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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
10
A 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.
A 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).
Hospital Universitario La Paz
Madrid, Madrid, Spain
RECRUITINGIncidence 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.
Time frame: Through study completion, an average of 5 years
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.
Time frame: Through study completion, an average of 5 years
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.
Time frame: Through study completion, an average of 5 years
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
Time frame: Through study completion, an average of 5 years
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
Time frame: Through study completion, an average of 5 years
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.
Time frame: Through study completion, an average of 5 years
Presence of soluble NKG2DL, and ANTI-MICA and ANTI-MICB antibodies
Evaluate the presence of soluble NKG2DL and ANTI-MICA and ANTI-MICB antibodies in the serum of patients under CART-NKG2D therapy. This outcome will only be measured in arm B.
Time frame: Through study completion, an average of 5 years
Overall rate response in both arms
Response assessment will be measured by bone marrow aspirate (or trephine in case of dry tap).
Time frame: Through study completion, an average of 5 years
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