The goal of our study will be to determine the clinical and biological safety of infusing immuno-selected NK (Natural Killer) CD3-/CD56+ cells, early after allogeneic transplantation with colony stimulating factor (G-CSF) mobilized peripheral blood stem cells and Reduced Intensity Conditioning (RIC), as a potential substitute to usual "Donor Lymphocyte Infusion" (DLI), that contain the whole range of immune effectors. The trial will include several progressive steps: dose escalation up to a level compatible with the cost-effectiveness potential of the device and clinical situation and recombinant interleukin-2 (r-IL2) activation of selected NK cells in vitro prior to re-infusion.
In the mid 90's, it has been shown that donor lymphocyte infusions (DLI), when given for Chronic Myelocytic Leukemia (CML) that has relapsed after conventional allogeneic stem cell transplantation (SCT), result in a high incidence of durable cytogenetic and molecular remissions. However, regular documented effects are the occurrence of secondary aplasia and/or graft-versus-host disease (GVHD) including the post RIC situation. These effects are related to the high content of cytotoxic T cells in the DLI. Attempts to deplete CD8+ T-cells from DLI have been conducted with promising results but are not totally satisfactory. More recently the infusion of r-IL2 ex-vivo activated autologous or allogeneic NK-selected cells have been studied and the safety established in patients presenting various malignancies. Indeed, NK are thoroughly characterized in terms of genotype, phenotype and function. Although a handful of clinical-grade reagents and devices exist that give access to the human NK cell compartment, an immuno-selection device exists that allows for the selection of NK cells from various types of hematopoietic cell collections in view of clinical applications: the process produces CD3-/CD56+ cells in two steps and have been used in the previous experiences.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
17
* level 1: 1 x 10e6 NK cells /kg; * level 2: 5 x 10e6 NK cells /kg; * level 3: \> 5.10e6 and ≤ 5.10e7 cellules NK/kg
Institut Paoli-Calmettes
Marseille, France
Occurence of grade 3-4 toxicity within 30 days of NK cells infusion
To establish the safety of donor NK cells infusion after HLA matched allogeneic transplant prepared by RIC.
Time frame: day 30
Number of infused cells population : CD3+, CD56+/CD16+, CD56-/CD16+, CD56+/CD16- (Determination)
Ex vivo NK cell selection reproductibility
Time frame: baseline: at the time of the NK cells infusion
relapse
Time frame: up to one year after infusion
number of NK cells function form baseline to Month 12 (kinetics)
Immunomonitoring: NK ontogeny after in vivo transfer, characterization of KIR expression (phenotype and genotype), documentation of functional activity against tumor cell line and EBV transformed B cell lines. These studies will allow calibrating further the kinetics of NK cells function (cytotoxicity and cytokine production) as well to answer different questions of fundamental immunology The following studies will be performed: 1. Analysis of early steps of aGVHD, immune activation and toxicity 2. Impact of the infusions on NK reconstitution and myeloid cells including dendritic cells 3. Antileukemic effects
Time frame: at Day1, Day2, Day9, Day30, Month3, Month6, Month12
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