Clinical trial NCT03605953: Expansion of Invariant NKT Cells for a Cell Immunotherapeutic Approach Allowing the Control of Graft Versus Host-disease and Preserving the Graft Versus Leukemia Effect After Allogeneic Hematopoietic Stem Cell Transplantation
Official title: Expansion of Invariant NKT Cells for a Cell Immunotherapeutic Approach Allowing the Control of Graft Versus Host-disease and Preserving the Graft Versus Leukemia Effect After Allogeneic Hematopoietic Stem Cell Transplantation
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Allogeneic Hematopoietic Stem Cell (HSC) Transplantation
Keywords: Cell therapy
immuno-modulation
immunotherapy
Hematology
Lead sponsor: Central Hospital, Nancy, France
Sponsor class: OTHER
First posted: 2018-07-30
Enrollment: 134
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: healthy donors of HSCT

Brief summary: Allogeneic hematopoietic stem cell (HSC) transplantation remains the most efficient cellular immunotherapeutic approach for the treatment of myeloid hematological malignancies. However, its use is hampered by the risk of developing acute graft-versus-host disease (aGVHD). Invariant NKT cells (iNKT) represent a good candidate of immuno-regulatory cells that could control GVHD while preserving the anti-leukemic effect (GVL) of HSCT. Our team have shown that higher numbers and expansion capacity of CD4- iNKT cells contained in the HSC graft were associated with reduced risk of aGVHD but preserved GVL effect and that some healthy donors have low numbers and expansion capacity CD4- iNKT cells 1.

The objective of this project is to develop a strategy allowing to expand human CD4- iNKT cells from healthy donors of HSC grafts that would be transposable to GMP-validated cell production. Our team proposes to first determine the best strategy to expand the CD4- iNKT cell subset from G-SCF mobilized peripheral blood stem cells (PBSC) obtained from healthy donors, at little scale using cultures GMP validated conditions, by comparing the convention expansion protocol using IL-2 alone to IL-7, IL-15, IL-4 or combination of those cytokines involved in the expansion of T cells and by culturing the cells in a bioreactor. Our team will then explore the characteristics of cells after expansion in terms of phenotype, transcription signature and functions in vitro (in mixed lymphocyte reaction) and in vivo in a well-established xenogeneic model of GVHD.


Eligibility criteria: Inclusion Criteria:

Hematopoietic stem cells :

* from major donors after mobilization by G-CSF, informed of the research and not having opposed it
* Collected after verification by the cell therapy centre of the presence of a sufficient quantity of CSH for transplantation

Exclusion Criteria:

Hematopoietic stem cells (HSCs) from donors seropositive for HIV, HCV, HTLV1 and HBV (except post-vaccination profile)

Primary outcomes:
measure: Kinetic of iNKT cells (flask culture)
timeFrame: from day 0 to day 14
measure: time of culture to reach the maximal expansion factor
timeFrame: day 14
measure: Percentage of cells alive
timeFrame: day 14
measure: Percentages of CD4- iNKT cells capable of producing IFN-γ after expansion
timeFrame: day 14
Secondary outcomes:
measure: Kinetic of iNKT cells(culture in bioreactor system)
timeFrame: From day 0 to day 14
measure: Expression of cytokine receptors CD4- iNKT data
timeFrame: day 14
measure: Expression of cytokine receptors CD4+ iNKT data
timeFrame: day 14
measure: transcriptional pattern CD4- iNKT data
timeFrame: day 14
measure: Transcriptional pattern CD4+ iNKT
timeFrame: day 14
measure: Percentage of recovery of CD4- iNKT cells after immunomagnetic selection
timeFrame: day 14
measure: Proportion of Th1 producing T cells stimulated by allogeneic dendritic cells
timeFrame: day 6 in a mixed lymphocyte reaction
measure: Proportion of Th17 producing T cells stimulated by allogeneic dendritic cells
timeFrame: day 6 in a mixed lymphocyte reaction
measure: Proportion of mice protected from GVHD mortality in a xeno-GVHD mouse model
timeFrame: survival proportions between day 28 and day 60 post-transplantation
measure: Ratio of iNKT/T cells to control xeno-GVHD mortality
timeFrame: survival proportions between day 28 and day 60 post-transplantation
measure: Proportion of mice protected from leukemia development
timeFrame: survival proportions between day 28 and day 60 post-transplantation
Other outcomes:
Locations:
Study officials:
References: