Pre-Inclusion criteria:
1. Diagnosis of systemic sclerosis according to ACR/EULAR 2013 classification (15).we include in the critera the fulfilling of 2013 EULAR/ACR criteria and specify disease duration (less than 2 years), score/clinical evidence for active disease :
2. Severe and resistant to low dose steroids and at least 2 immunosuppressive treatment including csDMARDs (methotrexate, azathioprine, mycophenolate mofetil) and at least one bDMARDs (Tocilizumab)
3. Early onset (less than 2 years).
4. Severity \& progression of disease be defined by :
1. .mRSS \>15 with at least one organ involvement (lung: FVC \<80%, renal involvement, cardiac involvement, Creatinine \< 1.5 mg/dl within 6 months).
2. mRSS \<15 and lung fibrosis progression (FVC -10% DLCO -15% within 6 months)
5. patients with active disease (as defined by EUSTAR ≥2.5) and to patients with a worsening disease despite 6 months of at least 2 immunosuppressive treatments including one DMARDs (methotrexate, azathioprine, mycophenolate mofetil), and one biological DMARD rituximab or tocilizumab.
6. Estimated survival time \> 24 weeks
7. Age: ≥18 ≤64 years old voluntary to participate in the study and sign the informed consent
8. Adequate organ functions assessed :
1. serum Creatinine clearance \> 40ml/mi
2. adequate bone marrow function (Hemoglobin ≥9g/dL ; PMN ≥ 1 G/L ; Platelets ≥ 100 G/L)
3. Alanine aminotransferase (ALT) ≤ 3 x ULN and total bilirubin \< 2.0 mg/dL (34 μmol/L) (or \< 3.0 mg/dL \[51 μmol/L\] for subjects with Gilbert's syndrome)
4. Adequate respiratory function: no dyspnea or grade I dyspnea (Common Terminology Criteria for Adverse Events (NCI CTCAE v 5.0) and oxygen saturation \>/= 92% on room air
9. Highly effective contraception methods
Inclusion criteria:
1. Adequate organ functions assessed:
1. serum Creatinine clearance \> 40ml/mi
2. adequate bone marrow function (Hemoglobin ≥9g/dL ; PMN ≥ 1 G/L ; Platelets ≥ 100 G/L)
3. Alanine aminotransferase (ALT) ≤ 3 x ULN and total bilirubin \< 2.0 mg/dL (34 μmol/L) (or \< 3.0 mg/dL \[51 μmol/L\] for subjects with Gilbert's syndrome)
4. Adequate respiratory function: no dyspnea or grade I dyspnea (Common Terminology Criteria for Adverse Events (NCI CTCAE v 5.0) and oxygen saturation \>/= 92% on room air
2. Adequate venous access for apheresis
3. Leucapheresis : a wash-out period of 6 weeks for conventional immunosuppressants (i.e. methotrexate, mycophenolate mofetil)
4. Leucapheresis : at least 12 weeks after biotherapy (i.e. tocilizumab, 6 months for rituximab),
Exclusion Criteria:
1. Craniocerebral trauma, conscious disturbance, epilepsy, cerebrovascular ischemia or cerebrovascular hemorrhagic diseases
2. ECG showing prolonged QT interval or history of severe heart diseases or FEVG \< 40%
3. Lung and / or heart severe dysfunction defined by CVF\<50% and/or DLCO \<40%
4. Pulmonary arterial hypertension defined by catheterism (mean AP \> 25mmHg at rest or \> 30mmHg after exercise, PAOP \< 15mmHG)
5. Clinically significant active, opportunistic, chronic or recurrent infection (including but not limited to: hepatitis B or C virus or HIV) or covid-19 \< 1 months including active or latent tuberculosis (TB) infection
6. Contra indication for autologous hematopoietic stem cell transplantation (AHSCT ) or relapsing at least one year after AHSCT
7. Active hematological or solid neoplasm
8. Concurrent therapy with systemic steroids (\>10 mg/d prednisone equivalent) within 2 weeks prior to inclusion, except inhaled steroids
9. Methylprednisolone or prednisone (maximum dose 20 mg) instead of immunosuppressive agents
10. T cell targeting drugs (e.g. mycophenolate mofetil, azathioprine, calcineurin inhibitors) within 6 weeks prior to leukapheresis
11. Previous adoptive T cell therapy or any gene therapy including CAR T cell therapy
12. Live vaccines within 6 weeks prior to leukapheresis
13. Hypersensitivity against any drug or its ingredients/impurities that is scheduled or likely to be given during trial participation, e.g. as part of the mandatory preparative chemotherapy or rescue medication/salvage therapies for treatment related toxicities
14. patients without social security coverage;
15. patients under guardianship;
16. Male or female patients seeking to conceive a child
17. Women of childbearing potential unless they are using a highly effective method of contraception starting from the time of enrolment and for at least 12 months following LD chemotherapy and until clearance of CAR-T cells, and sexually active male participants unwilling to use a condom. Female partners of sexually active male participants must be on a highly effective form of birth control from the time of enrolment and for at least 12 months following LD chemotherapy and until clearance of CAR-T cells.
18. pregnant or breastfeeding women;
19. patients with advanced cognitive disorders or any other cause preventing their informed consent;
20. active, clinically significant CNS pathology : If signs or symptoms exist which present diagnostic uncertainty, neurologist consultation will be obtained to confirm the diagnosis of any neurological condition
21. any comorbidity, whatever it may be, which may, in the opinion of the investigator, place the patient at additional risk or interfere with the monitoring of the study.
22. Concurrent participation in any other interventional trial and Contraindication to the lymphodepleting chemotherapy
