The goal of this clinical trial is to test the feasibility and safety of an academic production of two different anti-CD19 chimeric antigen receptor T cells (CART) products according to the different biomarkers of the disease in children and young adults with relapsed/refractory CD19+ B cell acute lymphoblastic leukemia (r/r B-ALL) or relapsed/refractory T-cell acute lymphoblastic leukemia (r/r T-ALL). The main questions it aims to answer are:

1. The safety and feasibility of autologous CART-19/22 in children, adolescents and young adults with a CD19+/- CD22+ relapse/ refractory disease for a r/r B-ALL.
2. The safety and feasibility of allogeneic CART-NKG2D (chimeric-antigen receptor Natural-killer group 2, member D) in children, adolescents and young adults with r/r T-ALL.

Incredible progress has been made in the treatment of relapsed/refractory CD19+ acute lymphoblastic leukemia (r/r ALL) by the application of anti-CD19 chimeric antigen receptor (CAR) T cells (CART19). However, equivalent progress has not been achieved in the treatment of relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL). Furthermore and although the majority of patients with CD19+ r/r ALL respond to CART19, 30-60% of patients relapse after this treatment, probably due to the short persistence of CAR T-cells and the immune escape or down-regulation of CD19 antigen. Patients with relapsed ALL after CART19 have a very poor prognosis and novel treatment approaches are urgently needed. To date, both relapse after CART19 malignancies and T-ALL represent an unmet medical need where no effective or targeted therapies currently exist. Recently, we and other groups have reported how T-ALL and acute myeloid leukemia (AML) cell lines were more sensitive to CART-NKG2D (chimeric-antigen receptor Natural-killer group 2, member D) cytotoxicity than B-ALL cell lines. We have previous experience in the production and administration, under compassionate use, of CART cells targeting dual CD19/CD22 antigens and NKG2D ligands. In this context, this phase I clinical trial is designed to test the feasibility and safety of an academic production of two different CART products according to the different biomarkers of the disease.

In the present study (ReALL_CART), we propose an umbrella design methodology using autologous dual CART-19/22 for CD19+/-CD22+/- relapse after CART19 or allogeneic CART-NKG2D for NKG2DL+ r/r T-ALL.

Inclusion Criteria:

• ARM A: CD19+/- CD22+ B-ALL with relapsed or refractory disease not responding to conventional chemotherapy and with no other curative therapy available. Treatment with previous CART CD19 therapy is permitted, but is not mandatory, OR:
• ARM B: T-ALL with relapsed or refractory disease not responding to conventional chemotherapy and with no other curative therapy available.
• Patients diagnosed with ALL must be suitable for allogeneic HSCT and willing to proceed to transplant if the CART treatment induces complete remission and the investigator believes it is the best option.
• For ARM B there must be a suitable haploidentical donor (following local standard operating procedures).
• Lansky (age <16 years) or Karnofsky (age ≥16 years) score of 50 or greater.
• Life expectancy greater than 12 weeks.
• Absolute neutrophil count (ANC) ≥ 500/μL unless, in the opinion of the investigator, cytopenia is due to underlying leukemia and is potentially reversible with leukemia therapy.
• Platelet count ≥ 50,000/μL unless, in the opinion of the investigator, cytopenia is due to underlying leukemia and is potentially reversible with leukemia therapy.
• Absolute lymphocyte count ≥ 100/μL.
• Adequate renal, hepatic, pulmonary, and cardiac function.
• Adequate venous access and absence of contraindications for lymphoapheresis
• Patients with a seizure disorder may be enrolled if well controlled with anticonvulsants.
• Patients or patients' legal representative, parent(s), or guardian able to provide written informed consent.

Exclusion Criteria:

• Enrolled in another clinical trial in the previous 4 weeks.
• Active infection requiring systemic medical therapy including clinically significant viral infection or uncontrolled viral reactivation of EBV, CMV, adenovirus, BK-virus, HHV-6 or Aspergillus.
• Any of the following cardiac criteria: cardiac echocardiography with LVSF<30% or LVEF<40%; or clinically significant pericardial effusion.
• Presence of CNS-3 disease or uncontrolled seizure disorder.
• Active immunosuppressive therapy with the exception of prednisone 10 mg/day (or equivalent), within 7 days prior to enrolment.
• GFR <30 ml/min or bilirubin >3 times the upper limit of normality (unless due to Gilbert's syndrome).
• Any other condition that, in the opinion of the PI, may interfere with the efficacy and/or safety evaluation of the trial.
• Pregnant or lactating women.
• Sexually active patients must be willing to utilize one of the more effective birth control methods for at least 12 months after the infusion and until CAR-T cells are no longer present on two consecutive tests. Male partner should use a condom. Women of child-bearing potential are defined as all women physiologically capable of becoming pregnant.
• Sexually active males should use a condom during intercourse for at least 12 months after the infusion and until CAR-T cells are no longer present on two consecutive tests.