Project Details
Projekt
Targeted Modulation of the NKG2D Axis to Trigger Anti-Leukemia NK Cell and T Cell Responses
Subject Area
Hematology, Oncology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 444949889
Natural killer (NK) cells play an important role in immunosurveillance by discriminating between healthy and malignantly transformed cells. Evasion to NK cell recognition has been demonstrated to be an important pathogenic mechanism in ALL. RNA profiling in pediatric B-ALL within our ALL-research consortium suggests that a low ULBP1 expression level correlates with an unfavorable outcome. Recently, partial down-regulation of NKG2D and other activating NK cell receptors on NK cells from ALL patients has also been demonstrated. Taken together, these data suggest that the NKG2D axis is crucial for the evasion of adult and pediatric B-ALL cells from NK cell recognition. Therefore, modulating the NKG2D axis represents a promising approach to restoring tumor recognition in ALL. In the proposed project, we aim to further validate the concept that modulating the NKG2D axis is a suitable strategy to increase NK and T cell responses against leukemia cells. Since published data and our work suggests that NK cells in B-ALL respond less effectively to NKG2D bispecific antibodies, we aim to further enhance NK cell responses by combinatorial approaches. Stronger NK cell activation will be realized by developing novel multi-specific dual-activating NK cell engagers. Additionally, we aim to combine our novel molecules with adoptively transferred genetically engineered, ex vivo expanded NK cells, which express high levels of NKG2D and other activating receptors and lack selected inhibitory receptors by CRISPR/Cas9 mediated knockout. Using adoptive NK cell transfer and our novel NK cell engagers as single agents or in combination with monoclonal antibodies, may modulate complex immune response against leukemia cells and restore immune recognition in ALL.
DFG Programme
Clinical Research Units
