Phase IIa Trial of Anti-CD19 CAR T-Cells in Systemic Sclerosis Resistant to Immunosuppressive Therapy

Official title

SCLEROCAR: A Phase IIa Trial Evaluating the Efficacy of Anti-CD19 Chimeric Antigen Receptor Engineered T-Cells in Patients With Systemic Sclerosis (SSc) Resistant to Immunosuppressive Drugs

Overview

The goal of this clinical trial is to evaluate whether anti-CD19 CAR T-cell therapy can improve disease activity in adults with severe, treatment-resistant systemic sclerosis (SSc). The study will also assess the safety of this therapy and how CAR T-cells behave in the body. The main questions are: Does CAR T-cell therapy reduce skin thickening and other signs of SSc? What side effects occur after receiving CAR T-cells? How do CAR T-cells expand, persist, and affect B-cells and autoantibodies? Participants will: Undergo leukapheresis Receive short lymphodepleting chemotherapy Receive one infusion of anti-CD19 CAR T-cells Stay in the hospital for about 10 days Attend follow-up visits for 24 months with clinical exams, blood tests, and organ-function assessments Optional skin or lymph-node biopsies may be performed in participants who consent to these procedures. This study aims to provide early evidence on whether CAR T-cell therapy could become a promising treatment option for systemic sclerosis.

Detailed description

Systemic sclerosis (SSc) is a rare and severe autoimmune disease characterized by fibrosis of the skin and multiple organs, vasculopathy, and immune dysregulation. Many patients continue to experience active and progressive disease despite conventional immunosuppressive treatments, including disease modifying antirheumatic drugs (DMARDs) and biologics. Therapeutic options remain limited, and there is a significant unmet medical need for innovative approaches targeting the underlying mechanisms of the disease.

Recent preliminary experience from studies conducted in autoimmune diseases-such as lupus, myositis, and systemic sclerosis-suggests that autologous anti CD19 CAR T cell therapy may help reduce disease activity. Reported observations include transient B cell depletion, decreases in autoantibody levels, and improvements in joint, pulmonary, and cardiac manifestations. These early results support further evaluation of CAR T cell therapy in systemic sclerosis in a structured clinical trial setting.

This Phase IIa, multicenter, single-arm study is designed to evaluate the feasibility and safety of autologous anti-CD19 CAR-T cell therapy in adults with active systemic sclerosis who are resistant to immunosuppressive treatments. The study also aims to generate early clinical and biological data to assess the potential value of this therapeutic strategy in this population.

Eligible participants will undergo leukapheresis for T-cell collection. Following standard manufacturing of autologous anti-CD19 CAR-T cells in a GMP (Good Manufacturing Practice)-certified facility, participants will receive a short course of lymphodepleting chemotherapy, followed by a single intravenous infusion of CAR-T cells. They will remain hospitalized for intensive monitoring during the early post-infusion period, in accordance with established procedures for CAR-T cell therapies. Participants with known hypersensitivity to drugs required for treatment-related toxicity are excluded, as specified in the protocol.

After discharge from the hospital, participants will have follow-up visits for up to 24 months. These visits will include clinical and biological assessments as well as appropriate imaging tests to monitor disease activity, treatment safety, and overall health status. Biological samples will also be collected at specific times for centralized analysis.

The study incorporates exploratory immunological and translational research components. These may include monitoring circulating CAR T cells, characterizing immune cell subsets, and evaluating selected biomarkers. Optional skin and lymph node biopsies may be performed in consenting participants to analyze immune cell phenotypes and tissue level changes associated with treatment. Additional exploratory analyses may assess the spatial organization and distribution of immune cells within tissue samples, as described in the study protocol.

Overall, the study aims to provide early data on the use of anti CD19 CAR T cell therapy in systemic sclerosis, including feasibility, safety, and biological signals of activity. The results are expected to contribute to the development of innovative cell based therapeutic strategies for this severe autoimmune disease.

Interventions

• Biological CD19 CAR T Arm
  Autologous anti-CD19 CAR-T cells are generated from the participant's leukapheresis product in a Good Manufacturing Practice (GMP)-certified facility using a lentiviral vector. Prior to infusion, participants will receive a short course of lymphodepleting chemotherapy. A single intravenous infusion of autologous anti-CD19 CAR-T cells will be administered on Day 0 at a target dose of 1 × 10⁶ CAR-T cells/kg. Participants will then be monitored in the hospital in accordance with standard post-CAR

Primary outcome measures

• modified Rodnan skin score (mRSS) [Time frame: 6 Months]

Secondary outcome measures (12)

• Change in European Scleroderma Trial And Research (EUSTAR) activity index [Time frame: From 3 months to 1 month before CAR-T cell infusion]
• Change in European Scleroderma Trial And Research (EUSTAR) activity index [Time frame: 1 month before CAR-T cell infusion]
• Change in European Scleroderma Trial And Research (EUSTAR) activity index [Time frame: Day 0 (CAR-T cell infusion)]
• Change in European Scleroderma Trial And Research (EUSTAR) activity index [Time frame: Day 28 after CAR-T cell infusion]
• Change in European Scleroderma Trial And Research (EUSTAR) activity index [Time frame: 3 Months]
• Change in European Scleroderma Trial And Research (EUSTAR) activity index [Time frame: 6 Months]
• Change in European Scleroderma Trial And Research (EUSTAR) activity index [Time frame: 12 Months]
• Change in European Scleroderma Trial And Research (EUSTAR) activity index [Time frame: 24 Months]
• modified Rodnan skin score (mRSS) [Time frame: From 3 months to 1 month before CAR-T infusion]
• modified Rodnan skin score (mRSS) [Time frame: 1 month before CAR-T infusion]
• modified Rodnan skin score (mRSS) [Time frame: Day 0 (CAR-T infusion)]
• modified Rodnan skin score (mRSS) [Time frame: Day 28 after infusion]

Eligibility criteria

Pre-Inclusion criteria:

• Diagnosis of systemic sclerosis according to ACR/EULAR 2013 classification (15).we include in the critera the fulfilling of 2013 EULAR/ACR criteria and specify disease duration (less than 2 years), score/clinical evidence for active disease :
• Severe and resistant to low dose steroids and at least 2 immunosuppressive treatment including csDMARDs (methotrexate, azathioprine, mycophenolate mofetil) and at least one bDMARDs (Tocilizumab)
• Early onset (less than 2 years).
• Severity \& progression of disease be defined by :

• .mRSS >15 with at least one organ involvement (lung: FVC <80%, renal involvement, cardiac involvement, Creatinine < 1.5 mg/dl within 6 months).
• mRSS <15 and lung fibrosis progression (FVC -10% DLCO -15% within 6 months)
• patients with active disease (as defined by EUSTAR ≥2.5) and to patients with a worsening disease despite 6 months of at least 2 immunosuppressive treatments including one DMARDs (methotrexate, azathioprine, mycophenolate mofetil), and one biological DMARD rituximab or tocilizumab.
• Estimated survival time > 24 weeks
• Age: ≥18 ≤64 years old voluntary to participate in the study and sign the informed consent
• Adequate organ functions assessed :

• serum Creatinine clearance > 40ml/mi
• adequate bone marrow function (Hemoglobin ≥9g/dL ; PMN ≥ 1 G/L ; Platelets ≥ 100 G/L)
• Alanine aminotransferase (ALT) ≤ 3 x ULN and total bilirubin < 2.0 mg/dL (34 μmol/L) (or < 3.0 mg/dL \[51 μmol/L\] for subjects with Gilbert's syndrome)
• Adequate respiratory function: no dyspnea or grade I dyspnea (Common Terminology Criteria for Adverse Events (NCI CTCAE v 5.0) and oxygen saturation >/= 92% on room air
• Highly effective contraception methods

Inclusion criteria

• Adequate organ functions assessed:

• serum Creatinine clearance > 40ml/mi
• adequate bone marrow function (Hemoglobin ≥9g/dL ; PMN ≥ 1 G/L ; Platelets ≥ 100 G/L)
• Alanine aminotransferase (ALT) ≤ 3 x ULN and total bilirubin < 2.0 mg/dL (34 μmol/L) (or < 3.0 mg/dL \[51 μmol/L\] for subjects with Gilbert's syndrome)
• Adequate respiratory function: no dyspnea or grade I dyspnea (Common Terminology Criteria for Adverse Events (NCI CTCAE v 5.0) and oxygen saturation >/= 92% on room air
• Adequate venous access for apheresis
• Leucapheresis : a wash-out period of 6 weeks for conventional immunosuppressants (i.e. methotrexate, mycophenolate mofetil)
• Leucapheresis : at least 12 weeks after biotherapy (i.e. tocilizumab, 6 months for rituximab),

Exclusion criteria

• Craniocerebral trauma, conscious disturbance, epilepsy, cerebrovascular ischemia or cerebrovascular hemorrhagic diseases
• ECG showing prolonged QT interval or history of severe heart diseases or FEVG < 40%
• Lung and / or heart severe dysfunction defined by CVF<50% and/or DLCO <40%
• Pulmonary arterial hypertension defined by catheterism (mean AP > 25mmHg at rest or > 30mmHg after exercise, PAOP < 15mmHG)
• Clinically significant active, opportunistic, chronic or recurrent infection (including but not limited to: hepatitis B or C virus or HIV) or covid-19 < 1 months including active or latent tuberculosis (TB) infection
• Contra indication for autologous hematopoietic stem cell transplantation (AHSCT ) or relapsing at least one year after AHSCT
• Active hematological or solid neoplasm
• Concurrent therapy with systemic steroids (>10 mg/d prednisone equivalent) within 2 weeks prior to inclusion, except inhaled steroids
• Methylprednisolone or prednisone (maximum dose 20 mg) instead of immunosuppressive agents
• T cell targeting drugs (e.g. mycophenolate mofetil, azathioprine, calcineurin inhibitors) within 6 weeks prior to leukapheresis
• Previous adoptive T cell therapy or any gene therapy including CAR T cell therapy
• Live vaccines within 6 weeks prior to leukapheresis
• Hypersensitivity against any drug or its ingredients/impurities that is scheduled or likely to be given during trial participation, e.g. as part of the mandatory preparative chemotherapy or rescue medication/salvage therapies for treatment related toxicities
• patients without social security coverage;
• patients under guardianship;
• Male or female patients seeking to conceive a child
• Women of childbearing potential unless they are using a highly effective method of contraception starting from the time of enrolment and for at least 12 months following LD chemotherapy and until clearance of CAR-T cells, and sexually active male participants unwilling to use a condom. Female partners of sexually active male participants must be on a highly effective form of birth control from the time of enrolment and for at least 12 months following LD chemotherapy and until clearance of CAR-T cells.
• pregnant or breastfeeding women;
• patients with advanced cognitive disorders or any other cause preventing their informed consent;
• active, clinically significant CNS pathology : If signs or symptoms exist which present diagnostic uncertainty, neurologist consultation will be obtained to confirm the diagnosis of any neurological condition
• any comorbidity, whatever it may be, which may, in the opinion of the investigator, place the patient at additional risk or interfere with the monitoring of the study.
• Concurrent participation in any other interventional trial and Contraindication to the lymphodepleting chemotherapy

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

France · 4 centers

• CHRU Lille — Lille
• Montpellier University Hospital — Montpellier
• APHP Necker — Paris
• Chu Rouen — Rouen

Identifiers

NCT: NCT07493395 · RECHMPL24_0438

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗