Anti-CD19 Chimeric Antigen Receptor T Cells for Refractory Autoimmune Diseases

Inclusion Criteria:

1. Systemic lupus erythematosus (SLE) 1.1. Refractory systemic lupus erythematosus (SLE) and / or refractory lupus nephritis (LN)

2. Male or female patients, aged 3-65 years (including 3 and 65 years);

3. Systemic lupus erythematosus that meets the 2019 American Society of Rheumatology (ACR) / European Association of Rheumatology Consortium (EULAR) classificationcriteria (see Annex 2);

4. Nuclear antibody (ANA) test is clearly positive, namely ANA titer 1:80 (based on theequivalent results of Hep-2 immunofluorescence or enzyme immunoassay) and / or thetest at the screening visit (based on ELISA test, 30 IU / mL).

5. Refractory systemic lupus erythematosus (SLE) and / or refractory lupus nephritis (LN):

6. Patients take at least 7.5 mg of prednisolone daily to maintain low disease activityor a SLEDAI 2K score (see attachment 3) of 8 or higher.

7. Recurrence of disease activity after failure of conventional therapy or afterremission. Definition of conventional treatment: using corticosteroids (1 mg / kg /day) and cyclophosphamide for 6 months; or any of the following immunomodulatorydrugs for more than 3 months: antimalarial drugs, azathioprine, mycophenolatemofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biological agentssuch as rituximab, belimumab, and teacept.

5. Physical strength status score (ECOG): 0-2 points; 6) The estimated survival periodof 90 days; 1.2. Immune thrombocytopenia in refractory lupus (SLE-ITP)

1. Age range: 18-70 years (including 18 and 70 years), gender limitation.

2. Patients with refractory systemic lupus erythematosus (immune thrombocytopenia):meeting SLE 2019 ACR / EULAR classification criteria, with at least 2 consecutiveroutine blood tests showing platelets lower ; no abnormal morphology of blood cellsin peripheral blood smear; morphological characteristics of bone marrow cellsmeeting immune thrombocytopenia. Refractory systemic lupus erythematosus (immunethrombocytopenia) was defined as at least 1 course of MP shock (1g 3 days) orhigh-dose hormone (1mg / kg d equivalent dose of glucocorticoid) combined with 1 ormore immunosuppressive agents. Thrombocytopenia except for other than non-SLEcauses, such as infection, myelosuppression, macropleic, hypersplenism, etc.

3. Clinician assessment of the patients condition allowed the use of 10mg prednisone orits equivalent dose during the study and allowed the discontinuation of allimmunosuppressive agents (excluding hydroxychloroquine).

1.3. refractory lupus thrombotic microangiopathy (SLE-TMA)

1. Age range: 18-70 years (including 18 and 70 years), gender limitation.

2. Meet SLE-TMA standard; meet one of the following criteria, associated with SLEMicrovascular hemolytic anemia, associated with elevated lactate dehydrogenase andperipheral blood smear fragmentation; and thrombocytopenia, except for otherreasons; Renal biopsy suggested a TMA.

Refractory systemic lupus erythematosus was defined as no TMA response with at least 1 course of MP shock (1g 3 days) or high-dose hormone (1mg / kg d equivalent dose glucocorticoid) combined with 1 or more immunosuppressants.

The clinician assessed the patients condition allowed a glucocorticoid dose of up to 10mg prednisone or its equivalent dose during the study and allowed discontinuation of all immunosuppressive agents (excluding hydroxychloroquine).

1.4.SLE Myelitis

1. Age: 18-60 years old.

2. Diagnosis: meet the diagnostic criteria for SLE.

3. Myelitis: acute or subacute paraplegia, sensory plane, sphincter dysfunction, andtendon reflex or plantar reflex abnormalities; including but not limited to spinalcord lesions confirmed by MRI. And other causes of myelitis.

4. Severity: lower limb muscle strength grade 3

5. Refractory / recurrent nature:

Refractory: ineffective against high-dose hormone shock therapy and / or combined with other immunosuppressants; Relapse: at least two recurrences in the past 12 months, or three times in the past 24 months, and one recurrence in the 12 months prior to screening.

1.5.SLE Pulmonary arterial hypertension (SLE-PAH)

1. Age range: 18-70 years (including 18 and 70 years), gender is unlimited.

2. Refractory systemic lupus erythematosus (SLE) and / or refractory lupus nephritis
 (LN):
 

3. Patients take at least 7.5 mg of prednisolone daily to maintain low disease activity
or a SLEDAI 2K score (see attachment 3) of 8 or higher.
 

4. Recurrence of disease activity after failure of conventional therapy or after
remission. Definition of conventional treatment: using corticosteroids (1 mg / kg /
day) and cyclophosphamide for 6 months; or any of the following immunomodulatory
drugs for more than 3 months: antimalarial drugs, azathioprine, mycophenolate
mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, and biological agents
such as rituximab, belimumab, and teacept.
 

5. Physical strength status score (ECOG): 0-2 points; 6) The estimated survival period
of 90 days; 1.2. Immune thrombocytopenia in refractory lupus (SLE-ITP)
 

1. Age range: 18-70 years (including 18 and 70 years), gender limitation.
 

2. Patients with refractory systemic lupus erythematosus (immune thrombocytopenia):
meeting SLE 2019 ACR / EULAR classification criteria, with at least 2 consecutive
routine blood tests showing platelets lower ; no abnormal morphology of blood cells
in peripheral blood smear; morphological characteristics of bone marrow cells
meeting immune thrombocytopenia. Refractory systemic lupus erythematosus (immune
thrombocytopenia) was defined as at least 1 course of MP shock (1g 3 days) or
high-dose hormone (1mg / kg d equivalent dose of glucocorticoid) combined with 1 or
more immunosuppressive agents. Thrombocytopenia except for other than non-SLE
causes, such as infection, myelosuppression, macropleic, hypersplenism, etc.
 

3. Clinician assessment of the patients condition allowed the use of 10mg prednisone or
its equivalent dose during the study and allowed the discontinuation of all
immunosuppressive agents (excluding hydroxychloroquine).
 
 1.3. refractory lupus thrombotic microangiopathy (SLE-TMA)
 

4. Age range: 18-70 years (including 18 and 70 years), gender limitation.
 

5. Meet SLE-TMA standard; meet one of the following criteria, associated with SLE
Microvascular hemolytic anemia, associated with elevated lactate dehydrogenase and
peripheral blood smear fragmentation; and thrombocytopenia, except for other
reasons; Renal biopsy suggested a TMA.
 
 Refractory systemic lupus erythematosus was defined as no TMA response with at least 1
 course of MP shock (1g 3 days) or high-dose hormone (1mg / kg d equivalent dose
 glucocorticoid) combined with 1 or more immunosuppressants.
 
 The clinician assessed the patients condition allowed a glucocorticoid dose of up to 10mg
 prednisone or its equivalent dose during the study and allowed discontinuation of all
 immunosuppressive agents (excluding hydroxychloroquine).
 
 1.4.SLE Myelitis
 

6. Age: 18-60 years old.
 

7. Diagnosis: meet the diagnostic criteria for SLE.
 

8. Myelitis: acute or subacute paraplegia, sensory plane, sphincter dysfunction, and
tendon reflex or plantar reflex abnormalities; including but not limited to spinal
cord lesions confirmed by MRI. And other causes of myelitis.
 

9. Severity: lower limb muscle strength grade 3
 

10. Refractory / recurrent nature:
 
 Refractory: ineffective against high-dose hormone shock therapy and / or combined with
 other immunosuppressants; Relapse: at least two recurrences in the past 12 months, or
 three times in the past 24 months, and one recurrence in the 12 months prior to
 screening.
 
 1.5.SLE Pulmonary arterial hypertension (SLE-PAH)
 

11. Age range: 18-70 years (including 18 and 70 years), gender is unlimited.
 

12. Patients with refractory connective tissue disease (pulmonary arterialhypertension):

13. confirmed as systemic lupus erythematosus according to the 1997 ACR or EULAR / ACRrevision standard in 2019;

14. meeting the diagnostic criteria for PAH confirmed by a right heart catheter (asdefined by 2022 ESC / ERS guidelines for the treatment of pulmonary hypertension):

1. mean pulmonary artery pressure (mPAP) 20mmHg at rest; 2) pulmonary vascular wedgepressure (PAWP) 15mmHg,and pulmonary vascular resistance (PVR)> 2 WUs at rest;

3. PAH did not reach risk stratification for patients in the low-risk group. Low-riskpatients need to meet: 1) WHO cardiac function grades I-II; 2) 6 min walkingdistance (6 MWD)> 440 m; 3) BNP <50 ng/L, or NT-proBNP <300 ng/L; 4) right atrialpressure (RAP) <8mmHg and heart index (CI) 2.5 L · min 1 · m 2.

4. Subjects had received a standard dose of treatment before the first dose of studydrug, including glucocorticoids (prednisone 0-30mg / day, or other equivalent) forat least 4 weeks; antimalarials, single-agent immunosuppressors (allowed to applyimmunosuppressors limited to: mycophenol ester or mycophenolic acid 1.5g / day,azathioprine or 6-mercaptopurine 2mg / kg / day, methotrexate 15mg / week,leflunomide 20mg / day) for at least 12 weeks and not increased or replaced within 24 weeks after medication. Less than three (including prostaglandin analogues,endothelin receptor, antagonists, PDE-5 inhibitors, guanylate cyclase agonists) andhave been stable for at least 4 weeks and do not increase or change within 24 weeksafter drug treatment.

5. Clinician assessment of the patients condition allowed the use of glucocorticoidsnot to 10mg prednisone or its equivalent dose during the study and allowed thewithdrawal of all immunosuppressive agents (excluding hydroxychloroquine).

1.6.SLE-Protein loss enteropathy (SLE-PLE)

1. Age range: 18-70 years (including 18 and 70 years).

2. Refractory SLE-PLE:

3. confirmed as systemic lupus erythematosus according to the 1997 ACR or EULAR / ACRrevision standard in 2019;

4. Meet the SLE-PLE standard: meet one of the following standards. Clinical symptomsand laboratory findings associated with PLE, including hypoalbuminemia (urinaryprotein loss, severe liver disease or malnutrition, which is not completelyexplained by other pathological mechanisms) Refractory systemic lupus erythematosuswas defined as no PLE response after at least 1 course of MP shock (1g 3 days) orhigh-dose hormone (1mg / kg d equivalent dose of glucocorticoids) combined with 1 ormore immunosuppressants.

The clinician assessed the patients condition allowed a glucocorticoid dose of up to 10mg prednisone or its equivalent dose during the study and allowed discontinuation of all immunosuppressive agents (excluding hydroxychloroquine).

（3）Blood pregnancy tests were negative for women of reproductive age within 7 days before trial pretreatment; any fertile male and female patient must agree to effective contraception throughout the study and for at least 2 years. According to the researchers, a patient with fertility means a biological ability to have a living baby and a normal sexual life. Female patients without fertility (i. e., meet at least one following criteria): hysterectomy or bilateral oophorectomy, or medical confirmation of ovarian failure, or postmenopause (at least 12 consecutive months of menopause in the absence of pathological or physiological causes).

2. Sjogrens Syndrome (SS) 2.1.SS-ITP

3. The age at screening was 18 ~ 65 years old (including 18 and 65 years old);

4. Classification classification of primary Sjogrens Syndrome according to the 2002International Classification or ACR / EULAR in 2016, the diagnosis of primarySjogrens syndrome for at least 6 months;

5. Positive antinuclear antibody (titer 1:80) at screening, and / or anti-SSA antibody,and / or anti-SSB antibody;

6. Active relapse / refractory SS should meet at least one of the following scenarios:

7. Relapse / refractory immune thrombocytopenia: refractory to first-line therapy,platelet-inducing drugs in second-line therapy and / or rituximab therapy / hormonedependence or intolerance, platelet <30109 / L, and PGA> 1.

2.2.SS Myelitis

1. Age: 18-60 years old.

2. Diagnosis: Meet the diagnostic criteria for Sjogrens syndrome (SS) (such as theAmerican College of Rheumatology (ACR) criteria).

3. The diagnosis of NMOSD requires neurological evaluation and MRI imagingconfirmation, meeting the NMOSD diagnostic criteria as follows: The NMOSD diagnostic criteria for AQP 4-IgG positivity; At least 1 core clinicalfeature; AQP 4-IgG using the best available assay.

4. Severity: lower limb muscle strength grade 3

5. Infractability and recurrence:

Refractory: ineffective against high-dose hormone shock therapy and / or combined with other immunosuppressants; Relapse: at least two recurrences in the past 12 months or three in the past 24 months and one in the 12 months prior to screening.

2.3.SS-PAH

1）Age range: 18-70 years (including 18 and 70 years), gender is unlimited. 2）Patients with refractory connective tissue disease (pulmonary arterial hypertension):

1. Meet the 2002 AECG classification criteria or 2016 ACR / EULAR classificationcriteria, and diagnosed as primary Sjogrens syndrome;

2. meeting the diagnostic criteria for PAH confirmed by a right heart catheter (asdefined by the 2022 ESC / ERS guidelines for the treatment of pulmonaryhypertension): 1) mean pulmonary artery pressure (mPAP) 20mmHg at rest; 2) pulmonaryvascular wedge pressure (PAWP) 15mmHg; and pulmonary vascular resistance (PVR)> 2WUs at rest;

3. PAH did not reach risk stratification for patients in the low-risk group. Low-riskpatients need to meet: 1) WHO cardiac function grades I-II; 2) 6 min walkingdistance (6 MWD)> 440 m; 3) BNP <50 ng/L, or NT-proBNP <300 ng/L; 4) right atrialpressure (RAP) <8mmHg and heart index (CI) 2.5 L · min 1 · m 2.

4. Subjects had received a standard dose of treatment before the first dose of studydrug, including glucocorticoids (prednisone 0-30mg / day, or other equivalent) forat least 4 weeks; antimalarials, single-agent immunosuppressors (allowed to applyimmunosuppressors limited to: mycophenol ester or mycophenolic acid 1.5g / day,azathioprine or 6-mercaptopurine 2mg / kg / day, methotrexate 15mg / week,leflunomide 20mg / day) for at least 12 weeks and not increased or replaced within 24 weeks after medication. Less than three (including prostaglandin analogues,endothelin receptor, antagonists, PDE-5 inhibitors, guanylate cyclase agonists) andhave been stable for at least 4 weeks and do not increase or change within 24 weeksafter drug treatment.

5. Clinician assessment of the patients condition allowed the use of glucocorticoidsnot to 10mg prednisone or its equivalent dose during the study and allowed thewithdrawal of all immunosuppressive agents (excluding hydroxychloroquine).

6. Systemic sclerosis (SSc) 3.1.SSc-ILD And skin sclerosis

7. the diagnosis of SSc was confirmed according to the 2013 ACR / EULAR classificationcriteria

8. Course of disease for 6 years after the first presentation of non-Raynaud phenomenon

9. Age is 18 years old, 70 years old, gender is not limited in patients with ILD (1)ILD confirmed by chest HRCT, range 20%, ground glass shadow or grid shadow (2) Lungfunction: FVC% 60%, and DLCO 40% (3) MMF or CTX for more than 3 months (shortness ofbreath aggravation, or 5% decrease in FVC% or 10% decrease in DLCO%, or chest HRCTaggravation, except for infection and other factors)

10. Skin sclerosis:

(1) Patients with dcSSc (2) mRSS 12 points, or new skin involvement areas or skin progression (mRSS 3 points) were recorded in the past 6 months (3) Previous application of hormones / immunosuppressants / JAK inhibitors / biological agents has poor efficacy 3.2.SSc-PAH

1)Age range: 18-70 years (including 18 and 70 years), gender is unlimited. 2)Patients with refractory connective tissue disease (pulmonary arterial hypertension):

1. Meet the 1980 ACR or ACR / EULAR classification criteria in 2013 and make adiagnosis of systemic sclerosis.

2. meeting the diagnostic criteria for PAH confirmed by a right heart catheter (asdefined by the 2022 ESC / ERS guidelines for the treatment of pulmonaryhypertension): 1) mean pulmonary artery pressure (mPAP) 20mmHg at rest; 2) pulmonaryvascular wedge pressure (PAWP) 15mmHg; 3) and pulmonary vascular resistance (PVR)> 2WUs at rest;

3. PAH did not achieve risk stratification for patients in the low-risk group. Low-riskpatients need to meet: 1) WHO cardiac function grades I-II; 2) 6 min walkingdistance (6 MWD)> 440 m; 3) BNP <50 ng/L, or NT-proBNP <300 ng/L; 4) right atrialpressure (RAP) <8mmHg and heart index (CI) 2.5 L · min 1 · m 2.

4. Subjects had received a standard dose of stable treatment before the first dose ofstudy drug, including glucocorticoids (prednisone 0-30mg / day, or equivalent) forat least 4 weeks; antimalarials, single-agent immunosuppressive agents (limited tomoxachenolate or mycophenolic acid 1.5g / day, azathioprine or 6-mercaptopurine 2mg / kg / day, methotrexate 15mg / week, leflunomide 20mg / day) for at least 12 weeksand not increased or replaced within 24 weeks after treatment. Less than three (including prostaglandin analogues, endothelin receptor, antagonists, PDE-5inhibitors, guanylate cyclase agonists) and have been stable for at least 4 weeksand do not increase or change within 24 weeks after drug treatment.

5. Clinician assessment of the patients condition allowed the use of glucocorticoidsnot to 10mg prednisone or its equivalent dose during the study and allowed thewithdrawal of all immunosuppressive agents (excluding hydroxychloroquine).

6. Antiphospholipid syndrome (APS)

7. Selected patients or their legal representatives shall voluntarily sign the informedconsent form.

8. Age range: 18-70 years (including 18 and 70 years), gender is unlimited.

9. Patients with refractory APS (immune thrombocytopenia, microangiopathic APS): APSwith microangiopathy and / or immune thrombocytopenia (APS-ITP).

Patients with refractory microangiopathic APS: according to the 2023 ACR / EULAR classification criteria for APS nephropathy, myocardial lesions, alveolar hemorrhage, adrenal hemorrhage or microthrombosis, or meet the 2003 CAPS classification criteria. Refractory APS was defined as a shock to corticosteroids or high-dose hormone combined with at least one immunosuppressive agent (including CTX, tacrolimus, MMF and cyclosporin) induced remission for 3 months with continued progression or no resolution of microangiopathy.

Patients with refractory APS-ITP: at least 2 consecutive routine blood tests showed platelets lower than 50109 / L; microscopic morphology of blood cells in peripheral blood smear; morphological characteristics of bone marrow cells were immune thrombocytopenia. Refractory APS-ITP (immune thrombocytopenia) was defined as receiving at least 1 course of MP shock (1g 3 days) or a high dose of hormone (1mg / kg d equivalent dose of glucocorticoid) combined with 1 or more immunosuppressive agents did not achieve at least partial response. Except thrombocytopenia other non-APS causes, such as infection, bone marrow suppression, macropleism and hypersplenism.

The clinician assessed the patients condition allowed a glucocorticoid dose of up to 10mg prednisone or its equivalent dose during the study and allowed discontinuation of all immunosuppressive agents (excluding hydroxychloroquine).

5. Idiopathic inflammatory myopathy (IIM)

6. Age range: 1870 years (including 18 and 70 years), gender unlimited, weight 40 kg atscreening.

7. Classification criteria: IIM patients: must meet the "positive" or "very likely"diagnosis (Lundberg et al 2017) according to the EULAR / ACR adult idiopathicinflammatory myopathy (IIM) classification criteria, or by the 2010 Connors et al.

8. Definition of refractory IIM: at least one immunosuppressive agent (e. g.,azathioprine, methotrexate, mycophenolate, cyclosporine, tacrolimus, cyclohamide,leflunomide, etc.) that has received stable doses for over 2 months, Whencorticosteroids were reduced to 10mg daily prednisone or its equivalent dose orabove, At least one of the following deterioration occurred: (i) ILD progression,The symptoms of shortness of breath worsened after the activity, Or an increased ILDscore for lung HRCT, Or pulmonary function FVC% predicted decrease greater than 5%,Or DLco% decrease of> 10%; And (ii) deterioration of myositis, MMT-8 decreased> 5points / 150 points, Or creatine kinase elevated> 100U / L.

9. Definition of recurrent IIM: The reappearance of active IIM after 6 months ofsustained disease remission causes new organ involvement or aggravation of theoriginal involved organ, or the need for increased glucocorticoids andimmunosuppressive agents.

10. The clinician assessing the patients condition allowed the use of glucocorticoiddoses not exceeding 10mg prednisone or its equivalent dose during the study periodand permitted the discontinuation of all immunosuppressants.

11. Anti-neutrophil cytoplasic antibody-associated vasculitis (AAV: GP A/MPA)

12. Severe patients diagnosed with GPA or MPA according to 2022 ACR / EULAR criteria,treated with cyclophosphamide or hormone with rituximab (BVAS score of 0), orrelapsed with maintenance therapy with rituximab or cyclophosphamide.(Recurrence isdefined as the occurrence of at least one primary item, or 3 secondary items, or anabnormality of 1 or 2 secondary items in two consecutive follow-ups);

13. The patient is positive for ANCA (anti-MPO or PR3 antibody) at present or during thecourse of the disease.

Exclusion Criteria: An individual who meets any of the following criteria will beexcluded from participation in this study:

1. intracranial hypertension or cerebral consciousness disorder: Intracranial pressureis kept above 15mmHg; Organic encephalopathy syndrome, cerebrovascular accident,encephalitis or central nervous system vasculitis, visual impairment and other brainlesions that require intervention.

2. Symptomatic heart failure or severe arrhythmia: Left ventricular ejection fraction (LVEF) <45% within 12 months prior to screening; Abnormal electrocardiogram (ECG):left bundle branch, double bundle branch block or other clinically significantabnormal electrocardiogram; Congenital long QT interval (QT) syndrome or Fridericiacorrection formula (QTcF) 470 ms; Congestive heart failure (New York HeartAssociation Class III or IV); 3. Severe respiratory failure or other respiratorysymptoms that are difficult to control: 4. Along with other types of malignanttumors; 5. Diffuse endovascular coagulation; 6. Sepsis or other infections that aredifficult to control: uncontrolled active systemic bacterial, viral, fungal orparasitic infections (except nail fungal infections) or other clinically significantactive diseases; 7. Uncontrolled diabetes: fasting blood glucose (FBG)≥8.0mmol/L, 2hours postprandial blood glucose (PBG) 15 mmol/L, glycated hemoglobin (HbA 1 c)after at least 3 months of diet, exercise or related treatment; combined withdiabetic ketoacidosis or other uncontrollable diabetic complications; 8. Receivedorgan transplantation (excluding bone marrow transplantation); 9. eGFR CKD-EPI < 30ml/min/1.73m^2； 10. Patients who cannot continue the immunosuppressive agents for 7days, or repeat the disease and the investigators evaluate the risk of seriousadverse reactions.