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. SCLEROCAR

This phase IIa trial investigates the efficacy of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in patients with systemic sclerosis who have demonstrated resistance to immunosuppressive drugs. The primary objective is to evaluate the clinical efficacy of CAR T ANTI-CD19 cell therapy on skin fibrosis as assessed by the modified Rodnan skin score (mRSS) at month 6 following CAR T cell administration. This endpoint is clinically relevant as skin fibrosis represents a hallmark manifestation of systemic sclerosis and the mRSS serves as a validated quantitative measure of disease severity and therapeutic response in this patient population resistant to conventional immunosuppressive treatment.

The secondary objectives include:

• To evaluate the clinical efficacy of CAR T ANTI-CD19 cell therapy on disease activity using the EUSTAR index and mRSS, as well as pulmonary function and cardiac function at months 3, 6, and 12.

• To evaluate the safety profile of CAR T ANTI-CD19 cell therapy at the target dose of 1 × 10⁶ cells/kg (0.75 to 1.25 × 10⁶) during the 12-month post-injection follow-up period.

• To evaluate the pharmacokinetic profile of the transferred CAR T cells in systemic sclerosis.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consists of adult patients aged **18 to 65 years**, including both male and female subjects. Participants are diagnosed with **systemic sclerosis** according to **ACR/EULAR classification criteria** and present with disease that is refractory to standard immunosuppressive therapy. Eligible patients demonstrate either stable but active disease, as defined by a **EUSTAR score** of 2.5 or higher, or worsening disease despite at least six months of treatment with a minimum of two immunosuppressive agents, including one **disease-modifying antirheumatic drug** (such as **methotrexate**, **azathioprine**, or **mycophenolate mofetil**) and one biological DMARD (either **rituximab** or **tocilizumab**). Participants must have adequate organ function and venous access suitable for **apheresis**. A wash-out period is required prior to leukapheresis, specifically six weeks for conventional immunosuppressants and at least three months following biotherapy with tocilizumab or six months for rituximab. The trial includes a vulnerable population as designated in the study design.

This is a Phase IIa, interventional clinical trial evaluating the efficacy of anti-CD19 chimeric antigen receptor engineered T-cells in patients with systemic sclerosis resistant to immunosuppressive drugs. The investigational medicinal product, MB-CART19.1, consists of autologous T-cells transduced with lentiviral vector expressing a chimeric antigen receptor directed against CD19. The product is administered as an infusion via intravenous route. The trial involves a genetically modified organism as the T-cells are transduced ex vivo with a lentiviral vector containing the gene of interest, CAR anti CD19. The maximum daily dose and maximum total dose are both specified as one administration. The treatment period is limited to one day.

The trial is designed to enroll patients diagnosed with systemic sclerosis according to ACR/EULAR classification who have refractory disease despite previous treatment. Eligible participants must have active disease as defined by EUSTAR score of 2.5 or higher, or worsening disease despite at least six months of treatment with at least two immunosuppressive agents including one DMARD (methotrexate, azathioprine, or mycophenolate mofetil) and one biological DMARD (rituximab or tocilizumab). Participants must be between 18 and 65 years of age and have adequate organ function and venous access for apheresis. A wash-out period of six weeks for conventional immunosuppressants and at least three months after biotherapy (six months for rituximab) is required before leukapheresis.

The primary endpoint of the trial is the improvement of disease activity from baseline to month 6 after CAR T anti-CD19 cell administration, measured by a change of at least 5 points in the modified Rodnan Skin Score (mRSS). Secondary endpoints include changes in the EUSTAR activity index, changes in mRSS, changes in lung capacity parameters including forced vital capacity (FVC) and DLCO, extension of fibrosis through pulmonary computed tomography, changes in cardiac ejection fraction and global longitudinal strain, changes in scleroderma-adapted Health Assessment Questionnaire (SHAQ) score, changes in Health Assessment Questionnaire Disability Index (HAQ-DI) score, incidence rate of adverse events, incidence rate of adverse events of special interest, and pharmacokinetic parameters linked to CAR T quantification including Tmax, Cmax, and AUC, as well as the subpopulations of B and T immune cells.

The estimated recruitment start date is September 15, 2025, with an estimated trial end date of March 31, 2028. Participant involvement extends from the screening visit through the end-of-study visit at month 6 following CAR T cell administration. The trial protocol includes a screening visit to assess eligibility criteria and baseline measurements, a leukapheresis procedure to collect autologous T-cells for manufacturing, conditioning treatment prior to CAR T cell infusion, the infusion visit for administration of the investigational product, and subsequent follow-up visits to assess efficacy and safety parameters. The primary efficacy assessment occurs at month 6 post-infusion, which also serves as the end-of-study visit for the primary endpoint evaluation.

The experimental treatment in this clinical trial is MB-CART19.1, an autologous T-cell product transduced with a lentiviral vector expressing a chimeric antigen receptor directed against CD19. This product is also referred to as CD19 CAR transduced T cells. The active substance consists of autologous T-cells that have been genetically modified ex vivo using a lentiviral vector to express an anti-CD19 CAR. This constitutes an advanced therapy medicinal product classified as cell therapy involving genetically modified cells. The gene of interest is CAR anti CD19, and the modification involves T cells as the target cell type for genetic modification.

MB-CART19.1 is administered as an infusion via the intravenous route. The dosing regimen consists of a single administration, with a maximum daily dose of 1 unit and a maximum total dose of 1 unit. The treatment period is limited to 1 day, reflecting the single-dose nature of this CAR T-cell therapy. The product is manufactured by Miltenyi Biomedicine GmbH and is not formulated as a paediatric preparation.

Efficacy will be assessed through evaluation of disease activity and skin fibrosis in patients with **systemic sclerosis**. The primary efficacy endpoint is the improvement in disease activity from baseline to month 6 after **CAR T anti-CD19** cell administration, measured by a change of at least 5 points in the **modified Rodnan Skin Score (mRSS)**. Secondary efficacy parameters include changes in the **EUSTAR activity index (EUSTAR AI)**, changes in **mRSS**, changes in lung capacity measured by **forced vital capacity (FVC)** and **DLCO**, extension of fibrosis assessed through pulmonary computed tomography, changes in cardiac ejection fraction and global longitudinal strain, changes in the **scleroderma-adapted Health Assessment Questionnaire (SHAQ)** score, and changes in the **Health Assessment Questionnaire Disability Index (HAQ-DI)** score. Additionally, pharmacokinetic parameters related to **CAR T** cell quantification will be evaluated, including **Tmax**, **Cmax**, and **AUC**, as well as the subpopulations of B and T immune cells.