Cellular Immunotherapy to Combat Fibrosis and Inflammation in Systemic Sclerosis

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Systemic sclerosis (SSc) is an autoimmune disease that affects multiple organ systems and is characterized by chronic inflammation, vasculopathy, and fibrosis. The standardized mortality ratio for SSc has not changed significantly in the past 40 years, and one in three patients dies within 10 years of diagnosis. The scientific premise of our proposal is that pro-fibrotic macrophages (MØs) are key drivers of SSc. Our hypothesis is that targeting activated MØs in SSc will provide a novel and effective approach to treat the disease, and that the elimination of these MØs will result in decreased fibrosis. We have designed a novel therapeutic approach to eliminate pro-fibrotic MØs using chimeric antigen receptor (CAR) T cells, and localized anti-CD206 CAR T cell treatment reduces dermal thickness and gene expression associated with disease progression in a bleomycin (BLM) mouse model of skin fibrosis. Given the systemic nature of SSc and the mortality associated with internal organ involvement, we propose to determine the efficacy of systemic administration of anti-CD206 CAR T cells for the treatment of pulmonary and dermal fibrosis. Specific Aim 1: Determine if elimination of profibrotic MØs by CAR T cell immunotherapy reduces skin and lung fibrosis. Depletion of the myeloid subsets targeted by CD206-CAR T cell immunotherapy and their impact on skin and lung fibrosis are unknown. We will use CITE-seq to identify MØ subsets in skin and lung pre and post- CAR T cell treatment and will measure collagen deposition, markers of inflammation, and tissue thickness. Specific Aim 2: Determine anti-CD206 CAR T cell persistence in vivo using a systemic model of fibrosis. Successful treatment of SSc will depend on CAR T persistence and maintenance of effector function. To monitor anti-CD206 CAR T cells in preclinical in vivo studies, we will develop and validate a quantitative PCR assay to measure copy number of the anti-CD206 CAR gene.