Anti-CD19 CAR T-Cell Therapy in Refractory Systemic Autoimmune Diseases

In recent years, B cells have become more appreciated as major players and also as therapeutic targets in systemic autoimmune diseases. Systemic autoimmune diseases, such as Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (SSc), Dermatomyositis/Polymyositis (DM/PM), and ANCA Associated Vasculitis (AAV) are among the most life-threatening diseases. Even though clinical presentation and organ involvement may be different, these diseases share common pathways of B cell activation. Despite the substantial advances in their management, some patients with systemic autoimmune diseases fail to respond to the current state-of-the art therapies, and are at high risk for severe organ failure and even death. Therefore, new treatments for such refractory cases are urgently needed. A strong preclinical rationale supports the use of anti-CD19 CAR T cells in systemic autoimmune disease. Experimental animal models back the concept that anti-CD19 CAR T cell therapy could be a powerful approach to target autoimmunity and inflammation in B cell mediated autoimmune disease. "CD19-CAR_Lenti" (the ATMP) consists of autologous CD19 Chimeric Antigen Receptor (CAR) transduced CD4/CD8 enriched T cells, derived from a leukapheresis product and processed at Officina Farmaceutica of IRCCS Ospedale Pediatrico Bambino Gesù through a validated process by using the CliniMACS Prodigy® device. CD19-CAR_Lenti is a suspension of fresh CD4/CD8- enriched CD3+ T cells that have been gene-modified with a self-inactivating (SIN) lentiviral vector expressing a CAR directed against human CD19. CATARSIS is a basket study on four prototypic systemic autoimmune diseases, which a) show a severe life-threatening disease course, b) are associated with a current high unmet need for treatment, c) show an involvement of B lymphocytes in disease pathogenesis and d) respond at least partially to treatment with B cell depleting antibodies. The investigators will conduct a prospective, open-label, single-dose, non-randomized?randomized Participants are assigned to the study groups by chance, like a coin toss, rather than chosen by the doctor or the participant. This is done so the groups are comparable., interventional phase I clinical study, using a "basket" design, to assess the safety, feasibility, and preliminary efficacy of ex vivo generated autologous anti-CD19 CAR T cells targeting a common pathogenic pathway (activated B cells and plasmablasts) in subjects with severe, treatment-failure systemic autoimmune disease (SLE, SSc, DM/PM and AAV). In particular, the investigators will assess incidence and grading of severity of Cytokine Release Syndrome?Cytokine Release Syndrome A reaction in which the immune system releases a large amount of signalling proteins at once, causing fever and sometimes low blood pressure or breathing problems. It can occur after some immune therapies, such as CAR-T cells or bispecific antibodies. (CRS) and of CAR T cell Associated Neurotoxicity Syndrome (ICANS?ICANS Nervous-system side effects, such as confusion or difficulty speaking, that can occur after some immune therapies. Usually temporary, but monitored closely.) within the first 4 weeks after ATMP administration, incidence and severity of infections and leukopenia and/or hypogammaglobulinemia during the entire study period (24 weeks), and overall Response Rate (ORR) at week 24 based on specific disease activity composite indexes, each of them validated for the specific disease. Duration of B cell depletion in the peripheral blood, duration of persistence of CAR T cells in the peripheral blood, and changes in the levels of disease-associated serum autoantibodies will be assessed as well through specific laboratory measurements. A total of 8 subjects with B cell-mediated autoimmune disease will be included in the CATARSIS study, following a Bryant and Day two stages design. Subjects will receive a single intravenous infusion of 1 x 10\^6 /kg body weight CAR T cell. Recruitment and outpatient visits will be performed in the UOC Reumatologia - Dipartimento di scienze dell'Invecchiamento, Ortopediche e Reumatologiche (FPG) and Dipartimento Oncoematologia, Terapia Cellulare, Terapie Geniche e Trapianto Emopoietico (OPBG). Treatment and pre-treatment specific procedures (leukapheresis, lymphodepletion) of subjects and the inpatient visits will be performed in the UOC Ematologia e Trapianto di cellule staminali emopoietiche - Dipartimento di diagnostica per Immagini, Radioterapia Oncologica ed Ematologia (FPG) and Dipartimento Oncoematologia, Terapia Cellulare, Terapie Geniche e Trapianto Emopoietico (OPBG) by trained investigators. ATMP manufacturing will be performed in a certified facility at Officina Farmaceutica, IRCCS Ospedale Pediatrico Bambino Gesù, under licenses by local regulatory authorities and highest technical standards.