C-CAR168 CAR T Cell Therapy for Refractory Autoimmune Disease

Multi-center, Phase 1/2 Study of an Autologous Anti-CD20/BCMA CAR T Cell Therapy (C-CAR168) for the Treatment of Autoimmune Disease Refractory to Standard Therapy

This multi-center, open-label, Phase 1/2 study aims to evaluate the safety, tolerability, and preliminary efficacy of C-CAR168, an autologous anti-CD20/BCMA CAR-T therapy, in patients with autoimmune diseases refractory to standard treatments. The study includes both dose escalation and dose expansion phases, with participants grouped into condition-specific cohorts.

The purpose of this study is to:

1. Test the safety and ability for subjects with autoimmune refractory to standard treatment to tolerate the C-CAR168.
2. Determine the recommended Phase 2 dose of C-CAR168 in subjects with autoimmune disease refractory to standard treatment.

Participants will be asked to:

• Undergo screening to determine eligibility based on entry criteria.
• Taper steroid use before leukapheresis.
• Undergo leukapheresis for the manufacturing of C-CAR168.
• Temporarily discontinue immunosuppressive therapy at least 7 days prior to leukapheresis.
• Receive bridging therapy (steroids) if necessary to maintain disease stability during C-CAR168 manufacturing.
• Undergo lymphodepletion therapy with fludarabine and cyclophosphamide.
• Receive a single intravenous infusion of C-CAR168 at the assigned dose level on Day 0.
• Attend regular safety and efficacy assessments for up to 24 months post-infusion.
• Undergo dose-limiting toxicity evaluation during the first 28 days post-infusion (for those in the dose escalation phase).
• Follow withdrawal procedures if necessary, including a discharge visit within 14 days if their condition deteriorates, unacceptable toxicity occurs, they no longer meet criteria, or they choose to withdraw.

Inclusion Criteria:

1. Informed Consent: Voluntary signed consent required.

2. Age & Gender: Males and females, 18-70 years old.

3. Diagnosis: Clinical diagnosis of SLE per EULAR/ACR criteria for at least 6 months.

4. Lupus Nephritis (LN): Biopsy-confirmed active proliferative LN (Class III/IV ± V) within the past 12 months.

5. Refractory Disease:

   • Treated with at least two immunosuppressants for ≥8 weeks.
   • Stable but active disease despite standard therapy (steroids, IS, monoclonal antibodies).
   • Steroid dose ≤30 mg/day (if applicable).

6. Disease Activity at Screening:

   • SLE without LN: SLEDAI-2K ≥8 and 1 BILAG A or 2 BILAG B scores.
   • LN Patients: Proteinuria ≥1.0 g/day or UPCR ≥1.0 g/g.

7. Autoantibody Status:

   o Positive ANA (≥1:80), anti-dsDNA (≥30 IU/mL), and/or anti-Smith antibody.

8. Infection Status: No active infection within 2 weeks before leukapheresis.

9. Life Expectancy: Greater than 6 months.

10. Adequate Organ Function:

    • Bone Marrow: ANC ≥1.0×10⁹/L, ALC ≥0.5×10⁹/L, Hb ≥80 g/L, PLT ≥75×10⁹/L.
    • Coagulation: INR/APTT ≤1.5×ULN.
    • Cardiac: LVEF ≥45% by ECHO/MUGA.
    • Pulmonary: SpO₂ ≥92% on room air.
    • Liver: ALT/AST ≤2.5×ULN, total bilirubin <2.0 mg/dL.
    • Renal: Creatinine clearance ≥40 mL/min (Cockcroft-Gault).

11. Pregnancy & Contraception:

    • Women of childbearing potential must have a negative pregnancy test at screening.
    • Both male and female participants must use highly effective contraception for 1 year post-treatment.

Exclusion Criteria:

1. Any other concomitant diseases requiring long term systemic steroids (oral or intravenously) treatment that may confound the interpretation of study results or have interference with background steroid tapering for the subjects.

2. Any of the following:

   • Positive for Hepatitis B surface antigen (HBsAg)/core antibody (HBcAb)/e antibody (HBeAb)/e antigen (HBeAg).
   • Positive for Hepatitis C Virus (HCV) antibodies.
   • Positive for Human Immunodeficiency Virus (HIV) antibodies.
   • Positive for syphilis antigen or antibody.

3. Have an uncontrolled active infection.

4. History of major organ transplantation (such as heart, lung, liver, kidney) or history of bone marrow/hematopoietic stem cell transplantation.

5. History of any of stroke, unstable angina, myocardial infarction, congestive heart failure (NYHA Class III or IV), severe cardiomyopathy or ventricular arrhythmia requiring medication or mechanical control within 6 months of screening.

6. History of ≥ Grade 2 bleeding within the past 30 days.

7. Received a live vaccine within 4 weeks prior to signing the ICF.

8. Received any of the following treatments:

   • Prednisone treatment of ≥ 100 mg/d or equivalent corticosteroid therapy for ≥14 days within the previous 8 weeks.
   • Receive plasma exchange, plasma separation, hemodialysis, or intravenous injection of immunoglobulin (IVIG) within 14 days prior to leukapheresis.
   • Use of any other investigational clinical study drug within 28 days prior to leukapheresis. However, if the subject is not responsive to the treatment or have progressed and at least 3 half-lives have passed before the leukapheresis, he/she could be enrolled.
   • Previously received any CAR-T cell products or other genetically modified T cell therapies.
   • Rituximab/ocrelizumab/obinutuzumab within 6 months prior to screening

9. Pregnant or breastfeeding women.

10. History of seizure disorder, cerebrovascular ischemia/hemorrhage, dementia or cerebellar disease or other severe neuropsychiatric syndromes.

11. History of deep vein thrombosis or pulmonary embolism within six months of infusion (line associated DVT is allowed)

12. Diagnosed with malignant tumors within 5 years prior to signing the ICF, with the following exceptions: non-melanoma skin cancer that has been treated with radical therapy, localized prostate cancer, biopsy-confirmed cervical carcinoma in situ or squamous intraepithelial lesions detected by cervical smear, and completely excised breast carcinoma in situ.

13. Poor compliance, unwilling or unable to adhere to the study protocol based on the investigator's assessment.

14. Allergies to fludarabine, cyclophosphamide and/or known allergies to excipients of C-CAR168 cell product.