Phase IIa Trial of Anti-CD19 CAR T-Cells in Systemic Sclerosis Resistant to Immunosuppressive Therapy

Prior treatment

• Contra indication for autologous hematopoietic stem cell transplantation (AHSCT ) or relapsing at least one year after AHSCT
• Concurrent therapy with systemic steroids (\>10 mg/d prednisone equivalent) within 2 weeks prior to inclusion, except inhaled steroids
• T cell targeting drugs (e.g. mycophenolate mofetil, azathioprine, calcineurin inhibitors) within 6 weeks prior to leukapheresis
• Previous adoptive T cell therapy or any gene therapy including CAR T cell therapy
• Live vaccines within 6 weeks prior to leukapheresis
• Concurrent participation in any other interventional trial and Contraindication to the lymphodepleting chemotherapy

Other illness

• Craniocerebral trauma, conscious disturbance, epilepsy, cerebrovascular ischemia or cerebrovascular hemorrhagic diseases
• Lung and / or heart severe dysfunction defined by CVF\<50% and/or DLCO \<40%
• Pulmonary arterial hypertension defined by catheterism (mean AP \> 25mmHg at rest or \> 30mmHg after exercise, PAOP \< 15mmHG)
• 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
• 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
• patients with advanced cognitive disorders or any other cause preventing their informed consent;
• 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

Lab values

• ECG showing prolonged QT interval or history of severe heart diseases or FEVG \< 40%
• 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.

Other

• Active hematological or solid neoplasm
• Methylprednisolone or prednisone (maximum dose 20 mg) instead of immunosuppressive agents
• patients without social security coverage;
• patients under guardianship;
• Male or female patients seeking to conceive a child
• pregnant or breastfeeding women;
• 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.

• Adequate organ functions assessed:
  • serum Creatinine clearance \> 40ml/mi
  • adequate bone marrow function (Hemoglobin ≥9g/dL ; PMN ≥ 1 G/L ; Platelets ≥ 100 G/L)
  • 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)
  • 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
• Adequate venous access for apheresis
• Leucapheresis : a wash-out period of 6 weeks for conventional immunosuppressants (i.e. methotrexate, mycophenolate mofetil)
• Leucapheresis : at least 12 weeks after biotherapy (i.e. tocilizumab, 6 months for rituximab),

Criteria the registry did not label

• Pre-Inclusion criteria:
• 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 :
• 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)
• Early onset (less than 2 years).
• Severity \& progression of disease be defined by :
  • .mRSS \>15 with at least one organ involvement (lung: FVC \<80%, renal involvement, cardiac involvement, Creatinine \< 1.5 mg/dl within 6 months).
  • mRSS \<15 and lung fibrosis progression (FVC -10% DLCO -15% within 6 months)
• 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.
• Estimated survival time \> 24 weeks
• Age: ≥18 ≤64 years old voluntary to participate in the study and sign the informed consent
• Adequate organ functions assessed :
  • serum Creatinine clearance \> 40ml/mi
  • adequate bone marrow function (Hemoglobin ≥9g/dL ; PMN ≥ 1 G/L ; Platelets ≥ 100 G/L)
  • 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)
  • 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
• Highly effective contraception methods