Allogeneic Hematopoietic Stem Cell (HSC) Transplantation
Conditions
Keywords
Cell therapy, immuno-modulation, immunotherapy, Hematology
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.
Interventions
None listed
Sponsors
Central Hospital, Nancy, France
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Kinetic of iNKT cells (flask culture) | from day 0 to day 14 |
| time of culture to reach the maximal expansion factor | day 14 |
| Percentage of cells alive | day 14 |
| Percentages of CD4- iNKT cells capable of producing IFN-γ after expansion | day 14 |
Secondary
| Measure | Time frame |
|---|---|
| Transcriptional pattern CD4+ iNKT | day 14 |
| Percentage of recovery of CD4- iNKT cells after immunomagnetic selection | day 14 |
| Proportion of Th1 producing T cells stimulated by allogeneic dendritic cells | day 6 in a mixed lymphocyte reaction |
| Kinetic of iNKT cells(culture in bioreactor system) | From day 0 to day 14 |
| Proportion of mice protected from GVHD mortality in a xeno-GVHD mouse model | survival proportions between day 28 and day 60 post-transplantation |
| Ratio of iNKT/T cells to control xeno-GVHD mortality | survival proportions between day 28 and day 60 post-transplantation |
| Proportion of mice protected from leukemia development | survival proportions between day 28 and day 60 post-transplantation |
| Proportion of Th17 producing T cells stimulated by allogeneic dendritic cells | day 6 in a mixed lymphocyte reaction |
| Expression of cytokine receptors CD4- iNKT data | day 14 |
| Expression of cytokine receptors CD4+ iNKT data | day 14 |
| transcriptional pattern CD4- iNKT data | day 14 |
Contacts
Primary ContactMarie-Thérèse RUBIO, PU-PH
Outcome results
None listed