Anti-CD19 Chimeric Antigen Receptor T Cells for Refractory Autoimmune Diseases

This is a single-center, open-label, single-arm, dose-escalation trial. In this study, we will recruit seven kinds of refractory autoimmune diseases including moderate-to-severe Systemic lupus erythematosus (SLE), refractory Pemphigus, refractory Idiopathic inflammatory myopathy (IIM), Systemic sclerosis (SSc), Refractory ANCA-Associated Vasculitis/Nephritis,refractory Rheumatoid arthritis(RA) and moderate-to-severe refractory Psoriasis.

Patients with Refractory Autoimmune Diseases will receive CD19 CAR T cells. The primary objective is to evaluate the safety and efficacy of CD19 CAR T cell therapy in subjects with Refractory Autoimmune Diseases and to determine the optimal biological dose (OBD) in phase I and to learn about the efficacy CD19 CAR T-cell therapy in patients with Refractory Autoimmune Diseases in phase II.

The primary endpoint is to evaluate the incidence and severity of cytokine release syndrome and severe neurotoxic adverse events within 28 days after CAR-T cell infusion.A total number of 3o subjects will be enrolled.

Inclusion criteria

• 1.Refractory Moderate-to-Severe Systemic lupus erythematosus (SLE) 1.1.Age 18-70 years. 1.2.Estimated life expectancy ≥ 3 months. 1.3.Documented disease history and diagnosis for ≥ 6 months prior to screening. 1.4.Participants must agree to use effective contraception throughout the study; women of child-bearing potential must have a negative pregnancy test.

1.5.Signed informed consent, agreement to the treatment protocol, and willingness to attend follow-up evaluations per schedule.

1.6.Relevant medical history and clinical manifestations: provide a copy of inpatient records from a tertiary hospital or outpatient records and diagnostic certificates within the last 3 months.

1.7.Required laboratory tests, including but not limited to: CBC, urinalysis, ANA, anti-dsDNA, ENA panel, C3/C4, immunoglobulins, antiphospholipid antibodies, etc.

1.8.Meets current international or domestic classification criteria: the 1997 ACR SLE classification criteria OR the 2019 EULAR/ACR SLE classification criteria, and is judged to have moderate-to-severe SLE.

1.9.SELENA-SLEDAI score ≥ 8; PGA ≥ 1; and at least one BILAG-2004 organ-system score of 1A or 2B.

1.10.Inadequate response to, or intolerance of, at least 12 weeks of standardized therapy prior to screening.

2.Refractory Idiopathic inflammatory myopathy (IIM) 2.1.Age 18-70 years. 2.2.Estimated life expectancy ≥ 3 months. 2.3.Documented disease history and diagnosis for ≥ 6 months prior to screening. 2.4.Participants must agree to use effective contraception throughout the study; women of child-bearing potential must have a negative pregnancy test.

2.5.Signed informed consent, agreement to the treatment protocol, and willingness to attend follow-up evaluations per schedule.

2.6.Relevant medical history and clinical manifestations: provide a copy of inpatient records from a tertiary hospital or outpatient records and diagnostic certificates within the last 3 months.

2.7.Fulfillment of the 2017 EULAR/ACR classification criteria for dermatomyositis or polymyositis.

2.8.Inadequate response to, or intolerance of, at least 12 weeks of standardized therapy prior to screening.

3.Refractory Systemic sclerosis (SSc) 3.1.Age 18-70 years. 3.2.Estimated life expectancy ≥ 3 months. 3.3.Documented disease history and diagnosis for ≥ 6 months prior to screening. 3.4.Participants must agree to use effective contraception throughout the study; women of child-bearing potential must have a negative pregnancy test.

3.5.Signed informed consent, agreement to the treatment protocol, and willingness to attend follow-up evaluations per schedule.

3.6.Relevant medical history and clinical manifestations: provide a copy of inpatient records from a tertiary hospital or outpatient records and diagnostic certificates within the last 3 months.

3.7.Fulfillment of the 2013 ACR/EULAR classification criteria for systemic sclerosis, with clinical or radiographic evidence of pulmonary involvement.

3.8.Required laboratory tests, including but not limited to: CBC, urinalysis, ANA, anti-dsDNA, ENA panel, C3/C4, immunoglobulins, etc.

3.9.Classification per current international or domestic standards: the 1980 ACR criteria for SSc OR the 2013 ACR/EULAR criteria for SSc.

3.10.Inadequate response to, or intolerance of, at least 12 weeks of standardized therapy prior to screening.

4.Refractory Pemphigus 4.1.Age 18-70 years. 4.2.Estimated life expectancy ≥ 3 months. 4.3.Documented disease history and diagnosis for ≥ 6 months prior to screening. 4.4.Participants must agree to use effective contraception throughout the study; women of child-bearing potential must have a negative pregnancy test.

4.5.Signed informed consent, agreement to the treatment protocol, and willingness to attend follow-up evaluations per schedule.

4.6.Relevant medical history and clinical manifestations: provide a copy of inpatient records from a tertiary hospital or outpatient records and diagnostic certificates within the last 3 months.

4.7.Fulfillment of at least one clinical manifestation plus one histopathological or immunodiagnostic criterion, OR at least two clinical manifestations plus two immunodiagnostic criteria:

• Clinical manifestations: flaccid cutaneous bullae and fragile blisters that rupture easily, resulting in persistent erosions; mucosal blisters or erosions; positive Nikolsky sign.
• Histopathology: intraepidermal or intraepithelial acantholysis.
• Immunodiagnostic criteria: direct immunofluorescence (DIF) showing intercellular IgG and/or complement deposition in epidermal/epithelial cells of lesional or perilesional normal skin; positive serum anti-epithelial cell antibodies by indirect immunofluorescence; positive serum anti-desmoglein antibodies by ELISA.

4.8.Pemphigus Disease Area Index (PDAI) ≥ 9 (moderate 9-24, severe ≥ 25). 4.9.Inadequate response to, or intolerance of, at least 12 weeks of standardized therapy prior to screening.

5.Refractory Moderate-to-Severe Psoriasis 5.1.Age 18-70 years. 5.2.Estimated life expectancy ≥ 3 months. 5.3.Documented disease history and diagnosis for ≥ 6 months prior to screening. 5.4.Participants must agree to use effective contraception throughout the study; women of child-bearing potential must have a negative pregnancy test.

5.5.Signed informed consent, agreement to the treatment protocol, and willingness to attend follow-up evaluations per schedule.

5.6.Relevant medical history and clinical manifestations: provide a copy of inpatient records from a tertiary hospital or outpatient records and diagnostic certificates within the last 3 months.

5.7.In accordance with the 2023 Chinese Guidelines for the Diagnosis and Treatment of Psoriasis, meets the diagnostic criteria for moderate-to-severe plaque psoriasis: dark-red or infiltrated erythematous plaques covered by white/silvery scales, demonstrating the wax-drip, film, and Auspitz signs.

5.8.At screening: Body Surface Area (BSA) involvement ≥ 10%, Psoriasis Area and Severity Index (PASI) ≥ 10, and static Physician's Global Assessment (sPGA) ≥ 3.

5.9.Inadequate response to, or intolerance of, at least 12 weeks of standardized therapy prior to screening.

6.Refractory Moderate-to-Severe Rheumatoid Arthritis 6.1.Age 18-70 years. 6.2.Estimated life expectancy ≥ 3 months. 6.3.Documented disease history and diagnosis for ≥ 6 months prior to screening. 6.4.Participants must agree to use effective contraception throughout the study; women of child-bearing potential must have a negative pregnancy test.

6.5.Signed informed consent, agreement to the treatment protocol, and willingness to attend follow-up evaluations per schedule.

6.6.Relevant medical history and clinical manifestations: provide a copy of inpatient records from a tertiary hospital or outpatient records and diagnostic certificates within the last 3 months.

6.7.Required laboratory and imaging assessments, including but not limited to: ESR, CRP, rheumatoid factor, ANA, anti-CCP antibodies, and other relevant autoantibodies; bilateral hand/foot radiographs.

6.8.Meets current international or domestic classification criteria: the 1987 ACR criteria for RA OR the 2010 ACR/EULAR criteria for RA.

6.9.Inadequate response to, or intolerance of, at least 12 weeks of standardized therapy prior to screening.

7.Refractory ANCA-Associated Vasculitis/Nephritis 7.1.Age 18-70 years. 7.2.Estimated life expectancy ≥ 3 months. 7.3.Documented disease history and diagnosis for ≥ 6 months prior to screening. 7.4.Participants must agree to use effective contraception throughout the study; women of child-bearing potential must have a negative pregnancy test.

7.5.Signed informed consent, agreement to the treatment protocol, and willingness to attend follow-up evaluations per schedule.

7.6.Relevant medical history and clinical manifestations: provide a copy of inpatient records from a tertiary hospital or outpatient records and diagnostic certificates within the last 3 months.

7.7.Meets the 2022 ACR/EULAR classification criteria for vasculitis. 7.8.Renal biopsy indicating kidney involvement, or clinical manifestations consistent with small-vessel vasculitis together with positive myeloperoxidase (MPO) or proteinase-3 (PR3) antibodies.

7.9.Persistent or newly emerging renal and/or systemic vasculitic manifestations despite maintenance therapy of the same intensity as initial immunosuppressive treatment.

7.10.Inadequate response to, or intolerance of, at least 12 weeks of standardized therapy prior to screening.

Exclusion criteria

• (1) Clinically significant (as determined by the investigator) history of cardiac, endocrine, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic, or other major diseases.

(2) Pregnant or lactating women. (3) History of active tuberculosis (TB) infection within 3 years prior to the screening visit.

(4) History of traumatic brain injury, altered consciousness, epilepsy, cerebral ischemia, or any cerebrovascular hemorrhagic disorders.

(5) Prolonged QT interval on ECG or history of severe arrhythmias or other significant cardiac disorders.

(6) Active infection (excluding uncomplicated urinary tract infection and bacterial pharyngitis).

(7) Active hepatitis B virus or hepatitis C virus infection. (8) Confirmed positive anti-HIV antibody test. (9) Positive Treponema pallidum antibody test judged by the investigator to be clinically significant.

(10) Any known or suspected congenital or acquired immunodeficiency that may compromise the subject's immune status.

(11) Prior treatment with CD19 CAR-T cell therapy or CD19-targeted antibody drugs.

(12) Prior exposure to any gene therapy. (13) ALT/AST > 3× ULN, or bilirubin > 2.0× ULN, or serum creatinine > 2× ULN, or creatinine clearance < 30 mL/min.

(14) Any condition that, in the opinion of the investigator, may increase patient risk or interfere with study results.