Significant impact of antibiotic exposure on GI-GVHD, NRM, and GRFS following allogeneic HCT with non-myeloablative Flu-TBI conditioning.

Background: Acute gastro-intestinal graft--host disease (GI-GVHD) and non-relapse mortality (NRM) after allogeneic HCT are closely related to loss of microbial diversity and intestinal dominance by single taxa resulting from the use of antibiotics, dietary changes, and mucosal barrier injury. There is a paucity of data on the impact of use of antibiotics in HCT after Flu-TBI-based non-myeloablative (NMA) conditioning where there is absence of mucositis and limited malnutrition.

Methods: We did a retrospective single-center analysis of patients receiving Flu-TBI-based NMA HCT for a high-grade myeloid malignancy, mostly AML, and MDS, or acute lymphoblastic leukemia (ALL).

Decitabine enhances targeting of AML cells by CD34 progenitor-derived NK cells in NOD/SCID/IL2Rg mice.

Combining natural killer (NK) cell adoptive transfer with hypomethylating agents (HMAs) is an attractive therapeutic approach for patients with acute myeloid leukemia (AML). However, data regarding the impact of HMAs on NK cell functionality are mostly derived from in vitro studies with high nonclinical relevant drug concentrations. In the present study, we report a comparative study of azacitidine (AZA) and decitabine (DAC) in combination with allogeneic NK cells generated from CD34 hematopoietic stem and progenitor cells (HSPC-NK cells) in in vitro and in vivo AML models.

Successful Transfer of Umbilical Cord Blood CD34 Hematopoietic Stem and Progenitor-derived NK Cells in Older Acute Myeloid Leukemia Patients.

Older acute myeloid leukemia (AML) patients have a poor prognosis; therefore, novel therapies are needed. Allogeneic natural killer (NK) cells have been adoptively transferred with promising clinical results. Here, we report the first-in-human study exploiting a unique scalable NK-cell product generated from CD34 hematopoietic stem and progenitor cells (HSPC) from partially HLA-matched umbilical cord blood units.

The Aryl Hydrocarbon Receptor Antagonist StemRegenin1 Improves In Vitro Generation of Highly Functional Natural Killer Cells from CD34(+) Hematopoietic Stem and Progenitor Cells.

Early natural killer (NK)-cell repopulation after allogeneic stem cell transplantation (allo-SCT) has been associated with reduced relapse rates without an increased risk of graft-versus-host disease, indicating that donor NK cells have specific antileukemic activity. Therefore, adoptive transfer of donor NK cells is an attractive strategy to reduce relapse rates after allo-SCT. Since NK cells of donor origin will not be rejected, multiple NK-cell infusions could be administered in this setting.

Efficient nontoxic delivery of PD-L1 and PD-L2 siRNA into dendritic cell vaccines using the cationic lipid SAINT-18.

Dendritic cell (DC)-based vaccination is an appealing strategy to boost graft-versus-tumor immunity after allogeneic stem cell transplantation (allo-SCT), and thereby prevent or counteract tumor recurrence. By exploiting minor histocompatibility antigens (MiHA) presented on hematopoietic cells, donor CD8 T-cell immunity can be selectively targeted to patient's hematological tumor cells without the risk of inducing graft-versus-host disease. Previously, we demonstrated that silencing RNA (siRNA) of programmed death-ligand 1 (PD-L1) and PD-L2 on DCs markedly augments the expansion and function of MiHA-specific CD8 T cells.

Immunotherapeutic approaches to treat multiple myeloma.

Cellular immunotherapy can be an effective adjuvant treatment for multiple myeloma (MM), as demonstrated by induction of durable remissions after allogeneic stem cell transplantation. However, anti-myeloma immunity is often hampered by suppressive mechanisms in the tumor micro-environment resulting in relapse or disease progression. To overcome this immunosuppression, new cellular immunotherapies have been developed, based on the important effector cells in anti-myeloma immunity, namely T cells and natural killer cells.