An Exploratory Clinical Study of SCAR02 Targeting BCMA and CD19 for the Treatment of Refractory Autoimmune Diseases

An Exploratory Clinical Study of a Fourth-generation Autologous CAR-T Cell Injection (SCAR02) Targeting BCMA and CD19 for the Treatment of Refractory Autoimmune Diseases

This is an open label, single-site, dose-escalation study in up to 18 participants with refractory autoimmune diseases. This study aims to evaluate the safety and efficacy of the treatment with Anti-BCMA and CD19 CART

Inclusion Criteria:

1. Sign the informed consent form.
2. At the time of signing the informed consent form, the age of 18 years old or above, both male and female.
3. Bone marrow hematopoietic function is satisfied: white blood cell count ≥3×10^9/L; neutrophil count ≥1×10^9/L (not receiving colony-stimulating factor within 2 weeks prior to screening); hemoglobin ≥60g/L.
4. Liver function fulfillment: ALT≤3×ULN; AST≤3×ULN; TBIL≤3×ULN.
5. Renal function fulfillment: creatinine clearance CrCl ≥ 60mL/min.
6. Coagulation function meets: international standard ratio INR <1.5 times ULN, prothrombin time PT <1.5 times ULN.

Patients with rheumatoid arthritis must also meet the following enrollment criteria:

1. Diagnosis of rheumatoid arthritis according to the 2010 ACR / EULAR diagnostic criteria.
2. Fulfillment of one of the following conditions: DAS28-ESR >3.2 or CDAI >10 at 3 months after use of a standard treatment regimen prior to screening; inability to taper hormones (prednisone) to less than 7.5 mg/day; and number of swollen joints and/or number of joints with tenderness ≥3. Standard treatment regimen is defined as the stable use of any of the following (alone or in combination): corticosteroids, nonsteroidal anti-inflammatory drugs ( NSAIDs) and csDMARDs, including methotrexate, leflunomide, hydroxychloroquine, salazosulfapyridine, elamodex, tretinoin, and paeonia lactiflora total, as well as biological agents (including TNF inhibitors, non-TNF inhibitors, and JAK inhibitors).
3. Stable treatment with 1 or 2 cs DMARD(s) prior to enrollment as follows: at least 12 weeks of methotrexate and at least 4 weeks of administration at a dose of 7.5-25 mg/week; at least 4 weeks of stable hydroxychloroquine doses of ≤400 mg/d; at least 4 weeks of stable oral salicylazosulfapyridine 1 to 3 g/d; at least 4 weeks of stable oral leflunomide 10-20 mg /d.

Patients with SLE will also be required to meet the following enrollment criteria:

1. Diagnosis of SLE according to the 2019 EULAR/ACR classification criteria for SLE.
2. A history of SLE for at least 6 months prior to screening, with the disease remaining active 2 months after the use of a standard treatment regimen prior to screening. Standard treatment regimen is defined as stable use of any of the following (alone or in combination): corticosteroids, antimalarials, nonsteroidal anti-inflammatory drugs (NSAIDs), and other immunosuppressive or biologic agents, including azathioprine, mertiomaxolide, cyclophosphamide, methotrexate, leflunomide, tacrolimus, cyclosporine, belimumab, rituximab, and tetracycline.
3. BILAG-2004 assessment of the presence of at least 1 grade A or 2 grade B organ scores.
4. Positive for at least one of the following antibodies: anti-nuclear antibody, anti-ds-DNA antibody, anti-Sm antibody.
5. SLEDAI-2000 score ≥ 8 during the screening period.

Patients with dry syndrome were also required to meet the following enrollment criteria:

1. Diagnosis of dry syndrome according to the 2002 International Classification Criteria for Primary Dry Syndrome or the 2016 ACR/EULAR classification criteria.
2. Diagnosis of pSS-TP with platelet count <30 x 10^9/L.
3. History of dry syndrome for at least 6 months prior to screening and disease still active 2 months after use of conventional treatment regimen prior to screening. Definition of conventional therapy:Use of glucocorticoids (above 1 mg/Kg/d) and cyclophosphamide, and any of the following immunomodulatory drugs for more than 6 months: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, and cyclosporine, as well as biologics, such as rituximab, belimumab, and tetraciprazole.

Patients with systemic sclerosis were also required to meet the following enrollment criteria:

1. Diagnosis of systemic sclerosis according to the 2013 ACR classification criteria for systemic sclerosis.
2. Positive antinuclear antibodies at screening.
3. Presence of clear evidence of HRCT progression.
4. History of systemic sclerosis for at least 6 months prior to screening, and active disease 2 months after use of a conventional treatment regimen prior to screening. Definition of conventional therapy:Use of glucocorticoids (above 0.5 mg/Kg/d) and cyclophosphamide for more than 6 months, as well as any of the following immunomodulatory medications: antimalarials, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, and cyclosporine, as well as biologics, such as rituximab and belimumab.

Exclusion Criteria:

1. pre-screening presence of clinically significant CNS disease or pathological changes not caused by the disease itself, including, but not limited to: stroke, apoplexy, aneurysm, epilepsy, convulsions, aphasia, severe craniocerebral injury, dementia, Parkinson's disease, cerebellar disorders, organic brain syndromes, or insanity.
2. Those suffering from relatively serious heart diseases such as angina pectoris, myocardial infarction, heart failure and arrhythmia.
3. History of major organ transplantation or hematopoietic stem cell/bone marrow transplantation.
4. vaccination, B-cell targeted therapy within 4 weeks prior to screening.
5. History of any malignant disease.
6. Patients with end-stage renal failure.
7. Presence or suspected presence of uncontrolled fungal, bacterial, viral or other infections.
8. History of severe allergy to drugs used in clinical studies or raw materials of test drugs, such as cyclophosphamide, fludarabine, DMSO.
9. The patient is positive for HBV surface antigen, or HBV core antibody and positive for DNA by RT-PCR; positive for HCV antibody or positive for HIV antibody or positive for syphilis or positive for CMV DNA or positive for EBV DNA.
10. Females who are pregnant or breastfeeding or who plan to have a pregnancy within 2 years of return infusion of the test drug; partners of male patients who plan to become pregnant within 2 years of treatment with the test drug.
11. Evidence of active tuberculosis infection.
12. other circumstances assessed by the investigator as unsuitable for enrollment.