Basket trial for B-cEll driven severe auToimmunE and aLoimmune diseases (chronic Graft vErsUs host diseaSe) treated with anti-CD19 CAR T-cell thErapy

Lab values

• Leukapheresis - Exclusion criteria: Patients having any of the following criteria will not proceed with leukapheresis: 1) Clinical suitability for a less burdensome and/or approved therapeutic approach, as judged by the investigator 2) ANC <1.000/µL 3) Hb <8 g/dL 4) PLTs <30.000/µL 5) CD3+<100/µL (peripheral blood) 6) Any condition, including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study 7) Uncontrolled severe concomitant disease or severe hepatic insufficiency defined as Child-Pugh score ≥10 (C) or unstable coronary artery disease 8) Any concomitant severe and/or uncontrolled active infection 9) HIV or HBV infection (positive for HBcAb or HBsAg and NAT) or active HCV (with a period<12 weeks between achieving a sustained virological response to specific treatment and leukapheresis), according to the guidelines of the American Association for the Study of Liver Diseases 10) Pregnant or lactating females 11) Known hypersensitivity to any drug components 12) Previous CAR T-cell administration for autoimmune disease 13) Treatment with immunosuppressive or cytotoxicagents within 7 days prior to leukapheresis; cyclophosphamide must be discontinued at least 3 weeks before leukapheresis 14) Treatment with systemic glucocorticoids at a prednisone-equivalent dose >10 mg/day or >0.3 mg/kg/day (whichever is higher), starting from 7 days prior to leukapheresis 15) Active malignancy in the last 5 years before screening (except for adequately treated basal cell or squamous cell carcinoma; in situ carcinoma of the cervix or breast treated curatively and without recurrence for at least 3 years prior to the study; hematological malignancy which led to allo-HSCT for those patients included for cGVHD, provided there is no evidence of hematological disease by molecular or cytogenetical or flow-measurable residual disease or CT/MRI/PET scan within 2 months).
• Lymphodepletion and drug product infusion - Patients having any of the following criteria will not proceed with lymphodepletion: 1) Clinical suitability for a less onerous and/or approved therapeutic approach, as judged by the investigator 2) Any condition, including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study 3) Uncontrolled severe concomitant disease or severe hepatic insufficiency defined as Child-Pugh score ≥10 (C) or unstable coronary artery disease 4) Any concomitant severe and/or uncontrolled active infection 5) HIV or HBV infection (positive for HBcAb or HbsAg and NAT) or active HCV (with a period< 12 weeks between achieving a sustained virological response to specific treatment and leukapheresis), according to the guidelines of the American Association for the Study of Liver Diseases 6) Pregnant or lactating females 7) Treatment with systemic glucocorticoids at a prednisone-equivalent dose >40 mg/day or >0.4 mg/kg/day (whichever is higher), starting from 2 weeks prior to CD19-CART01 infusion (9 days before the start of the lymphodepleting regimen: day -14) or >20 mg/day or >0.3 mg/kg/day (whichever is higher) starting from 1 week prior to CD19-CART01 infusion (2 days before the start of the lymphodepleting regimen: day -7) 8) Treatment with immunosuppressive or cytotoxic agents within 7 days prior to CD19-CART01 infusion 9) B-cell depleting agents within 28 days prior to IMP infusion 10) Leukapheresis product must contain at least 1x109 PBMCs (leukapheresis lower than 1x109 will not be use) 11) CAR T-cell production deviations including: <20% transduction of target lymphocytes, < 80% viability, killing efficiency < 60%, Vector Copy Number >10 copies/cell

• Leukapheresis - common inclusion criteria: 1) Age: 12-70 years 2) Life expectancy ≥12 weeks 3) Performance status: Lansky/Karnofsky score ≥ 50% 4) Patient has evidence of adequate organ function within 7 days of procurement as defined by: a) total bilirubin ≤3 x ULN, unless attributed to Gilbert’s Syndrome b) AST ≤5 x ULN c) ALT ≤5 x ULN d) renal function not requiring dialysis e) LVEF ≥45% 5) Adequate venous access for apheresis or eligible for appropriate catheter placement and absence of other contraindications to leukapheresis 6) Negative CVC blood cultures within 7 days before leukapheresis 7) Females of childbearing potential must have a negative pregnancy test performed within 8 days before screening 8) Patients of childbearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for 12 months after dosing of the IMP 9) Patient is willing and able to adhere to the study visit schedule and other protocol requirements 10) Voluntary signature of informed consent by the patient, legal guardian or parents (in the case of patients aged <18 years); pediatric patients will be involved in an age-appropriate discussion.
• Leukapheresis - Neuromyelitis optica (adult and pediatric cohort): 1) NMOSD AQP4-IgG positive(see Appendix 14.1) 2) At least 1 of the following conditions: a) at least 1 relapse after 3 months of therapy with anti-CD20 or drugs approved for NMOSD (eculizumab, inebilizumab, satralizumab, ravulizumab), in the last year, or 2 relapses in the last 24 months, including 1 in the last 12 (undergoing treatment) b) side effects or contraindications to the use of drugs approved for NMOSD
• Leukapheresis - Chronic GVHD (cGVHD) (adult and pediatric cohort): cGVHD refractory to at least 3 lines of therapy, with involvement of at least one of the following organs: a) skin (NIH score of 2-3 with sclerotic features involving BSA >50%)(see Appendix 14.1) b) joint and fascia (NIH score 2-3)(see Appendix 14.1) c) lung(NIH score of 2-3)(see Appendix 14.1) d) liver (NIH score 2-3)(see Appendix 14.1)
• Lymphodepletion and IMP administration: 1) Life expectancy ≥12 weeks 2) Performance status: Lansky/Karnofsky score ≥50% 3) Patient has evidence of adequate organ function within 7 days of the beginning of lymphodepleting therapy as defined by: a) total bilirubin ≤3 x ULN, unless attributed to Gilbert’s syndrome b) AST ≤5 x ULN c) ALT ≤5 x ULN d) renal function not requiring dialysis e) LVEF ≥45% 4) Females of childbearing potential must have a negative pregnancy test within 8 days before the start of lymphodepletion 5) Patients of childbearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for 12 months after dosing of the IMP 6) Patient is willing and able to adhere to the study visit schedule and other protocol requirements 7) Voluntary signature of informed consent by the patient, legal guardian or parents (in the case of patients aged <18 years); pediatric patients will be involved in an age-appropriate discussion.
• Leukapheresis - Systemic lupus erythematosus (adult cohort): 1) Fulfilling the 2019 ACR/EULAR classification criteria of SLE(see Appendix 14.1) 2) Presence of anti-dsDNA, anti-histone, anti-nucleosome or anti-Sm antibodies 3) Active disease, as demonstrated at screening by a SLEDAI-2K ≥ 6 and/or a SLEDAI 2K ≥ 4 with at least one clinical criterion(see Appendix 14.1) 4) Insufficient response to glucocorticoids and to at least 2 of the following treatments: hydroxychloroquine, mycophenolate mofetil, belimumab, methotrexate, rituximab; Childhood systemic lupus erythematosus (pediatric cohort) 1) Fulfilling the 2019 ACR/EULAR classification criteria of SLE (see Appendix 14.1) 2) Active disease at screening, defined as a SLEDAI-2K ≥ 8 (except SLEDAI-2K domain of lupus headache) (see Appendix 14.1) 3) Insufficient response to glucocorticoids and to at least 2 of the following treatments: hydroxychloroquine, mycophenolate mofetil, belimumab, methotrexate, rituximab
• Leukapheresis - Systemic sclerosis (adult cohort): 1) Fulfilling the 2013 ACR/EULAR classification criteria of SSc(see Appendix 14.1) 2) Diffuse SSc with respective autoantibody profile 3) Signs for fast progression including: a) disease duration ≤5 years (from onset of first non-Raynaud manifestation) b) mRSS score 10-40 at screening(see Appendix 14.1) c) elevated acute phase reactant levels (CRP ≥6 mg/L, ESR ≥28mm/h or platelet count ≥330.000/µL) d) mRSS increase ≥3 units, or involvement of one new body area and mRSS increase ≥ 2 units, or two new body areas with increase of at least 1, or at least one tendon friction rub over 6 months (see Appendix 14.1) 4) Insufficient response to glucocorticoids and to at least 2 of the following treatments: mycophenolate mofetil, azathioprine, nintedanib, methotrexate, rituximab
• Leukapheresis - Juvenile Systemic Sclerosis (pediatric cohort): 1) Fulfilling the 2013 ACR/EULAR classification criteria of SSc(see Appendix 14.1) 2) Diffuse SSc with a mRSS score 10-35 at screening(see Appendix 14.1) 3) Active disease defined as at least 1 of the following at screening: a) progressive skin involvement: mRSS increase ≥ 3 units, or involvement of one new body area and mRSS increase ≥ 2 units, or involvement of two new body areas (each within the previous 6 months)(see Appendix 14.1) b) radiological signs of ILD at HRTC or DLCO <70% c) myocardial involvement d) pulmonary arterial hypertension (PAH) e) gastrointestinal involvement defined as increased intestinal wall thickness documented by MRI or esophageal aperistalsis 4) Insufficient response to glucocorticoids and to at least 2 of the following treatments: mycophenolate mofetil, cyclophosphamide, azathioprine, methotrexate, rituximab
• Leukapheresis - Dermatomyositis/Polymyositis (adult cohort): 1) Fulfilling the 2017 ACR/EULAR classification criteria for probable or definite DM or PM (see Appendix 14.1) and at least one of the following items: a) Positive MSA b) Positive muscle biopsy (for patients with PM who are negative for MSA) c) Pathognomonic skin lesions (for patients with DM, Gottron sign and/or papules and/or heliotrope rash) 2) In addition, to confirm that myositis is active, patients must have proximal muscle weakness as defined by MMT <142 (see Appendix 14.1)and 2 of the following criteria: VAS patients Global ≥2 cm(see Appendix 14.1), VAS physician Global ≥2 cm(see Appendix 14.1), HAQ >0.25(see Appendix 14.1), at least one muscle enzyme (CK and/or aldolase) >2 times upper limit of normal OR if muscle enzymes are normal (as occurs in 50% of patients with active muscular DM) evidence of proximal muscle edema on a recent MRI OR signs of active myositis (irritative signs) at a recent EMG 3) Insufficient response to glucocorticoids and to at least 2 of the following treatments: mycophenolate mofetil, cyclosporin A, azathioprine, tacrolimus, methotrexate, rituximab, intravenous immunoglobulins
• Leukapheresis - Juvenile dermatomyositis (pediatric cohort): 1) Fulfilling the 2017 ACR/EULAR classification criteria for probable or definite DM (see Appendix 14.1) 2) Active disease defined as: a) clinical criteria: CMAS <48 or MMT8 <78 unilateral or <125/150 bilateral and PGA >2.5/10cm (mandatory criteria) (see Appendix 14.1) b) laboratory or radiologic criteria: levels of CPK, aldolase, LDH, AST, or ALT ≥3 times the ULN at screening or evidence of active disease at MRI 3) Insufficient response to glucocorticoids and to at least 2 of the following treatments: methotrexate, mycophenolate mofetil, ciclosporin A, adalimumab, abatacept, rituximab, intravenous immunoglobulins
• Leukapheresis - Immune-mediated necrotizing myopathies (adult cohort): Fulfilling the European Neuromuscular Centre (ENMC) criteria for immune-mediated necrotizing myopathies (IMNM) (see Appendix 14.1): 1) Patients with “anti-HMGCR myopathy”: a) elevated serum CK levels b) proximal muscle weakness, and c) anti-HMGCR autoantibodies 2) Patients with “anti-SRP myopathy”: a) elevated serum CK levels b) proximal muscle weakness, and c) anti-SRP autoantibodies 3) Patients with “antibody negative IMNM”: a) elevated CK levels b) proximal muscle weakness c) no myositis-specific autoantibodies, and d) a muscle biopsy revealing features of inflammation
• leukapheresis - ANCA-associated vasculitis (adult and pediatric cohort): 1) Fulfilling the 2022 ACR/EULAR classification criteria for MPA/GPA/EGPA(see Appendix 14.1) 2) Presence of ANCA to either proteinase 3 or myeloperoxidase 3) At least one major or three nonmajor items or at least two renal items of hematuria and proteinuria on the Birmingham Vasculitis Activity Score (BVAS), version 3(see Appendix 14.1) 4) Failure of at least 1 of the following treatments: glucocorticoids associated with cyclophosphamide or with B-cell targeting therapy
• Leukapheresis - Myasthenia gravis (adult cohort): 1) Presence of anti-AChR, or anti-MusK or anti-LRP4 antibodies 2) Myasthenia Gravis Foundation of America (MGFA) class IIA-IV(see Appendix 14.1) 3) Basal MG-ADL score ≥6(see Appendix 14.1) 4) Presence of at least 1 of the following criteria: a) persistence of MG-ADL ≥6 despite immunosuppressive therapy and II-line drugs such as anticomplement or neonatal Fc receptor inhibitors of Ig (see Appendix 14.1) b) side effects or contraindications to the use of II-line immunosuppressants and drugs and/or inability to reduce the steroid c) need for plasmapheresis and monthly Iv Ig within the past 6 months d) at least 1 myasthenic crisis in the past 6 months