Evaluation of Anti-CD19 CAR T-Cell Therapy in Refractory Systemic Autoimmune Diseases: A Study of Autologous T-Cells with Drug Combination

The primary objective of this study is to assess the **safety** of anti-CD19 CAR T cell therapy in subjects with active B-driven autoimmune diseases, including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermatomyositis/polymyositis (DM/PM), and antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Additionally, the study aims to preliminarily evaluate the clinical efficacy of this therapy in the same patient population. The clinical relevance of this objective lies in the potential to provide a novel therapeutic option for patients with refractory systemic autoimmune diseases, which are often challenging to treat with conventional therapies.

Secondary objectives include investigating the duration of B cell depletion and CAR T cell persistence following anti-CD19 CAR T cell administration. Furthermore, the study seeks to evaluate changes in the levels of disease-associated serum autoantibodies. These secondary objectives are crucial for understanding the long-term effects and potential mechanisms of action of the therapy, which could inform future treatment strategies and improve patient outcomes.

The clinical trial involves participants diagnosed with **Refractory Systemic Autoimmune Diseases**, specifically targeting active B-driven autoimmune conditions such as Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (SSc), Dermatomyositis/Polymyositis (DM/PM), and ANCA-associated Vasculitis (AAV). The study population includes both male and female adults aged between 18 and 65 years. Participants are required to have received a double vaccination against SARS-CoV-2 within the last six months. The trial population was selected based on their ability to understand and voluntarily sign an informed consent form, adhere to the study visit schedule, and meet specific contraceptive requirements. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, emphasizing the need for careful monitoring and adherence to ethical standards throughout the study.

The clinical trial is designed to evaluate the safety and preliminary efficacy of **anti-CD19 CAR T cell therapy** in subjects with active B-driven **autoimmune diseases** such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermatomyositis/polymyositis (DM/PM), and antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This trial is structured as a Phase I and Phase II integrated clinical trial, employing a randomized, double-blind, controlled design to ensure robust and unbiased results. The estimated duration of the trial is from May 2024 to February 2026, with participant involvement expected to last up to 24 weeks, followed by long-term follow-up.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, including age, informed consent, and vaccination status against SARS-CoV-2. Following successful screening, participants will receive the investigational medicinal product (IMP) and attend regular follow-up visits to monitor safety and efficacy outcomes. The primary endpoints include the incidence and grading of **Cytokine Release Syndrome (CRS)** and **CAR T cell Associated Neurotoxicity Syndrome (ICANS)** within the first four weeks post-administration, as well as the incidence and severity of infections and leukopenia or hypogammaglobulinemia throughout the study period. Secondary endpoints focus on the duration of B cell depletion and persistence of CAR T cells in peripheral blood, along with changes in disease-associated serum autoantibodies.

The end-of-study visit will conclude the participant's active involvement, with long-term follow-up to assess sustained outcomes. Participants may be withdrawn from the study early if they experience severe adverse events, fail to adhere to the study protocol, or withdraw consent. The trial aims to provide valuable insights into the potential of CAR T cell therapy for treating refractory systemic autoimmune diseases, contributing to the advancement of therapeutic options for these challenging conditions.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **LEVETIRACETAM** is utilized in this study as a non-experimental treatment. It is a chemical substance administered via **intravenous infusion**. The pharmaceutical form is denoted as PHF00169MIG. The specific dosage and frequency of administration are not detailed in the provided data.

**FLUDARABINE** is another non-experimental treatment used in the trial. It is administered through **intravenous infusion** and is presented in the pharmaceutical form PHF675. The active substance details are not specified, and the dosage and frequency are not provided.

The experimental treatment in this trial is **CD19-CAR_Lenti**, which consists of **autologous T-cells transduced with a lentiviral vector expressing a chimeric antigen receptor directed against CD19**. This cell therapy is administered as a **cell suspension for injection** via the **intravenous** route. The dosing schedule and participant compliance monitoring details are not included in the data.

**TOCILIZUMAB** is included as a non-experimental treatment, administered through **intravenous infusion**. It is a protein-based substance with the pharmaceutical form PHF00231MIG. The specific dosage and administration frequency are not specified.

Lastly, **CYCLOPHOSPHAMIDE** is used as a non-experimental treatment, also administered via **intravenous infusion**. It is a chemical substance with the pharmaceutical form PHF00231MIG. The data does not provide specific information on dosage or frequency of administration.

The clinical trial aims to assess the efficacy of anti-CD19 CAR T cell therapy in subjects with active B-driven autoimmune diseases, including Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (SSc), Dermatomyositis/Polymyositis (DM/PM), and ANCA-associated Vasculitis (AAV). Efficacy will be evaluated through both primary and secondary endpoints. The primary endpoints focus on the incidence and grading of severity (graded 0-4) of **Cytokine Release Syndrome (CRS)** and CAR T cell Associated Neurotoxicity Syndrome (ICANS) within the first four weeks after administration of the Advanced Therapy Medicinal Product (ATMP). Additionally, the incidence and severity of infections, leukopenia, and/or hypogammaglobulinemia will be monitored throughout the study period.

Secondary endpoints include the duration of B cell depletion in the peripheral blood, with CD19+ B cells assessed by fluorescence-activated cell sorting (FACS) expected to be equal to 0 up to week 24 and during long-term follow-up. The persistence of CAR T cells in the peripheral blood will also be measured, with CAR+ CD3+ cells assessed by FACS expected to be greater than 0 up to week 24 and during long-term follow-up. Changes in the levels of disease-associated serum autoantibodies at week 24 will be evaluated, including the incidence of seroconversion, with specific parameters such as anti-dsDNA levels being less than the lower limit of normal (LLN) and antinuclear antibodies (ANA) being less than 1.100, with all others being "negative." These assessments will provide a comprehensive evaluation of the therapy's efficacy in the targeted autoimmune conditions.