Natural killer (NK) cells are extremely promising for cellular antitumor therapy in terms of efficacy and safety, particularly in the control of hematological malignancies. The aim of this thesis was to provide deeper insights on receptor/ligand leukemia interactions and investigate possible tools to enhance the NK cell anti-leukemia activity. Two clinical contexts of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) were under evaluation 1) αβT-cell and B-cell depleted haplo-HSCT in pediatric leukemia patients, and 2) haplo-HSCT with post-transplant cyclophosphamide (PT-Cy) in adult AML patients. Regarding the first platform, we tested the in vitro effect of different NK cell engagers (NKCEs), which can trigger either NKp46 or NKp30 together with CD16A, and target either CD19 or CD20 to induce killing of pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL). We used as target cells different BCP-ALL cell lines and primary leukemias, and as effector cells resting NK cells derived from healthy donors and pediatric leukemia patients after αβT/B-depleted haplo-HSCT. The NKCEs potentiated the killing of NK-cell resistant BCP-ALL cells and enhanced the degranulation and cytokine production of NK cells. These data strongly support the therapeutic use of NKp46/CD16A/CD19-NKCE to fight relapsed/refractory leukemia in pre- or post-transplantation setting. Regarding the other platform, we investigated the phenotype of NK cells after transplantation, and we evaluated the effect of immune checkpoint inhibitor (ICI), targeting NKG2A, to unleash NK-cell activity against leukemia. The data pave the way for the use of an anti-NKG2A antibody (as Monalizumab) at early-time points after transplantation to enhance the anti-leukemia activity of NK cells.

Novel insights into NK cell/leukemia molecular interactions and possible tools to potentiate the anti-leukemia NK cell activity

COLOMAR CARANDO, NATALIA
2022-04-29

Abstract

Natural killer (NK) cells are extremely promising for cellular antitumor therapy in terms of efficacy and safety, particularly in the control of hematological malignancies. The aim of this thesis was to provide deeper insights on receptor/ligand leukemia interactions and investigate possible tools to enhance the NK cell anti-leukemia activity. Two clinical contexts of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) were under evaluation 1) αβT-cell and B-cell depleted haplo-HSCT in pediatric leukemia patients, and 2) haplo-HSCT with post-transplant cyclophosphamide (PT-Cy) in adult AML patients. Regarding the first platform, we tested the in vitro effect of different NK cell engagers (NKCEs), which can trigger either NKp46 or NKp30 together with CD16A, and target either CD19 or CD20 to induce killing of pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL). We used as target cells different BCP-ALL cell lines and primary leukemias, and as effector cells resting NK cells derived from healthy donors and pediatric leukemia patients after αβT/B-depleted haplo-HSCT. The NKCEs potentiated the killing of NK-cell resistant BCP-ALL cells and enhanced the degranulation and cytokine production of NK cells. These data strongly support the therapeutic use of NKp46/CD16A/CD19-NKCE to fight relapsed/refractory leukemia in pre- or post-transplantation setting. Regarding the other platform, we investigated the phenotype of NK cells after transplantation, and we evaluated the effect of immune checkpoint inhibitor (ICI), targeting NKG2A, to unleash NK-cell activity against leukemia. The data pave the way for the use of an anti-NKG2A antibody (as Monalizumab) at early-time points after transplantation to enhance the anti-leukemia activity of NK cells.
NK cells, haploidentical-hematopoietic stem cell transplantation, NK cell engagers, Immune checkpoint inhibitor
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11567/1079072
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