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.
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.
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.
Parallel
Autologous CD19/CD22 CAR T cells
Biological/VaccineA total of two doses of autologous CD19/CD22 CAR T cells (first dose of up to 0.75x106/kg fresh cells), and a second infusion of unfrozen cells (same dose) if there has been no ≥ grade 1 cytokine-release syndrome (CRS) in the next 72 h; intravenously.
Allogeneic CART-NKG2D cells
Biological/VaccineA total of up to 3x106/kg allogeneic CART-NKG2D cells divided in three doses of up to 1x106/kg will be infused; intravenously. First infusion of fresh cells, and the 2nd and 3rd infusion of unfrozen cells (same dose) if there has been no ≥ grade 1 CRS (every 48 hours).
Incidence and severity of adverse events in patients that received autologous CART-19/22
An adverse event is any harmful and unintended reaction to an investigational medicinal product, regardless of the dose administered. Adverse events will be assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, with the exception of CRS and ICANS, which will be graded according to ASBMT Consensus Grading. If CTCAE grading does not exist for an AE, the severity of mild, moderate, severe, life-threatening and fatal, corresponding to Grades 1-5, will be used.
Incidence and severity of adverse events in patients that received allogenic CART-NKG2D T
An adverse event is any harmful and unintended reaction to an investigational medicinal product, regardless of the dose administered. Adverse events will be assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, with the exception of CRS and ICANS, which will be graded according to ASBMT Consensus Grading. If CTCAE grading does not exist for an AE, the severity of mild, moderate, severe, life-threatening and fatal, corresponding to Grades 1-5, will be used.
Expression of CD19/CD22 and NKG2DL on primary B- or T- cell ALL, respectively
The expression of CD19/CD22 and NKG2DL on primary B and T cell malignancies will be measured, respectively, by flow cytometry.
Persistence of CART19/22 and CART-NKG2D cells in patients' samples
The persistance of CART19/22 and CART-NKG2D cells in patients' blood, bone marrow and cerebrospinal fluid samples will be measured
Cytokine profile
Peripheral blood cytokine profile from the patients' serum. The following cytokines will be analysed: IFN-γ, TNF-α, GMCSF, IL-2, IL-1ß, IL-6, IL-8, IL-10, IL12
DNA methylation profile of NKG2DL
Identify the DNA methylation profile of NKG2DL (MICA, MICB AND ULBPs 1-3) in primary T-cell malignancies' samples. This outcome will only be measured in arm B.
Incidence of serious adverse events
Serious adverse events are described as any untoward medical occurrence that, at any dose: * Results in death * Is life-threatening * Requires inpatient hospitalization or prolongation of existing hospitalization * Results in persistent or significant disability/incapacity * Is a congenital anomaly or birth defect * Other important medical events
Performance status
The performance status of the included patients will be measured by the Lansky scale if they are younger than 16 years old, or by the Karnofsky scale if they are 16 years old or older.
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