Clinical trial NCT06947460: CD19-BCMA CART Cell Therapy for Refractory SLE-LN, SSc, and pSS-PAH
Official title: CD19-BCMA CART Cell Therapy for Refractory Systemic Lupus Erythematosus Nephritis (SLE-LN), Systemic Sclerosis (SSc), and Primary Sjogren Syndrome Combined With Pulmonary Artery Hypertension (pSS-PAH): a Single-center, Open, Non-randomized, Single-arm Clinical Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Refractory Lupus Nephritis
Systemic Sclerosis
Primary Sjogren&#39;s Syndrome Combined With Pulmonary Hypertension
Lead sponsor: Beijing GoBroad Hospital
Sponsor class: OTHER
First posted: 2025-04-27
Enrollment: 45
Sex: ALL
Minimum age (years): 6
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a single-center, open-label, non-randomized, single-arm clinical trial. Patients with refractory lupus neritis (SLE-LN), systemic sclerosis (SSc), and primary Sjogren syndrome combined with pulmonary artery hypertension (pSS-PAH) receive CD19-BCMA CAR T cell therapy. The primary objective is to prospectively assess the safety of CD19-BCMA CAR T cell therapy in patients with SLE-LN, SSc, and pSS-PAH. The primary endpoint is the type and incidence of dose-limiting toxicity (DLT) within 28 days after CD19-BCMA CAR T cell infusion It is anticipated that 45-54 subjects will be recruited.


Eligibility criteria: Inclusion Criteria:

* 1. Refractory lupus nephritis (LN): Definition: A treatment regimen using at least one immunosuppressive agent (including glucocorticoids, CTX, tacrolimus, mycophenolate mofetil, and cyclosporine) that does not induce remission after 3 to 6 months, while proteinuria or persistent antibody positivity does not decrease (or worsen).

Diagnostic criteria: According to the 2019 American College of Rheumatology (ACR) criteria and the 2018 International Society of Nephrology (ISN)/Society of Nephrology (RPS) criteria (see Appendix 3), confirmed by renal tissue biopsy as active, proliferative lupus nephritis, type III or IV \[excluding type III (C), IV-S (C), and IV-G (C)\], or type III/IV combined with type V. Biopsy must be performed within 6 months prior to the screening visit or during the screening period.

1. Male or female patients aged 10-65 years old;
2. Systemic lupus erythematosus that meets the 2019 American College of Rheumatology (ACR)/European Union of Rheumatology Associations (EULAR) classification criteria (see Annex 4);
3. The result of the anti nuclear antibody (ANA) test is clearly positive, that is, the ANA titer is ≥ 1:80 (equivalent test result based on Hep-2 immunofluorescence detection method or enzyme immunoassay method), and/or at the screening visit, the anti dsDNA serum antibody test is positive (≥ 30 IU/mL based on ELISA detection method) according to the test results of the research center laboratory.
4. B cell CD19+expression and discontinuation of immunosuppressive agents for more than 1 week;
5. The subject's blood routine lymphocyte count is greater than 0.5 × 109/L, and there are no contraindications for cell collection;
6. No severe allergic constitution;
7. Physical condition score (ECOG) 0-2 points;
8. Expected survival period ≥ 90 days;
9. The subjects and/or their guardians are able to understand and willing to sign a written informed consent form; 2. Systemic sclerosis (SSc): (1) The selected patient or their legal representative voluntarily signs the informed consent form.

(2) Age range: 6-65 years old (including 6 and 65 years old), gender is not limited.

(3) According to the SSc classification criteria proposed by the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) in 2013, the highest score under the same item, ≥ 9 points, can be classified as SSc (see Annex 5).

(4) Or if one sufficient condition is met, that is, the skin of both fingers thickens and extends to the proximal end of the metacarpophalangeal joint, it can be directly classified as SSc.

(5) The subject's blood routine lymphocyte count is greater than 0.5 × 109/L, and there are no contraindications for cell collection; 3. Primary Sjogren's syndrome with pulmonary hypertension (pSS PAH):

1. The selected patient or their legal representative voluntarily signs the informed consent form.
2. Age range: 18-65 years old (including 18 and 65 years old), gender is not limited.
3. Patients with refractory connective tissue disease (pulmonary arterial hypertension):

1) Diagnosed with primary Sjogren's syndrome in accordance with the 2002 AECG classification criteria or the 2016 ACR/EULAR classification criteria (see Annex 6); 2) Confirmed by right heart catheterization to meet the diagnostic criteria for PAH (as defined in the 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary arterial hypertension): ① Resting mean pulmonary arterial pressure (mPAP) ≥ 20mmHg; ② Pulmonary artery wedge pressure (PAWP) ≤ 15mmHg; ③ Resting pulmonary vascular resistance (PVR)\>2WU; (4) PAH did not reach the risk stratification of low-risk group patients. Low risk patients need to meet: ① WHO heart function classification I-II; ② 6-minute walking distance (6MWD)\>440 meters; ③ BNP\<50ng/L， Or NT proBNP\<300ng/L; ④ Right atrial pressure (RAP)\<8mmHg and cardiac index (CI) ≥ 2.5 L · min-1 · m-2.

(5) The subjects have received stable doses of standard treatment, including corticosteroids (prednisone 0-30mg/day, or equivalent other formulations) for at least 4 weeks prior to the first administration of the study drug; Antimalarial drugs and monotherapy immunosuppressants (allowed immunosuppressants are limited to: mycophenolate mofetil or mycophenolate mofetil ≤ 1.5g/day, azathioprine or 6-mercaptopurine ≤ 2mg/kg/day, methotrexate ≤ 15mg/week, leflunomide ≤ 20mg/day) should be used for at least 12 weeks, and should not be increased or replaced within 24 weeks after drug treatment. Prior to drug treatment, use PAH targeted drugs of less than three types (including prostaglandin analogs, endothelin receptor antagonists, PDE-5 inhibitors, and guanylate cyclase agonists), which have been stable for at least 4 weeks and have not been increased or replaced within 24 weeks after drug treatment.

(6) Clinicians assess the patient's condition and allow the use of corticosteroids at a dose not exceeding 10mg prednisone or its equivalent during the study period, and allow the discontinuation of all immunosuppressants (excluding hydroxychloroquine).

(7) Women of childbearing age have a negative blood pregnancy test within 7 days prior to the pre-treatment treatment; Any male and female patient with fertility must agree to use an effective contraceptive method throughout the entire study process and for at least one year through the infusion of cell injection. According to researchers' judgment, the patient's fertility refers to their biological ability to give birth to live infants and have normal sexual activity. Female patients who are infertile (i.e. meet at least one of the following criteria): have undergone hysterectomy or bilateral oophorectomy, or have been medically confirmed to have ovarian failure, or have been medically confirmed to be postmenopausal (with at least 12 consecutive months of amenorrhea without pathological or physiological reasons).

(8) Having appropriate organ function, it must meet the following standards: Aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal (ULN); Alanine aminotransferase (ALT) ≤ 3 times ULN; Total serum bilirubin ≤ 2 times ULN, unless the patient has a record of Gilbert syndrome; Gilbert syndrome patients with bilirubin ≤ 3.0 times ULN and direct bilirubin ≤ 1.5 times ULN can be included; There must be a minimum level of lung reserve, with oxygen saturation greater than 95% in non oxygenated states.

The subject's blood routine lymphocyte count is greater than 0.5 × 109/L, and there are no contraindications for cell collection;

Exclusion Criteria:

* 1. Refractory lupus nephritis (LN):

  1. Intracranial hypertension or cerebral consciousness disorders;
  2. Symptomatic heart failure or severe arrhythmia;
  3. Symptoms of severe respiratory failure;
  4. Accompanied by other types of malignant tumors;
  5. Diffuse intravascular coagulation;
  6. Suffering from sepsis or other difficult to control infections;
  7. Have uncontrollable diabetes and other endocrine diseases;
  8. Serious mental disorder;
  9. Head MRI examination shows obvious lesions in the skull;
  10. Received organ transplantation (excluding bone marrow transplantation);
  11. Female patients (those with fertility) have a positive HCG test in their blood;
  12. Hepatitis (including hepatitis B and C), AIDS and syphilis screening positive persons;
  13. The subjects cannot collect PBMCs, and there are no frozen PBMCs available for the production of CAR-T cells; 14）eGFR CKD-EPI \< 30 ml/min/1.73m\^2；

  15) Any active skin disease that may interfere with the evaluation of systemic lupus erythematosus research, including but not limited to psoriasis, dermatomyositis, systemic sclerosis, non systemic lupus erythematosus skin manifestations (such as skin vascular disease, pericapillary dilation, digital sclerosis, rheumatoid nodules, erythema multiforme, leg ulcers), or drug-induced lupus.

  16) Previously received CART treatment other than CD19-CART. 2. Systemic sclerosis (SSc)
  1. Overlapping connective tissue diseases; Rheumatoid arthritis, systemic lupus erythematosus, or inflammatory myopathy;
  2. The clinical manifestations can be explained by similar diseases of SSc, such as nephrogenic systemic fibrosis, generalized scleroplakia, eosinophilic fasciitis, diabetes scleroma, scleromyedema, erythematous acrodynia, porphyria, sclerotic lichen, graft-versus-host disease, diabetes and other hand joint diseases related to endocrine and metabolic diseases.
  3. Suffering from severe active central nervous system (CNS) lupus, including seizures, psychosis, cerebrovascular accidents, or CNS vasculitis requiring therapeutic intervention within 60 days after baseline;
  4. Dialysis patients or creatinine clearance rate less than 30mL/min;
  5. Pregnancy or breastfeeding;
  6. Merge active infections (such as sepsis, bacteremia, mycosis, uncontrolled pulmonary infections, and active tuberculosis);
  7. Hepatitis B surface antigen (HBsAg) and/or hepatitis B e antigen (HBeAg) are positive; Hepatitis B e antibody (HBe Ab) and/or hepatitis B core antibody (HBc Ab) are positive, and the number of HBV-DNA copies is greater than the measurable lower limit; Hepatitis C (HCV) antibody positive; Positive for human immunodeficiency virus (HIV) antibodies; Individuals who test positive for syphilis antibody (TP Ab);
  8. Having undergone major surgeries evaluated by researchers as unsuitable for inclusion within the previous 4 weeks prior to screening;
  9. Previously received CART treatment other than CD19-CART. 3. Primary Sjogren's syndrome with pulmonary hypertension (pSS PAH): (1) PH caused by other reasons: portal hypertension, hereditary hemorrhagic telangiectasia, etc; Congenital heart disease; Suspicious drugs and toxins; Chronic hypoxic disease-related pulmonary hypertension: moderate or severe obstructive pulmonary disease: FEV1\<55%； Moderate or severe restrictive lung disease: TLC\<60%； Chronic thromboembolic disease pulmonary hypertension: Pulmonary ventilation/perfusion imaging suggests moderate to high suspicion of pulmonary thromboembolism; (2) Suffering from severe active central nervous system (CNS) lupus, including seizures, psychosis, cerebrovascular accidents, or CNS vasculitis requiring therapeutic intervention within 60 days after baseline; (3) Dialysis patients or creatinine clearance rate less than 30mL/min; (4) Pregnancy or breastfeeding; (5) Merge active infections (such as sepsis, bacteremia, mycosis, uncontrolled pulmonary infections, and active tuberculosis); (6) Hepatitis B surface antigen (HBsAg) and/or hepatitis B e antigen (HBeAg) are positive; Hepatitis B e antibody (HBe Ab) and/or hepatitis B core antibody (HBc Ab) are positive, and the number of HBV-DNA copies is greater than the measurable lower limit; Hepatitis C (HCV) antibody positive; Positive for human immunodeficiency virus (HIV) antibodies; Individuals who test positive for syphilis antibody (TP Ab); (7) Having undergone major surgeries evaluated by researchers as unsuitable for inclusion within the previous 4 weeks prior to screening; (8) Previously received CART treatment other than CD19-CART.

Primary outcomes:
measure: Dose-limiting toxicity (DLT)
timeFrame: 28 days
measure: Adverse events (AEs)
timeFrame: 30 days
Secondary outcomes:
measure: Overall remission rate (ORR)
timeFrame: 90,120 Days
measure: Serious adverse event（SAE)
timeFrame: from 30 days to 2 years
Other outcomes:
Locations:
city: 北京
country: China
facility: 北京高博医院
state: 北京市昌平区
Study officials:
References: