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

• General

  1. Subjects must understand and voluntarily sign an informed consent form, including written consent for data protection;
  2. Adults aged ≥ 18 years and \< 65 years at time of consent;
  3. 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;
  4. Females of childbearing potential (FCBP) must have a negative urine pregnancy test at screening and must agree to use a highly effective contraceptive method (Pearl index \<1) starting from the time of signing the ICF and for 12 months after dosing of the IMP;
  5. Must be able to adhere to the study visit schedule and other protocol requirements;
  6. Double vaccination (2 doses) against SARS-CoV-2 or SARS-CoV-2 within the last 6 months.

• SLE subjects

  a) Fulfilling the 2019 ACR/EULAR classification criteria of SLE; b) Presence of anti-dsDNA, anti-histone, anti-nucleosome or anti-Sm antibodies; c) Active disease at screening, defined as ≥1 organ system with a British Isles Lupus Assessment (BILAG) A score (severe disease activity) or ≥2 organ systems with a BILAG B score (moderate disease activity); d) Insufficient response to glucocorticoids and at least 2 of the following treatments: hydroxychloroquine, mycophenolate mofetil, belimumab, methotrexate, rituximab.

• SSc subjects

  1. Fulfilling the 2013 ACR/EULAR classification criteria of SSc;
  2. Diffuse SSc with respective autoantibody profile;
  3. Signs for fast progression including i) disease duration ≤5 years (from onset of first non-Raynaud manifestation), ii) mRSS score 10-35 at screening, iii) elevated acute phase reactant levels (CRP ≥ 6 mg/L, ESR ≥ 28mm/h or platelet count ≥ 330 000/mm3), iii) mRSS increase ≥ 3 units or involvement of one new body area or mRSS increase ≥ 2 units in one body area or ≥1 tendon friction rub over 6 months;
  4. Insufficient response to glucocorticoids and to at least 2 of the following treatments:

mycophenolate mofetil, azathioprine, nintedanib, methotrexate, rituximab.

• DM/PM subjects

  a) Fulfilling the 2017 ACR/EULAR classification criteria for probable or definite DM or PM57, b) Muscle weakness as defined by MMT \< 142 and 2 of the following criteria: VAS patients Global ≥ 2 cm, VAS physician Global ≥ 2 cm, HAQ > 0.25, at least one muscle enzyme >1.3 times upper limit of normal, VAS global extra muscular activity ≥ 2 cm; c) Presence of at least one myositis-specific antibody; d) Insufficient response to glucocorticoids and to at least 2 of the following treatments: mycophenolate mofetil, ciclosporin A, tacrolimus, methotrexate, rituximab, and intravenous immunoglobulins.

• AAV subjects

  1. Fulfilling the 2022 ACR/EULAR classification criteria for MPA/GPA/EGPA,
  2. Presence of ANCA to either proteinase 3 or myeloperoxidase;
  3. At least one major or three non-major items or at least two renal items of hematuria and proteinuria on the BVAS;
  4. Failure of at least 1 of the following treatments: glucocorticoids, cyclophosphamide, or B-cell targeting therapy.

Exclusion criteria

• 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
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study;
• Impaired renal function, i.e., eGFR \< 30 ml/min;
• Patients with evidence on thorax CT of advanced fibrotic interstitial lung disease and whose latest pulmonary function test showed a Forced Vital Capacity (FVC) \< 40% of predicted or a Diffusing Capacity for Carbon Monoxide (DLCO) \< 30% of predicted
• Any concomitant severe active infection, including HIV (even with negative viral load), active hepatitis B (either positive for Hepatitis B core antibody [HBcAb] or positive hepatitis B surface antigen [HBsAg] and NAT tests) and/or C (\<12 weeks between achievement of a sustained virological response to the specific treatment and apheresis) according to the American Association for the Study of Liver Diseases guidelines, SARS-CoV 2 (COVID 19), or active tuberculosis as defined by a positive Quantiferon TB-test. If the presence of latent tuberculosis is established, then treatment according to local guidelines must have been initiated before enrolment;
• Pregnant or lactating females;
• Known hypersensitivity to either any drug components or any auxiliary medicinal products scheduled during trial participation, including during lymphodepletion;
• Malignancy in the last 5 years before screening. The inclusion of patients with previously completely resected carcinoma in situ who have not required treatment other than surgery is allowed.
• Previous CAR T cell administration;
• A therapeutic schedule not compatible with the wash-out requirements for the leukapheresis procedure (section 5.8.1 of CSP) and the medications permitted during the study (section 7.11 of CSP);
• Concurrent treatment with other investigational agents or participation in other investigational trials.
• Treatment, as part of an investigational clinical trial, with an experimental product with a definite or potential effect on T or B-cells in the previous 2 years.
• Requirement for immunization with live vaccine during the study period or within 14 days preceding leukapheresis;
• Subjects who are younger than 18 years or are incapable of understanding the aim, importance, and consequences of the study and giving legal informed consent;
• Have a history of alcohol or substance abuse within the preceding 6 months that, in the opinion of the Investigator, may increase the risks associated with study participation or study agent administration or may interfere with the interpretation of results;
• Subjects who possibly are dependent on the Sponsor, the Principal Investigator, or the Investigator (e.g., family members).
• Limited to patients diagnosed with SLE: patients with a history of severe central nervous system (CNS) involvement, including those who have presented aseptic meningitis, cerebral vasculitis, cerebrovascular disease, demyelinating syndrome, myelopathy, seizure disorder, status epilepticus, and severe lupus headache, will be excluded.
• Patients meeting the classification criteria for multiple connective diseases such as overlapping SLE and Sjogren's Syndrome (SS) or SLE and Rheumatoid Arthritis (RA) and patients diagnosed with Mixed Connective Tissue Disease (MCTD).