Phase 2 study of the infusion of differentiated autologous T-cells from peripheral blood, expanded and transduced with a lentivirus to express a chimeric antigen receptor with anti-CD19 specificity (A3B1) conjugated with the co-stimulatory regions 4-1BB and CD3z (ARI-0001 cells) in children and adolescents aged 0-18 years with CD19+ acute lymphoblastic leukaemia resistant or refractory to treatment.

Prior treatment

• Any other concomitant neoplasia, unless it has been in complete remission for 3 years or longer
• Active immunosuppressive therapy with the exception of hydrocortisone 12 mg/m2/day (or equivalent);
• Any experimental or non-commercialized therapy in the previous 4 weeks
• Any concomitant and uncontrolled medical or psychiatric disease that, under investigator consideration, would prevent the subject from participating in the study

Other illness

• Active acute or chronic graft versus host disease (GVHD) >grade 1
• Active infection that is uncontrolled or requiring systemic intravenous medical therapy;
• Active HIV, HBV or HCV infection

Lab values

• Prior therapies: • CAR-T cell therapy • Donor lymphocytes infusion <28 days before enrollment • Immunosuppressive therapy (cyclosporine, mophetil mycophenolate and others) must be stopped <14 days before enrollment • Alentuzumab, thymoglobulin (ATG) < 3 months before enrollment
• Severe organic impairment defined by cardiac ejection fraction <50%, pulmonary reserve defined as > Grade 1 dyspnea and pulse oxygenation <91% on room air, creatinine >1.5 times greater than the upper limit of normality (ULN) for sex and age or conjugated bilirubin >2 x ULN

Other

• Lactating or pregnant women
• Men or women of childbearing potential unable or unwilling to use highly efficient contraceptive measures during the study

• Age 0 to 18 years
• Diagnosis of relapsed /refractory CD19+ ALL defined as at least one of the following criteria: • First relapse if high-risk features. Definition of high risk 1st relapse will include at least one of the following: o any relapse before 6 months after completion of chemotherapy o high risk cytogenetics: t(4;11)(q21; q23) /AF4:: KMT2A or t (1;19) (q23; p13) / TCF3/PBX or t(17;19) (q22;p13)/ TCF3::HLF or hypodiploid (<44 chromosomes) or TP53 mutation and/ or TP53 deletion
• Disease burden defined as: • Morphologic relapse in bone marrow (≥5% blasts) or presence of leukemic blasts in an extramedullary site • MRD positivity (≥0.01%) by flow cytometry or PCR
• Subjects with the following features are NOT excluded: • Isolated extramedullary involvement • Down syndrome patients • CNS3 involvement if disease is stable and a thorough evaluation of risk/benefit assessment has been stablished by the principal investigator and the treating physician • Ph+ (BCR::ABL1) ALL if they are intolerant or have failed at least 1 TKI • Prior blinatumomab therapy provided blasts remain CD19+ >90% blasts at inclusion
• Performance status: Lansky (age <16 years) or Karnofsky (age ≥16 years) ≥ 50%
• Life expectancy >3 months
• Adequate venous access and no contraindications for lymphoapheresis
• Signature of informed consent (patient and/or legal guardian)