Fourth-gen CAR T Cells Targeting BCMA/CD19 for Refractory Systemic Lupus Erythematosus (SLE)

Systemic lupus erythematosus (SLE) is a type of autoimmune disorder characterized by the creation of autoantibody-generating immune complexes, affecting various systems and organs.

In SLE, autoreactive B cells can self-activate and morph into plasma cells that produce a high volume of autoantibodies. These cells can also expose their own antigens to autoimmune T cells, thereby stimulating T cells and leading to the release of inflammatory substances.

Conventional treatment for SLE focuses on achieving prolonged remission. In contrast, CD19-BCMA CAR-T cells offer a potential solution by eradicating the abnormal B cells responsible for antibody production. This allows for the rebuilding of the immune system and the restoration of normal immune function in patients, potentially leading to a life free from medication. This highlights the promising potential of CAR-T therapy in treating SLE.

• CD19- BCMA CAR-T cells (Biological), also known as EB-BH2024-2: The intervention in this clinical trial involves a novel approach using CD19/BCMA-Chimeric Antigen Receptor T (CAR T) cells combined with chemotherapy. The goal is to assess safety and efficacy in patients with specific hematologic malignancies. Treatment Regimen: Patients in the trial will undergo the following regimen: Fludarabine Phosphate (Days -4 to -2): IV administration of fludarabine phosphate over 30 minutes on days -4 to -2. It's part of the preparatory regimen to enhance the body's response to CAR T-cell therapy. Cyclophosphamide (Day -2): IV cyclophosphamide over 60 minutes on day -2. CD19/BCMA-Chimeric Antigen Receptor T Cells (Day 0): IV administration of investigational therapy, CD19/BCMA-CAR T cells, over 10-20 minutes on day 0. Additional Doses: Eligible patients responding well to the initial CD19/BCMA-CAR T cell infusion without unacceptable side effects and sufficient CAR T cell availability may receive 2 or 3 additional doses.

Primary outcomes

• Incidence and severity of dose limiting toxicities (DLTs) following chemotherapy preparative regimen and infusion of CD19/BCMA chimeric antigen receptor (CAR) T cells [28 days]: Will be recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at three dose levels until the maximum tolerated dose (MTD) is determined.

Secondary outcomes

• Rate of successful manufacture and expansion of the CD19/BCMA chimeric antigen receptor (CAR) T cells [10-14 days after apheresis or thawing of cryopreserved peripheral blood mononuclear cell]: satisfy the targeted dose level and meet the required release specifications outlined in the Certificate of Analysis (COA)

Sex: All, ages: 18 Years to 90 Years

Inclusion Criteria:

* 18-90 years old;
* Total score ≥ 10 on the EULAR/ACR 2019 SLE classification criteria.
* SELENA-SLEDAI≥8.
* Patients with CD19+ B-cell.
* Hemoglobin≥85 g/L.
* WBC≥2.5×10\^9/L.
* NEUT≥1×10\^9/L.
* BPC≥50×10\^9/L.
* AST/ALT below 2 times the upper limit of normal; Creatinine clearance ≥30 mL/min; blood bilirubin ≤2.0 mg/dl; echocardiography indicates that the ejection fraction is ≥50%.
* Adequate venous access for apheresis, and no other contraindications for leukapheresis.
* Women of childbearing age should have a negative serum or urine pregnancy test at screening and baseline.
* Subjects agree to take effective contraceptive measures during the trial until at least 1 year after CAR-T cells infusion.
* Agree to attend follow-up visits as required.
* Voluntary participation and informed consent signed by the patient or his/her legal/authorized representative.

Exclusion Criteria:

* Renal disease: severe lupus nephritis (serum creatinine > 2.5 mg/dL or 221 μmol/L) within 8 weeks --Prior to leukapheresis, or subjects who need hemodialysis.
* CNS disease: including epilepsy, psychosis, organic encephalopathy syndrome, cerebrovascular accident \[CVA\], encephalitis or CNS vasculitis, psychiatric patients with depression or suicidal thoughts.
* Patients with serious lesions and a history of present illness of vital organs such as the heart, liver,kidney blood and endocrine system.
* Patients with immunodeficiency, uncontrolled active infections and active or recurrent peptic ulcers;
* Received immunosuppressive therapy within 1 week prior to leukapheresis.
* Patients with HIV infection; Active infection of hepatitis B virus or hepatitis C virus.
* Patients with syphilis infection.
* The presence or suspicion of an active fungal, bacterial, viral or other infection that cannot be controlled during screening.
* Received live vaccine treatment within 4 weeks prior to screening.
* Severe allergies or hypersensitivity.
* Contraindication to cyclophosphamide in combination with fludarabine.
* Subjects who have undergone major surgery within 2 weeks prior to signing the informed consent form, or who are scheduled to have surgery (other than local anesthetic surgery) during the trial or within 2 weeks of the infusion.
* Cannula or drainage tubes other than central venous catheters.
* Pregnant or lactating women, or subjects who plan to have children within 1 year of treatment;
* Subjects with prior CD19 or BCMA-targeted therapy.
* Participated in any clinical study within 3 months prior to enrollment.
* Subjects with malignant tumour, except for Non-melanoma Skin Cancer with PFS>5yr; Cervical Cancer in situ; Bladder Cancer; Breast Cancer.