CAR-T Cells in Systemic B Cell Mediated Autoimmune Disease (CASTLE)

The investigational product is designed to effectively combat B cells in patients with autoimmune diseases. Autologous T cells enriched with CD4/CD8 are genetically engineered using a lentiviral vector to express chimeric antigen receptors (CARs) that target the CD19 antigen on the cell surface of B cells and their precursors. During treatment, patients undergo leukapheresis, lymophodepleting chemotherapy and administration of the expanded CD19-CAR-transduced T cells.

Study Overview

• Status: Recruiting
• Conditions: Systemic Lupus Erythematosus; Systemic Sclerosis; Dermatomyositis; Polymyositis
• Intervention / Treatment: Drug: anti-CD19 CAR T cell therapy

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Georg Schett, Prof. Dr. med. univ.; Phone Number: +49 9131 85 32093; Email: georg.schett@uk-erlangen.de
• Study Contact Backup: Name: Daniela Bohr, Dr.med; Phone Number: +49 9131 85 32093; Email: daniela.bohr@uk-erlangen.de

Study Locations

• Germany
  • Bavaria
    • Erlangen, Bavaria, Germany, 91054
      • Recruiting
      • Universitätsklinikum Erlangen
      • Contact: Georg Schett, Prof. Dr.
      • Contact: Daniela Bohr, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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.

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 < 8g/dl, absolute CD3+ T cell count < 100/μl,
• Uncontrolled severe concomitant disease, such as cancer (except basal or squamous cell skin cancer) and diabetes mellitus,
• 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,
• Prior treatment with anti-CD19 antibody therapy, adoptive T cell therapy or any prior gene therapy product (e.g. CAR T cell therapy),
• History of bone marrow/ hematopoietic stem cell or solid organ transplantation,
• 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,
• Diagnosis of severe neuropsychiatric SLE, inclusion body myositis or limited SSc,
• Pregnant or lactating females,
• Females who are intending to conceive during the study,
• Known hypersensitivity to any drug components,
• Malignancy in the last 5 years before screening,
• 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 to understand the aim, importance and consequences of the study and to give 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 interpretation of results,
• Subjects who possibly are dependent on the Sponsor, the Principal Investigator or other Investigators (e.g. family members).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Active dose; A prospective, open-label, non-randomized, single-dose interventional basket study. Single intravenous infusion of a freshly prepared advanced therapy medicinal product (ATMP) from autologous and expanded T cells transduced ex vivo with a CD19-CAR construct. No control intervention (e.g. another immunosuppressive therapy). Concomitant measures: Leukapheresis and lymphodepleting therapy for conditioning.

Drug: anti-CD19 CAR T cell therapy; Single-dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the safety of anti-CD19 CAR T cell therapy in subjects with active B-driven autoimmune disease (SLE, SSc and DM/PM).	Incidence and grading of severity (graded 0-4) of Cytokine Release Syndrome (CRS) and of CAR T cell-associated neurotoxicity (ICANS) within the first 4 weeks after ATMP administration.	up to d 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical efficacy SSc	Overall Response Rate (ORR) at week 24 measured by specific disease activity composite indexes, each of them validated for the specific disease: SSc: No progression of interstitial lung disease with worsening of FVC1 (>10 percentage) or worsening of FVC1 (5-10 percentage) plus increase in respiratory symptoms or worsening of FVC1 (5-10 percentage) plus progression of high-resolution computed tomography changes after 24 weeks.	at week 24
Clinical efficacy SLE	Overall Response Rate (ORR) at week 24 measured by specific disease activity composite indexes, each of them validated for the specific disease: SLE: Fulfillment of DORIS remission criteria of SLE at week 24.	at week 24
Clinical efficacy DM	Overall Response Rate (ORR) at week 24 measured by specific disease activity composite indexes, each of them validated for the specific disease: DM: 2016 ACR/EULAR moderate or major response.	at week 24
Cellular response	amount of CAR T cells in the peripheral blood (cells/µl); amount of B cells in the peripheral blood (cells/µl); expansion of CAR T cells in the patient over time in cells/µl	up to week 24
Serological response	Levels of respective serum autoantibodies at week 24 including incidence of sero-conversion measured in IE/ml; SLE: ANA-Titer, anti-dsDNA, anti-nucleosomes, anti-Sm, anti-cardiolipin IgG, C3 (mg/dl), C4 (mg/dl); SSc: ANA-Titer, anti-SCL70, anti-RNA polymerase III, anti-topoisomerase; DM: ANA-Titer, anti-Mi2, anti-Tif1, anti-MDA5, anti-Jo1, anti-NXP2	up to week 24
Success of IMP process	Success of the manufacturing process by GMP certification of the product (in percentage)	up to week 24
Physicians Global Assessment to measure quality of life	Physician's Global Assessment (PhGA) of disease activity (VAS 0-100mm), (0=no disease activity, 100=worst disease activity)	up to week 24
Patient's Global Assessment to measure quality of life	Patient's Global Assessment (PtGA) of disease activity (VAS 0-100mm), (0=no disease activity, 100=worst disease activity)	up to week 24
Health Assessment Questionnaire	Disease Index HAQ-DI (0-4 per question; 0=best function, 4=worst function)	up to week 24
Functional Assessment of Chronic Illness Therapy	Fatigue with FACIT Fatigue questionaire, from 8-44, (8=worst, 44=best, serious fatigue defined <30)	up to week 24
SLE-specific disease activity over time per subject	British Isles Lupus Assessment Group (BILAG) index Improvement of organ involvement according to BILAG A-E (A=severe organ involvement, E=mild organ involvement)	up to week 24
SSc-specific disease activity over time per subject	modified Rodnan Skin Score (mRSS) points 0-4 according to skin stiffness (0=no thickening, 3=severe thickening)	up to week 24
DM/PM-specific disease activity over time per subject	Physician's global assessment (PhGA) of extramuscular activity 0-100mm (0=no disease activity, 100=worst disease activity)	up to week 24
SLE-specific disease activity over time per subject	Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) points 1-8 according to organ involvement 1=mild organ involvement, 8=severe organ involvement)	up to 24 weeks
DM/PM-specific disease activity over time per subject	Manual Muscle Testing (MMT) points 0-150 (0=paraplegia, 150=full muscle strength)	up to 24 weeks

Collaborators and Investigators

• Sponsor: Miltenyi Biomedicine GmbH
• Investigators: Principal Investigator: Georg Schett, Prof. Dr. med. univ., Universitätsklinikum Erlangen

Study record dates

Study Major Dates

• Study Start (Actual): July 17, 2023
• Primary Completion (Estimated): May 31, 2026
• Study Completion (Estimated): May 31, 2026

Study Registration Dates

• First Submitted: December 15, 2023
• First Submitted That Met QC Criteria: April 3, 2024
• First Posted (Actual): April 4, 2024

Study Record Updates

• Last Update Posted (Estimated): September 30, 2025
• Last Update Submitted That Met QC Criteria: September 24, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Skin Diseases; Myositis; Skin and Connective Tissue Diseases; Lupus Erythematosus, Systemic; Scleroderma, Systemic; Dermatomyositis; Polymyositis
• Other Study ID Numbers: CASTLE; 2022-001366-35 (EudraCT Number); DRKS00032279 (Registry Identifier: Deutsches Register Klinischer Studien (DRKS))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No