Synthetic Natural Killer Cells for Immunotherapy

ended

"Cancer remains a leading cause of death worldwide, urging for innovative therapies. Infusion of natural killer (NK) cells, which possess an intrinsic capacity to eliminate cancer cells, is a promising treatment option for various tumours. Genetic engineering of NK cells before transfer allows to specifically tailor and modulate their anti-tumour responses. One particularly attractive strategy for broad implementation of NK cell immunotherapy in an “off-the-shelf” setting is to expand large numbers of NK cells from induced pluripotent stem cells (iPSCs). However, this approach is limited by two main bottlenecks: i) poor persistence of allogeneic iPSC-derived NK (iNK) cells due to rejection by the recipient immune system and ii) impaired functionality due to failure to achieve complete differentiation in vitro. The SYNKIT project seeks to address both of these current limitations through genetic engineering of iNK cells for increased persistence and function. Deletion of human leukocyte antigen (HLA) ""self-ligands"" allows the transferred cells to escape from host T cells. However, absence of HLA also triggers “missing-self” recognition and rejection by host NK cells. In addition, new insights from the host laboratory into the molecular mechanism underlying NK cell education have unravelled a pathway of functional disarming in NK cells that lack self-ligands, further diminishing the anti-tumour efficacy of HLA-deficient NK cells. In SYNKIT, I will use HLA-deficient iNK cells as a platform to assess how introduction of synthetic self-ligands modulates the allogenicity and functionality of iNK cells. The overall goal of SYNKIT is to identify synthetic self-ligands, which reduce recognition by the host immune system and yet prevent functional disarming of the engineered iNK cells, thereby resulting in optimised anti-tumour function. Successful completion of SYNKIT will pave the way for development of next generation immunotherapy to more effectively combat cancer. "