CAR-T cells in systemic B cell mediated autoimmune disease - CASTLE

Prior treatment

• Uncontrolled severe concomitant disease, such as cancer (except basal or squamous cell skin cancer) and diabetes mellitus,
• Prior treatment with anti-CD19 antibody therapy, adoptive T cell therapy or any prior gene therapy product (e.g. 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,
• Requirement for immunization with live vaccine during the study period or within 14 days preceding leukapheresis,

Other illness

• History of bone marrow/ hematopoietic stem cell or solid organ transplantation,
• Known hypersensitivity to any drug components,
• Malignancy in the last 5 years before screening,
• 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,

Lab values

• ANC \< 1.000/mm3, ALC \< 500/mm3 or hemoglobin \< 8g/dl, absolute CD3+ T cell count \< 100/μl,
• Severely impaired renal (eGFR ≤ 30 ml/min/m2), liver (Child Pugh C), heart (NYHA IV, EF ≤ 30%) and pulmonary (FV and DLCO ≤ 30%) function,
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if the subject 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

• Clinically suitability for a less burdensome and/or approved therapeutic approach, as judged by the investigator
• Diagnosis of severe neuropsychiatric SLE, inclusion body myositis or limited SSc,
• Pregnant or lactating females,
• Females who are intending to conceive during the study,
• Subjects who possibly are dependent on the Sponsor, the Principal Investigator or other Investigators (e.g. family members).

• General:
  • Subjects must understand and voluntarily sign an informed consent form including written consent for data protection,
  • Adults aged ≥ 18 years at time of consent,
  • Adequate renal (eGFR \> 30 ml/min/m2), liver (no Child Pugh C), heart (at worst NYHA III, EF \> 30%) and pulmonary (FV and DLCO \> 30%) function,
  • 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,
  • 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 in-dex \<1) starting from the time of signing the ICF and for 12 months after dosing of the IMP,
  • Must be able to adhere to the study visit schedule and other protocol requirements,
  • Double vaccination against SARS-CoV-2 or SARS-CoV-2 within the last 6 months.
• SLE specific:
  • Fulfilling the 2019 ACR/EULAR classification criteria of SLE,
  • Positivity of anti-dsDNA (\> 4 U/l), anti-histone (+ or more), anti-nucleosome (+ or more) or anti-Sm antibodies (+ or more),
  • 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: hydroxychloroquine, mycophenolate mofetil, belimumab, methotrexate, rituximab, cyclophosphamide. Insufficient response is defined as having increased disease activity based on the definition explained in the previous bullet point.
• SSc specific:
  • Fulfilling the 2013 ACR/EULAR classification criteria of SSc),
  • Positivity (+ or more) for at least one SSc-specific parameter (Scl70, RNA polymerase, Th/To, RP11/12, U3RNP autoantibodies),
  • 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 G/L), (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,
  • Insufficient response or intolerance/ contraindication to at least 2 of the following treatments: mycophenolate mofetil, azathioprine, nintedanib, methotrexate, rituximab. Insufficient response is defined as having increased disease activity based on the definition explained in the previous bullet point.
• DM/PM specific:
  • Fulfilling the 2017 ACR/EULAR classification criteria for probable or definite DM or PM,
  • Presence of active myositis in muscle biopsy or muscle MRI and/or signs of interstitial lung disease related to DM/PM,
  • Positivity (+ or more) for at least one myositis-specific antibody (aminoacyl tRNA synthetases, Mi2, MDA5, SAE, SRP, ARS, HMGCR, MJ, TIF1gamma),
  • Muscle weakness as define by MMT \< 142 and 2 of the following criteria: VAS patients Global ≥2cm, VAS physician Global ≥ 2cm, HAQ \> 0.25, at least one muscle enzyme \> 1.3 times upper limit of normal, 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. Insufficient response is defined as having increased disease activity based on the definition explained in the previous bullet point.