Anti-CD19 CAR T-Cell Therapy in Refractory Systemic Autoimmune Diseases
- Conditions
- Lupus Erythematosus, SystemicSystem; SclerosisANCA Associated VasculitisDermatomyositisPolymyositis
- Interventions
- Registration Number
- NCT06685042
- Brief Summary
The CATARSIS study explores the use of anti-CD19 CAR T-cell therapy as a novel approach for treating refractory systemic autoimmune diseases, specifically SLE, SSc, DM/PM, and AAV. These life-threatening conditions often resist current therapies, and B cells play a key role in their pathogenesis. The study employs CD19-CAR_Lenti, an autologous CAR T-cell product targeting CD19-positive B cells, aiming to reduce inflammation and autoimmunity. This open-label, single-dose, phase I basket trial will assess the safety, feasibility, and preliminary efficacy of CAR T-cell therapy, focusing on adverse events, infection rates, and overall response at 24 weeks. Eight participants will be included.
- Detailed Description
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, 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 (CRS) and of CAR T cell Associated Neurotoxicity Syndrome (ICANS) 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 8
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Anti-CD19 CAR T cell CAR T cell Single intravenous infusion of 1 x 106 /kg body weight CAR T cell ("CD19-CAR_Lenti" )
- Primary Outcome Measures
Name Time Method Number of subjects experiencing a CRS or an ICANS 4 weeks The first safety outcome variable will be measured as the number of subjects experiencing a Cytokine Release Syndrome (CRS) or an (Immune Effector Cell-associated Neurotoxicity Syndrome) ICANS within the first 4 weeks after ATMP administration in relation to the number of subjects enrolled in the study.
Incidence of infections, leukopenia and/or hypogammaglobulinemia 24 weeks The second safety outcome variable will be measured as the incidence of infections, leukopenia, and/or hypogammaglobulinemia during the entire study period in relation to the number of subjects enrolled in the study.
Overall Response Rate 24 weeks The efficacy outcome variable, Overall Response Rate (ORR), is defined as the ratio between the number of subjects experiencing a response at week 24 and the total number of enrolled subjects.
A response to treatment will be considered at week 24 as:
* SLE: Fulfillment of DORIS remission criteria of SLE.
* SSc: No progression of interstitial lung disease with worsening of FVC (\>10%) or worsening of FVC (5-10%) plus an increase in respiratory symptoms or worsening of FVC (5-10%) plus progression of high-resolution computed tomography changes after 24 weeks.
* DM/PM: 2016 ACR/EULAR Moderate or Major Response.
* AAV: Birmingham vasculitis activity score (BVAS) of 0.
- Secondary Outcome Measures
Name Time Method Time of persistence of CAR T cells 24 weeks Time of persistence of CAR T cells in the peripheral blood is defined as the time elapsed from the date of the study intervention and the date of disappearance of CAR T cells. CAR T cells will be identified as proportion of CAR+ cells relative to total CD3+ cells (0-100%) and in absolute number (cells per milliliter of peripheral blood).
Time of absence of B cells in the peripheral blood 24 weeks Time of absence of B cells in the peripheral blood is defined as the time elapsed from the date of the study intervention and the date of the rise of B cells after the intervention-induced nadir. B cells will be identified as proportion of CD19+ cells relative to total lymphocytes (0-100%) and in absolute number (cells per milliliter of peripheral blood).
Time to the disappearance of autoantibodies in the serum 24 weeks Time to the disappearance of autoantibodies in the serum is defined as the time elapsed from the date of the study intervention and the date of negativization of disease-specific autoantibodies. The negativity of an autoantibody is defined as its detection at a concentration (AU/mL) below the lower limit of positivity, according to the laboratory's reference ranges.
Trial Locations
- Locations (1)
Fondazione Policlinico Universitario A. Gemelli IRCCS
🇮🇹Rome, Lazio, Italy