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.
General
Subjects must understand and voluntarily sign an informed consent form, including written consent for data protection;
Adults aged ≥ 18 years and < 65 years at time of consent;
Male subjects, unless surgically sterile, must agree to use two acceptable methods for contraception (e.g., spermicide and condom) during the trial and refrain from fathering a child starting from the time of signing the Informed Consent Form (ICF) until 12 months after dosing of the IMP;
Clinically suitability for a less burdensome and/or approved therapeutic approach, as judged by the investigator;
ANC < 1.000/mm3, ALC < 500/mm3 or hemoglobin < 8 g/dl, absolute CD3+ T cell count ≤100/µl;
Evidence of significant and uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results.
Relevant cardiovascular disease: recent history of myocardial infarction, cardiac angioplasty or stenting, unstable angina, significant arrhythmia, congestive heart failure, or left ventricular ejection fraction < 50%, as determined by echocardiography
Single group
CAR T cell
Biological/VaccineThe investigational medicinal product (IMP) "CD19-CAR\_Lenti" consists of autologous CD19 Chimeric Antigen Receptor (CAR) transduced CD4/CD8 enriched T cells, derived from a leukapheresis product and processed by using the CliniMACS Prodigy® device (Miltenyi Biotec). CD19-CAR\_Lenti is a suspension of fresh CD4/CD8-enriched CD3+ T cells that have been genemodified with a self-inactivating (SIN) lentiviral vector expressing a CAR directed against human CD19. The SIN lentiviral vector is derived from clinically validated viral vectors described in the literature with a fully characterized sequence.
Number of subjects experiencing a CRS or an ICANS
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
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
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.
Time of persistence of CAR T cells
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
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
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.
B cell receptor and T cell receptor repertoire
B cell receptor and T cell receptor usage as determined by sequencing analysis of circulating B cells and T cells in the peripheral blood at screening and week 24.
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