An Exploratory Clinical Study of CD19 CAR NK Cell Injection for the Treatment of Relapsed/Refractory Autoimmune Diseases

Official title

An Exploratory Clinical Study of the Safety and Efficacy of CD19 Chimeric Antigen Receptor NK Cell Injection for the Treatment of Relapsed/Refractory Autoimmune Diseases

Overview

A single arm, open-label pilot study is designed to determine the safety and effectiveness of CD19 CAR NK cells in patients with autoimmune diseases. 36-72 patients are planned to be enrolled in the dose-escalation trial. The primary objective of the study was to evaluate the safety and feasibility of CD19 CAR-NK cells for the treatment of patients with autoimmune diseases. The secondary objective is to evaluate the efficacy of CD19 CAR-NK cells in patients with autoimmune diseases.

Interventions

• Biological anti-CD19 CAR NK cells
  Patients will receive Fludarabine (25 mg/m2 per day) and Cyclophosphamide (300mg/m2 per day) on day -5, -4, and -3. Multiple doses of CD19 CAR NK cells will infused using the dose-escalation strategy.

Primary outcome measures

• Incidence of Dose-Limiting Toxicity (DLT) [Time frame: up to 48 weeks after infusion]
• Incidence of Treatment Emergent Adverse Events (TEAEs) [Time frame: up to 48 weeks after infusion]

Secondary outcome measures (2)

• The overall response rate (ORR) [Time frame: Time Frame: 1, 3, 6, 12 and 12 months after infusion]
• Disease control rate (DCR) [Time frame: Time Frame: 1, 3, 6, 12 and 12 months after infusion]

Eligibility criteria

Common inclusion criteria:

• Age: ≥ 18 years old and ≤ 65 years old, male or female;
• The functions of important organs meet the following requirements:

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• Bone marrow hematopoietic function needs to meet: a. White blood cell count ≥ 3 x 10\^9/L b. Neutrophil count ≥ 1 x 10\^9/L (no colony-stimulating factor treatment within 2 weeks before examination); c. Hemoglobin ≥60g/L;
• Liver function:ALT ≤ 3 x ULN,AST≤3 x ULN, TBIL≤1.5 x ULN(excluding Gilbert syndrome, total bilirubin ≤ 3.0 x ULN) (No requirements for conditions caused by the disease itself);
• Renal function: creatinine clearance rate (CrCl) ≥ 60 ml/minute(Cockcroft/Fault formula);
• Coagulation function: International standardized ratio (INR) < 1.5 x ULN,prothrombin time(PT) < 1.5 x ULN;
• Cardiac function: Good hemodynamic stability. 3. Female subjects of childbearing potential and male subjects whose partner is a female of childbearing potential are required to use medically approved contraception or abstain from sex for at least 6 months during and at least 6 months after the end of the study treatment period; female subjects of childbearing potential have had a negative serum HCG test within 7 days prior to study enrollment and are not lactating; 4. Voluntarily participate in this clinical study, sign an informed consent form, have good compliance, and cooperate with follow-up.

Inclusion Criteria for Relapsing refractory dry syndrome:

• Meets 2002 AECG criteria or 2016 ACR/EULAR classification criteria for primary dry syndrome (pSS);
• Definition of disease activity: investigator-assessed disease ESSDAI score of 5 or higher;
• Definition of relapsed and refractory disease: ineffective conventional treatment or relapse of disease activity after remission. Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) and cyclophosphamide, as well as any of the following immunomodulatory drugs for more than 6 months: antimalarials, methotrexate, leflunomide, cyclophosphamide, azathioprine, mertiomate, tacrolimus, cyclosporine, and biologics, including rituximab, belimumab and tetracycline;

Inclusion criteria for Systemic Sclerosis:

• Meets 2013 ACR classification criteria for systemic sclerosis;
• If combined with interstitial pneumonia, interstitial changes suggestive of ground-glass exudates on chest HRCT and FVC or DLCO <70% predictive value on pulmonary function tests;
• IDefinition of relapsed and refractory disease: ineffective conventional treatment or relapse of disease activity after remission. Definition of routine treatment: use of glucocorticoids and one or more immunomodulatory drugs for more than 6 months, including antimalarials, methotrexate, leflunomide, cyclophosphamide, azathioprine, mycophenolate mofetil, tacrolimus, cyclosporine, and biologics including rituximab, belimumab, and tetanuscept;
• Definition of progressiveness; 1) Definition of cutaneous progression: increase in mRSS >10%; 2) Definition of lung disease progression: 10% decrease in FVC or 5% decrease in FVC with 15% decrease in DLCO (OMERACT progression).

Inclusion criteria for Recurrent refractory idiopathic inflammatory myopathy:

• Classification criteria for inflammatory myopathy in accordance with 2017 EULAR/ACR (including DM, PM, ASS, and NM);
• For those with muscle involvement, the MMT-8 score is lower than 142 and at least two abnormalities are found in the following five core measurements (PhGA, PtGA, or extramuscular disease activity score ≥ 2 points; total HAQ score ≥ 0.25; muscle enzyme levels are 1.5 times the upper limit of the normal range);
• Positive myositis antibodies;
• Ineffective conventional treatment or relapse of disease activity after remission. Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) and cyclophosphamide, as well as any of the following immunomodulatory drugs for more than 6 months: antimalarials, methotrexate, leflunomide, cyclophosphamide, azathioprine, mertiomate, tacrolimus, cyclosporine, and biologics, including rituximab, belimumab and tetracycline.

Inclusion criteria for relapsing refractory rheumatoid arthritis:

• Meets the diagnostic criteria of the 2010 ACR/EULAR classification. Diagnosis of moderately or severely active rheumatoid arthritis with a previous diagnosis of rheumatoid arthritis ≥ 6 months;
• A swollen joint count of ≥ 6 (based on 66 joint counts) and a tender joint count of ≥ 6 (based on 68 joint counts) during the Screening Period;
• C-reactive protein (CRP) ≥ 10 mg/L or erythrocyte sedimentation rate (ESR) ≥ 28 mm/h during the Screening Period;
• EULAR definition of refractory rheumatoid arthritis:

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• Failure of treatment according to EULAR recommended guidelines and failure of treatment with ≥2 b/tsDMARDs despite failure of treatment with csDMARDs. (i) unless treatment with bDMARDs/tsDMARDs is limited due to socioeconomic factors; and (ii) if treatment with csDMARDs is contraindicated, then failure of treatment with ≥2 b/tsDMARDs of different mechanisms also fulfills the condition);
• Symptom management of RA is considered problematic by both the patient and the physician;
• Signs suggestive of active or progressive disease if at least 1 of the following 5 items is met

• At least moderate disease activity (DAS28-ESR >3.2 or CDAI >10);
• Signs and/or symptoms suggestive of active disease;
• Inability to reduce glucocorticoids to less than 7.5 mg/day prednisone or equivalent;
• Rapid imaging progression (1-year increase of ≥5 points in van der Heijde modified Sharp score);
• Decreased quality of life due to RA, although RA is well controlled;
• Refractory rheumatoid arthritis is diagnosed if three of the above criteria are met.

Common exclusion criteria:

1\. Subjects with known severe allergic reactions, hypersensitivity, contraindication to any medications during the trial (cyclophosphamide, fludarabine, tozumabs), or subjects with a history of severe allergic reactions; 2. Subjects with active or suspected fungal, bacterial, viral, or other infections that are uncontrolled or require treatment; 3. Subjects with central nervous system disorders due to autoimmune diseases or non-autoimmune diseases(including epilepsy, psychosis, organic encephalopathy syndromes, cerebrovascular accidents, encephalitis, central nervous system vasculitis); 4. Subjects with relatively serious heart diseases, such as angina pectoris, myocardial infarction, heart failure, and arrhythmia; 5. Subjects with congenital immunodeficiency diseases; 6. Subjects with malignant tumors (except for non-melanoma skin cancer and in situ cervical, bladder, and breast cancers that have been disease-free for more than 5 years); 7. Subjects with end-stage renal failure; 8. SSubjects with positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and HBV DNA titer in peripheral blood higher than the upper limit of detection; subjects with positive hepatitis C virus (HCV) antibodies and positive peripheral blood HCV RNA; subjects with positive human immunodeficiency virus (HIV) antibodies; subjects with positive for syphili; 9. Subjects with mental illness and severe cognitive impairment; 10. Subjects who have received other clinical trial treatment within 3 months; 11. Pregnant or intending to conceive women; 12. In the opinion of the investigator, there are other reasons why subjects cannot be included in this study.

Exclusion criteria for relapsing refractory dry syndrome:

• Combined cirrhosis of the liver;
• Combination of aplastic anemia (AA), myelodysplastic syndrome (MDS), or other myeloproliferative disease (MPD).

Exclusion criteria for recurrent refractory idiopathic inflammatory myopathies:

• Drug-induced myositis;
• Inclusion body myositis;
• Tumor-associated myositis (myositis occurring within 2 years of tumor diagnosis).

Exclusion criteria for relapsed refractory rheumatoid arthritis:

Functional status of rheumatoid arthritis graded at level 4 according to ACR.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Changhai Hospital — Shanghai

Identifiers

NCT: NCT06464679 · CHEC2024-181

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗