CD19-BCMA Dual Nanobody Based CAR-T Cells for Patients With DSA

Clinical Trial of CD19-BCMA Dual Nanobody Based CAR-T Cells for Patients With Donor-specific Antibodies

This is an early-stage, open-label clinical study of CD19-BCMA dual nanobody based CAR-T Cell desensitization therapy for patients positive for Donor-Specific Antibodies. Enrolled subjects will participate in an early clinical study using the traditional "3+3" dose escalation design to determine the Maximum Tolerated Dose (MTD) of CAR-T cell infusion (i.e., three escalating dose levels: 0.5x10^6 CAR+ T cells/kg, 1x10^6 CAR+ T cells/kg, 2x10^6 CAR+ T cells/kg). The investigators and the sponsor will jointly form a Safety Review Committee (SRC). The final decision on whether to continue increasing the dose levels or to conduct an expansion study at a specific dose level will be based on the safety and efficacy data obtained from the three dose groups. Assessments will be performed every 4 weeks after cell infusion, with a total planned enrollment of 9-18 subjects.

Inclusion Criteria:

1. The subject or their legal guardian understands and voluntarily signs the Informed Consent Form (ICF).

2. Male or female, aged 3 years or older (inclusive) at the time of signing the ICF.

3. Expected survival period is not less than 12 weeks.

4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2 at the time of signing the ICF.

5. At the time of signing the ICF, the following must be satisfied:

   1. Meets the indications for allogeneic hematopoietic stem cell transplantation, is at a suitable stage for transplantation, and is planned to receive a haploidentical related donor allogeneic hematopoietic stem cell transplant.
   2. The patient has no available HLA-matched sibling donor, no other HLA-matched unrelated donor, and no related donor who is DSA-negative.
   3. The patient has a DSA level ≥5000 MFI.

6. Major organ function must meet the following requirements:

   1. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 5 × Upper Limit of Normal (ULN).
   2. Total bilirubin ≤ 2 × ULN.
   3. For adult subjects: Creatinine clearance ≥ 60 mL/min (Cockcroft-Gault formula) OR Serum creatinine ≤ 1.5 × ULN.
   4. For pediatric subjects: Serum creatinine must not exceed: 1.2 mg/dL for ages 12-13; 1.5 mg/dL for males aged 13-16; 1.4 mg/dL for females aged >13; 1.7 mg/dL for males aged >16.
   5. HBV-DNA, HCV-RNA, Syphilis antibody, HIV antibody, CMV/EBV DNA must be negative; no active infection.

7. Oxygen saturation > 92%.

8. Men and women of childbearing potential must agree to use effective contraception from the time of signing the ICF until 2 years after administration of the study drug. Women of childbearing potential include premenopausal women and women within 2 years of menopause. A negative blood pregnancy test is required for women of childbearing potential at screening.

Exclusion Criteria:

1. History of central nervous system (CNS) diseases, including but not limited to epilepsy, paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, neuropathy. Subjects with a history of conditions like lacunar infarction without related neurological symptoms before screening may be considered for exclusion based on the investigator's judgment.

2. Other severe, progressive, or uncontrolled gastrointestinal, urinary, endocrine, or respiratory diseases, deemed by the investigator as unsuitable for enrollment.

3. Participation in another clinical trial within 2 weeks prior to screening.

4. Other factors that may influence DSA levels: Received proteasome inhibitors or BTK inhibitors, rituximab, or other monoclonal antibodies targeting B cells or plasma cells (e.g., belimumab, telitacicept, daratumumab) within 2 weeks prior to signing the ICF.

5. Presence of any uncontrolled active infection at the time of signing the ICF or within 4 weeks prior to leukapheresis.

6. Positive HBsAg or positive HBcAb with detectable HBV DNA at screening; Positive HCV antibody with detectable HCV RNA at screening; Positive HIV antibody; Positive CMV DNA; Positive EBV DNA; Positive for both treponemal and non-treponemal syphilis antibodies.

7. Clinically significant cardiovascular diseases, including any of the following:

   1. QTc interval ≥ 480 ms (corrected using Fridericia's formula).
   2. New York Heart Association (NYHA) Class II or higher heart failure.
   3. Unstable angina or acute myocardial infarction within 6 months prior to signing the ICF.
   4. Left Ventricular Ejection Fraction (LVEF) < 50%.
   5. Poorly controlled hypertension (judged by the investigator based on the subject's individual condition).
   6. Clinically significant arrhythmias requiring antiarrhythmic treatment (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes, complete left bundle branch block, etc.).

8. Allergy to any component of the drugs used in this study.

9. Received large-field radiotherapy within 4 weeks prior to signing the ICF, except for palliative radiotherapy for non-target lesions during the study period.

10. Requirement for systemic corticosteroids (at a dose equivalent to or higher than prednisone 10 mg/day) or other immunosuppressive drugs within 3 days prior to leukapheresis or anticipated during the study period, except for the following:

    1. Nasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular).
    2. Systemic corticosteroid therapy not exceeding prednisone 10 mg/day or an equivalent physiological dose.
    3. Steroids used as premedication for allergic reactions (e.g., pre-CT scan).
    4. Used for managing adverse reactions post-infusion.

11. Major surgical procedure within 4 weeks prior to signing the ICF (excluding routine biopsy surgery), or anticipated major surgery during the study period.

12. History of active tuberculosis infection within 1 year prior to signing the ICF (subjects with a history of active tuberculosis more than 1 year ago may be included if the investigator judges there is no current evidence of active tuberculosis).

13. Administration of live/attenuated or inactivated vaccines within 4 weeks prior to signing the ICF, or planned administration during the screening period.

14. Pregnant or lactating women.

15. Men or women who refuse to use contraception from the time of signing the ICF until 12 months after study completion.

16. History of alcohol abuse, drug abuse, or psychiatric history.

17. Any comorbidities or other conditions that, in the investigator's opinion, may affect protocol compliance or make the subject unsuitable for participation.