Defining the window of opportunity for post-transplant ThINKK therapy and TRAIL as a biomarker of NK cell response.
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BACKGROUND AIMS: Cancer relapse is still the first cause of death following hematopoietic stem cell transplantation (HSCT) in children with refractory cancers. To improve the outcome of HSCT patients, we have developed Therapeutic Inducers of Natural Killer cell Killing (ThINKK), a first-in-class anticancer cellular immunotherapy. ThINKK are hematopoietic stem cell-derived analogs of plasmacytoid dendritic cells, aimed at increasing Natural Killer (NK) cell anticancer functions. To define the therapeutic window of opportunity for this novel approach, we aimed to assess the response of HSCT patients' NK cells to ThINKK stimulation and define biomarkers of response for future pharmacokinetic studies. METHODS: We gathered a cohort of pediatric patients with diverse underlying diseases. Post-transplant NK cell subset distribution was assessed using multiparametric flow cytometry. Following ex vivo stimulation with ThINKK, we investigated the activated phenotype of NK cells. We further tested the cytotoxicity of unstimulated and ThINKK-stimulated NK cells against a leukemia cell line deemed to be resistant to NK cell killing using flow cytometry-based NK cell cytotoxic assays. RESULTS: Despite increased proportions of CD56brightCD16- and CD56brightCD16low NK cell subsets in transplanted patients compared with healthy volunteers, both CD56bright and CD56dim NK cells post-transplant NK cells upregulated the surface expression of Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in response to ThINKK stimulation. Consistent with this finding, the stimulation of NK cells with ThINKK abrogated leukemia cell resistance to NK cell-mediated killing. CONCLUSIONS: These data pave the way toward adoptive transfers of ThINKK in the first months after transplant and confirms TRAIL as a biomarker for the future pharmacodynamics studies of our Phase 1 clinical trial.