A phase I/II study of CAR-expressing Allogenic iPSC derived NK cells for treatment of autoiMmune disease by B cELl depletion - CARAMEL

Prior treatment

• Uncontrolled severe concomitant disease, such as cancer (except basal or squamous cell skin cancer), diabetes mellitus or severe hepatic insufficiency defined as Child Pugh score ≥ 10 (C) or unstable coronary artery disease
• Requirement for immunization with live vaccine during the study period or within 14 days preceding LDC
• Prior treatment with anti-CD19 CAR-T cell therapy
• Any concomitant severe active infection, e.g., HIV, hepatitis B or C, SARS-CoV 2 (COVID 19), or active tuberculosis as defined by a positive Quantiferon TB-test; if presence of latent tuberculosis is established then treatment according to local guidelines must have been initiated prior to enrollment

Other illness

• Malignancy in the last 5 years before screening, except localized basal cell or squamous skin carcinoma, treated curatively and without evidence of recurrence. In situ carcinoma of the cervix or breast within the past 3 years is also allowed if treated curatively and without evidence of recurrence
• 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 interpretation of results
• History of allogeneic bone marrow/hematopoietic stem cell transplantation
• Known hypersensitivity to any drug components

Lab values

• Severely impaired renal (GFR ≤30 ml/min/1.73m2), liver (AST/ALT >3xN, Child Pugh C), heart (NYHA IV, EF <40 %) and pulmonary (FV and DLCO <30 %) function
• 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

Age

• Subjects who are younger than 18 years or are incapable to understand the aim, importance and consequences of the study and to give legal informed consent

Other

• Subjects who possibly are dependent on the Sponsor, the Principal Investigator or Investigator (e.g., family members)
• Diagnosis of severe neuropsychiatric SLE, inclusion body myositis or limited SSc
• Pregnant or lactating females as well as the intention to conceive during the study

• Fulfilling the 2019 ACR/EULAR classification criteria of SLE
• Presence of active myositis in muscle biopsy or muscle imaging and/or signs of interstitial lung disease related to IIM
• Positivity (+ or more) for at least one myositis-specific antibody (aminoacyl tRNA synthetases, Mi2, MDA5, SAE, SRP, ARS, HMGCR, MJ, TIF1gamma) at screening or documented medical history. Patients with positivity for TIF1gamma must have undergone a sufficient cancer screening prior screening.
• In patients with active myositis and muscle weakness: Muscle weakness as defined by MMT<142 and 2 of the following criteria: i) VAS patients global ≥2cm; ii) VAS physician global ≥2cm; iii) HAQ >0.25; iv) minimum of one muscle enzyme >1.3 times upper limit of normal; v) VAS global extra muscular activity ≥2cm
• Insufficient response or intolerance/contraindication to glucocorticoids and to at least 2 of the following treatments: mycophenolate mofetil, ciclosporin A, tacrolimus, methotrexate, rituximab, intravenous immunoglobulins, azathioprine, cyclophosphamide or JAKi; insufficient response is defined as having increased disease activity based on the definition explained in the previous bullet point
• Positivity of anti-dsDNA (>4U/L), anti-histone (+ or more), anti-nucleosome (+ or more) or anti-Sm antibodies (+ or more) at screening or documented medical history
• 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)
• Insufficient response or intolerance/contraindication to glucocorticoids and to at least 2 of the following treatments: azathioprine, mycophenolate mofetil, belimumab, methotrexate, rituximab, obinutuzumab, anifrolumab, cyclophosphamide; insufficient response is defined as having increased disease activity based on the definition explained in the previous bullet point
• Fulfilling the 2013 ACR/EULAR classification criteria of SSc
• Diffuse SSc with positivity (+ or more) of either Scl70, RNA polymerase, Th/To, RP11/12 or U3RNP autoantibodies at screening or documented medical history
• Signs for fast progression including (i) disease duration ≤7 5 years (from onset of first non-Raynaud manifestation), (ii) mRSS score 10-35≥ 15 at screening, (iii) elevated acute phase reactant levels (CRP ≥6 mg/L, ESR ≥28 mm/h or platelet count ≥330 G/L), (iv) 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
• Insufficient response or intolerance/contraindication to glucocorticoids and to at least 2 of the following treatments: mycophenolate mofetil, azathioprine, nintedanib, methotrexate, rituximab, cyclophosphamide, tocilizumab and not eligible or denying AHCT
• Fulfilling the 2017 ACR/EULAR classification criteria for probable or definite IIM