CAR-T in Subjects With Relapsed/Refractory Autoimmune Disease

This is a prospective, single-center, open, single-arm, dose-escalation clinical trial to evaluate the safety and efficacy of CAR-T cell therapy in patients with relapsed/refractory autoimmune diseases. Intravenous infusion will be used, and the trial procedure will be divided as follows:

• Screening period (D-28 to D-6):

After subjects voluntarily sign an informed consent form, a screening period will be conducted to determine whether subjects are eligible for the trial based on inclusion and exclusion criteria.

• Lymphocyte depletion pretreatment (Study D-5 to Study D-3):

Subjects will be pre-treated with Lymphocyte depletion starting 5 days prior to CAR-T cell infusion (FC regimen)

• Rest and Observation (Study D-2 to Study D-1):

Follow the study procedures and perform the relevant examinations during the rest and observation period.

• Cell Infusion and Primary Study Endpoint Observation Period (Study D0 to W12 post-infusion):Subjects will undergo CAR-T cell infusion at 2-day intervals (Study Day 0) after lymphocyte depletion pretreatment, and post-infusion observations and safety assessments will be performed before, during, and after the cell infusion (day of infusion, days 4, 7, 10, 14, 21, and 28 post-infusion), respectively. Evaluation of efficacy: Subjects will be evaluated for efficacy on the 14th, 28th day, 8th and 12th week after CAR-T cell infusion.
• Follow-up period (W12 to W52 after infusion):The follow-up period is for safety and efficacy evaluation. Safety follow-up: Subjects will be followed for 52 weeks after CAR-T cell infusion. Efficacy Evaluation: Subjects will be evaluated for efficacy at weeks 24, 36, and 52 after CAR-T cell infusion. In addition, the actual frequency of effectiveness evaluations may be increased at the discretion of the investigator.

Inclusion criteria

• age 18-65 years (including threshold) and gender;
• positive expression of CD19 in peripheral blood B cells as determined by flow cytometry;
• the function of vital organs meets the following requirements:

• Bone marrow function needs to meet the following requirements: a. White blood cell count ≥3×109/L; b. Neutrophil count ≥1×109/L (no colony-stimulating factor treatment within 2 weeks prior to the examination); c. Hemoglobin ≥60g/L;
• Liver function: ALT≤3×ULN (except for elevated ALT caused by inflammatory myopathy); AST≤3×ULN (except for AST elevation caused by inflammatory myopathy); TBIL≤1.5×ULN (except for Gilbert's disease).

TBIL≤1.5×ULN (except Gilbert's syndrome, total bilirubin≤3.0×ULN);

• Renal function: creatinine clearance (CrCl) ≥ 30 ml/minute (Cockcroft/Gault formula, except for disease-induced decline in CrCl);
• Coagulation: international normalized ratio (INR) ≤ 1.5 x ULN, prothrombin time (PT) ≤ 1.5 x ULN.
• Cardiac function: hemodynamic stability;
• female subjects of childbearing potential and male subjects with a partner of childbearing potential are required to use medically approved contraception or be abstinent from sexual intercourse for at least 6 months during and after study treatment; female subjects of childbearing potential must have had a negative serum HCG test within 7 days prior to study enrollment and must not be breastfeeding;
• Voluntarily participate in this clinical study and sign the informed consent form, good compliance and cooperate with follow-up visits.
• Specific inclusion criteria:
• Relapsed refractory systemic lupus erythematosus.
• meets the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for SLE;
• have a Disease Activity Score SLEDAI⁃2000 ≥ 6; and have at least one British Isles Lupus Assessment Group Index (BILAG-2004) Category A (severe manifestations) or two Category B (moderate manifestations) organ scores, or both; or have a Disease Activity Score SLEDAI-2000 ≥ 8;
• Definition of relapse-refractory: failure of conventional treatment for more than 6 months or recurrence of disease activity after remission.
• Relapsing Refractory/Progressive Diffuse Systemic Sclerosis
• meets the 2013 ACR's classification criteria for systemic sclerosis consistent with a diffuse presentation
• is positive for antibodies related to systemic sclerosis;
• diffuse cutaneous sclerosis manifestations or active interstitial lung disease (HRCT suggestive of ground-glass exudates);
• definition of relapsing-refractory: failure of conventional treatment for more than 6 months or recurrence of disease activity after remission.
• Definition of Progressive: Rapid cutaneous progression (>25% increase in mRSS); or pulmonary progression (10% decrease in FVC, or >5% decrease in FVC with 15% decrease in DLCO).
• Note: It is sufficient if one of Articles 4 and 5 is fulfilled.
• Relapsed refractory/progressive inflammatory myopathy
• meets the 2017 EULAR/ACR classification criteria for inflammatory myopathies (including DM , PM, ASS, and NM);
• is positive for antibodies to myositis;
• in those with muscle involvement, an MMT-8 score of less than 142 and abnormal findings on at least two of the following five core measurements (PhGA, PtGA, or Extramuscular Disease Activity Score ≥2; Total HAQ Score ≥0.25); Myosin level 1.5 times the upper limit of the normal range); or MMT-8 ≥142 in the presence of active interstitial lung disease (HRCT suggestive of ground-glass exudates);
• Definition of relapse refractory: failure of conventional treatment for more than 6 months or recurrence of disease activity after remission.
• Definition of progressive: the presence of exacerbation of myositis or rapidly progressive interstitial pneumonia.
• Note: It is sufficient if one of Articles 4 and 5 is fulfilled.
• Relapsed Refractory/Progressive Immune Thrombocytopenia
• meets the 2019 American Society of Hematology (ASH) classification criteria for immune thrombocytopenia;
• have bone marrow morphology characterized by increased or normal megakaryocytes with impaired maturation;
• exclude other secondary thrombocytopenia
• Definition of recurrent refractory: a patient who fails to achieve a satisfactory outcome after first-line standard therapy (e.g., glucocorticoids), including a full dose and course of therapy, i.e., platelet counts that cannot be maintained at a safe level (generally considered to be platelet counts > 30 × 10⁹ /L and without overt bleeding symptoms).
• Definition of progressive: a sustained decline in platelet count over the course of the disease, or a progressive worsening of bleeding symptoms, which may be accompanied by signs such as splenomegaly, and a progressively worse response to conventional therapy.
• Note: It is sufficient if one of Articles 4 and 5 is fulfilled.

Exclusion criteria

• A history of severe drug allergies or sensitivities;
• the presence or suspicion of fungal, bacterial, viral or other infections that are uncontrolled or require treatment
• persons with central nervous system disorders caused by ADs or not caused by ADs.
• those with intolerable cardiac function;
• subjects with congenital immunoglobulin defects.
• history of malignant tumors within the last five years.
• end-stage renal failure;
• subjects with positive Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (HBcAb) and peripheral blood HBV DNA titer higher than the upper limit of the test; subjects with positive antibody to Hepatitis C virus (HCV) and peripheral blood HCV RNA; subjects with positive antibody to Human Immunodeficiency Virus (HIV); and subjects with a positive test for Syphilis;
• mental illness and severe cognitive impairment;
• have participated in other clinical trials within 3 months prior to enrollment;
• immunosuppressants or biologics with a therapeutic effect for the indication within five half-lives prior to enrollment
• women who are pregnant or intend to become pregnant;
• subjects who, in the opinion of the investigator, have other reasons for not being included in the study.