An Exploratory Study of CD19/CD22/BCMA CAR-T Cells (BZE2204) in Subjects With Relapsed or Refractory Autoimmune Diseases

This is a single arm, open-label, dose escalation and expansion exploratory study, the primary objective is to evaluate the safety and tolerability of BZE2204 in patients with active relapsed or refractory autoimmune diseases, and determine the maximum tolerated dose (MTD) or recommended dose(RD) for future study. For the secondary objectives, pharmacokinetics(PK), pharmacodynamics (PD) and preliminary will be evaluated.

This study flow comprises of a screening phase( ≤28 days prior to apheresis), apheresis phase (occur upon enrollment, ≤10 days prior to infusion), baseline phase(2-3days before the infusion), BZE2204 CAR-T cells infusion on Day0,safety and efficacy assessments phase (Day1 to Month6), long-term follow-up phase (Month6~Month12).

Major Inclusion Criteria:

• Males or females, aged 18-70 years old
• Adequate bone marrow, hepatic, renal, coagulation and pulmonary function defined as:

• Bone marrow reservation: absolute neutrophil count (ANC) ≥1 ×10^9/L; absolute lymphocyte count (ALC)≥ 0.5 ×10^9/L; hemoglobulin ≥80 g/L; platelets ≥50 ×10^9/L(except for ITP);
• Hepatic function: i: Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 5 upper limit of normal(ULN) (except for elevations are evaluated to be related to autoimmune disease by investigators)and ii: total bilirubin ≤ 2 ULN, (except for Gilbert's syndrome patients, those with total bilirubin ≤ 3 ULN and direct bilirubin ≤ 1.5 ULN can be enrolled).
• Renal function: serum creatinine ≤ 1.5 ULN , or estimated glomerular filtration rate(eGFR) ≥ 60 mL/min/1.73m2 [eGFR=186×age^-0.203×SCr^-1.154（mg/dl）,female×0.742]
• Coagulation function: International normalized ratio (INR) or prothrombin time (PT) ≤1.5 ULN
• Pulmonary function: Have the minimum level of pulmonary reserve, defined as ≤ CTCAE (Common Terminology Criteria for Adverse Events) grade 1 dyspnea and the SaO2(oxygen saturation)≥ 91% on room air
• Life expectancy > 6 months
• Subjects with relapsed or refractory active IIM also need meet following criteria:

• Subjects with suspected or confirmed dermatomyositis(DM), polymyositis(PM), anti-synthetase syndrome(ASS) and immune-mediated necrotizing myopathy(IMNM, need to be assessed by the investigator that the patient has no safety instability) based on the 2017 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria
• Positive (+ or above) for at least one myositis-specific antibody (MSA) or myositis-associated antibody (MAA), including anti-TIF-1γ, NXP-2, Mi-2α, Mi-2β, MDA-5, SAE-1/2, SRP, HMGCR, Jo-1, PL-7, PL-12, HA, EJ, OJ, KS, Zo, Tyr, PM-Scl100, PM-Scl75, SSA/Ro-52, SSB/LA, Ku, RNA-PIII, cN1A, etc
• At screening, the subject must have moderate to severe IIM, defined as manual muscle testing (MMT) ≤ 141 and 2 of the following criteria are met; or CT suggests active interstitial lung disease(ILD)

• Physician global activity assessment (PGA) ≥ 2 cm (Visual analogue scale VAS 10 cm);
• Patient global activity assessment (PtGA) ≥ 2 cm ( VAS 10 cm scale);
• Extramuscular global assessment (Myositis Disease Activity Assessment Tool [MDAAT]) ≥ 2.0 cm (VAS 10 cm scale);
• Health assessment questionnaire (HAQ) > 0.25;
• Elevation in one or more muscle enzymes (CK, LDH, AST, ALT) is ≥ 1.5 ULN;
• Lack of efficacy or intolerance to corticosteroids and at least 1 immunosuppressant or biologic agents
• Subjects with relapsed or refractory active ITP also need meet following criteria

• Diagnosed with ITP for more than 3 months, including primary ITP and ITP secondary to autoimmune diseases
• Platelets <50 ×10^9/L with at least twice tests(≥24h interval)
• At least one platelet glycoprotein specific autoantibody positive
• Lack of efficacy for first line of therapy, or lack of efficacy/relapse post splenectomy
• Subjects with relapsed or refractory active SLE also need meet following criteria

• Diagnosed with SLE according to the 2019 EULAR/ACR classification criteria for at least 6 months
• Positive autoantibodies: antinuclear antibody (ANA) and/or anti-double strand-DNA(dsDNA) antibody and/or anti-Smith(Sm) antibody
• SLEDAI-2K scores ≥8 at screening. If the scores for low complement and/or anti-ds-DNA antibody are available, the SLEDAI-2K scores for clinical symptoms (except low complement and/or anti-ds-DNA antibody) should be ≥6
• Proliferative class III or IV , or class III+V or IV+V lupus nephritis(LN) confirmed by biopsies within 12 months; urine protein > 1.0g/24h or urine protein creatinine ratio (UPCR) >1000mg/g and PGA>1
• Lack of efficacy or intolerance to at least one immunosuppressant and/or one biologic in medical history; for LN patients, relapse during maintenance post induction therapy is also eligible.

Major Exclusion Criteria:

• A history of severe hypersensitivity or allergic reactions, or contraindications or hypersensitivity to any component of the investigational drug
• Presence of any serious heart diseases defined in the protocol
• A medical history of severe central nervous system or symptoms within 6 months
• Any concurrent malignancy or a history of malignancy with exceptions indicated in the protocol
• Clinically significant hemorrhage symptoms or definite bleeding tendencies (except for events caused by ITP) within 6 months prior to screening; arteriovenous thrombosis events within 6 months prior to screening
• Any positive results of contagious diseases as following:

• Human immunodeficiency virus (HIV) antibody positive;
• HBsAg positive; or HBcAb/HBeAb positive (subjects with HBV DNA copy numbers below the lower limit of detection can be enrolled);
• hepatitis C antibody (HCV-Ab) positive (the subjects with HCV RNA below the lower limit of detection can be enrolled) or a known medical history of hepatitis C;
• Treponema pallidum antibody (TP-Ab) positive
• Epstein-Barr virus(EBV), cytomegalovirus(CMV) antibody positive and copy number is above the limit
• Active tuberculosis or latent tuberculosis that has not been adequately treated
• Evidenced viral, bacterial or fungal infection that is uncontrolled or requires systemic antimicrobial therapy
• Requirements of wash-out period for specific treatment are not met(detailed in protocol)
• Subjects with relapsed or refractory active IIM will be excluded in the following situations:

• Inclusion body myositis, amyopathic dermatomyositis or secondary myositis with documented medical history
• Severe muscle damage
• Uncontrolled extra muscle damage relating to PM or DM
• Subjects with relapsed or refractory active ITP will be excluded if platelet < 10x10^9/L with active bleeding or bleeding score ≥5
• Subjects with relapsed or refractory active SLE will be excluded if the subject has lupus crisis within 3 month, active CNS lupus, severe hemolytic anemia, severe thrombocytopenic purpura etc
• Any situations evaluated by investigators that may prevent the subjects from participating in the study, or may confound the study results, or participation in this study is not in the best interests of the subjects.