-Sensitive Protein><Leukocytes><Leukocytes Reticuloendothelial System><Link><Lung Tissue Fibrosis><Lupus Erythematosus Disseminatus><Lymphatic cell><Lymphocyte><Lymphocytic><Lysis><Macrophage><Maintenance><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Marrow leukocyte><Marrow monocyte><Mediating><Mediator><Mission><Modification><Molecular><Molecular Interaction><Mφ><NIH><National Institutes of Health><Normal Tissue><Normal tissue morphology><Opsonic Glycoprotein><Opsonic alpha(2)SB Glycoprotein><Organ><Organism><Parents><Pathogenesis><Pathogenicity><Pathologic><Pathology><Pathway interactions><Patients><Peptides><Physiopathology><Process><Pulmonary Fibrosis><Research Resources><Resolution><Resources><SBIR><SLE><Scars><Signal Transduction><Signal Transduction Systems><Signaling><Small Business Innovation Research><Small Business Innovation Research Grant><Specificity><Surface><Systemic Lupus Erythematosus><Systemic Lupus Erythematous><Systemic Lupus Erythmatosus><Systemic Scleroderma><Systemic Sclerosis><T cells for CAR><T-Cell Activation><Technology><Testing><Therapeutic><Therapeutic Intervention><Tissues><Translations><Treatment Efficacy><United States><United States National Institutes of Health><White Blood Cells><White Cell><Work><Wound Repair><activate T cells><alpha 2-Surface Binding Glycoprotein><anti-cancer therapy><autoimmune condition><autoimmune disorder><autoimmunity disease><biologic><biological signal transduction><biomarker validation><cancer therapy><cancer-directed therapy><cell mediated therapies><cell-based immunotherapy><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><chimeric antigen T cell receptor><chimeric antigen receptor><chimeric antigen receptor (CAR) T cell therapy><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cell therapy><chimeric antigen receptor T cells><chimeric antigen receptor T therapy><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><chronic autoimmune disease><combat><curative intervention><curative therapeutic><curative therapy><curative treatments><cutaneous fibrosis><cytokine><dermal fibrosis><design><design and construct><design and construction><designing><develop therapy><developmental><disseminated lupus erythematosus><engineered T cells><fibrosis in the lung><fibrotic skin><genetically engineered T-cells><immune cell therapy><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><in vivo><injury to tissue><insight><intervention development><intervention efficacy><intervention therapy><living system><lung fibrosis><lymph cell><malignancy><marker validation><monocyte><mouse model><multiomics><multiple omics><murine model><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><panomics><parent><parent award><parent project><pathophysiology><pathway><pre-clinical study><preclinical study><profibrotic cytokine><progressive systemic sclerosis><reparative process><resolutions><response><single cell analysis><skin fibrosis><success><systemic autoimmune disease><systemic autoimmune disorder><systemic lupus erythematosis><therapeutic efficacy><therapeutic evaluation><therapeutic target><therapeutic testing><therapeutically effective><therapy development><therapy efficacy><tissue injury><tissue repair><transcriptomics><transgenic T- cells><translation><treatment development><white blood cell><white blood corpuscle><wound healing><wound recovery><wound resolution>