Clinical trial NCT01853358: Phase I of Infusion of Selected Donor NK Cells After Allogeneic Stem Cell Transplantation
Official title: Phase I of Infusion of Selected Donor NK Cells After HLA Identical Allogeneic Stem Cell Transplantation Prepared With Reduced Intensity Conditioning - DLI-NK/IPC 2012-003
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hematological Malignancy
Keywords: hematological malignancy
stem cell transplantation
Lead sponsor: Institut Paoli-Calmettes
Sponsor class: OTHER
First posted: 2013-05-15
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Patient treated with allogeneic stem cell transplantation

   * Presenting an hematological malignancy with an intermediate, high or very high risk index according to the disease risk index developed by the Dana Farber Cancer Institute
   * Donor: HLA matched related or unrelated (10/10) donor
   * Graft: Peripheral stem cell transplant
   * Reduced Intensity Conditioning as used in the current transplant program: Fludarabine, IV Busulfan and Thymoglobuline
2. Age above 18 and under 70
3. Eastern Cooperative Oncology Group (ECOG) 0-1 or Karnofsky index ≥ 70 %
4. Survival expectation \> 6 months
5. Affiliation to social security
6. Signed informed consent from Donor and Patient

Exclusion Criteria:

1. Active grade \>= 2 acute GVHD or corticotherapy ≥ 0.5 mg/kg/day at time of NK cell infusion
2. Active infection
3. Psychiatric disorder occurring after transplant
4. Pregnant or breast-feeding women or without contraception

Primary outcomes:
measure: Occurence of grade 3-4 toxicity within 30 days of NK cells infusion
timeFrame: day 30
Secondary outcomes:
measure: Number of infused cells population : CD3+, CD56+/CD16+, CD56-/CD16+, CD56+/CD16- (Determination)
timeFrame: baseline: at the time of the NK cells infusion
measure: relapse
timeFrame: up to one year after infusion
measure: number of NK cells function form baseline to Month 12 (kinetics)
timeFrame: at Day1, Day2, Day9, Day30, Month3, Month6, Month12
Other outcomes:
Locations:
city: Marseille
country: France
facility: Institut Paoli-Calmettes
Study officials:
affiliation: Institut Paoli-Calmettes
name: BLAISE Didier, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mfarrej B, Gaude J, Couquiaud J, Calmels B, Chabannon C, Lemarie C. Validation of a flow cytometry-based method to quantify viable lymphocyte subtypes in fresh and cryopreserved hematopoietic cellular products. Cytotherapy. 2021 Jan;23(1):77-87. doi: 10.1016/j.jcyt.2020.06.005. Epub 2020 Jul 25.