Domogala, AJ; (2017) The characterisation of NK cells generated in vitro from cord blood haematopoietic stem cells. Doctoral thesis , UCL (University College London).

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Abstract

Natural Killer (NK) cells are effective at targeting malignant cells without being direct effectors of graft-versus-host disease. NK cell immunotherapy has been shown to be safe in the clinic however efficacy has been inconsistent. We have previously shown that NK cells can be produced in large quantities from frozen cord blood (CB) CD34+ cells. We hypothesised that producing NK cells with optimum activation status that can proliferate and persist in vivo is fundamental for the development of a clinically relevant cellular product. Here, we assess if the cells can further respond to additional cytokine stimulation and if function is maintained post cryopreservation. Further, we consider how cell cytotoxicity compares to peripheral blood (PB) NK cells and CBNK cells against patient acute myeloid leukaemia (AML) blasts and solid tumours and which activation method is superior. We found that the differentiated NK cells could respond to interleukin-2 and proliferate in vitro and that their function was unaffected by cryopreservation. The differentiated NK cells could kill leukaemic cells and more importantly could persist for longer and in higher numbers in vivo over other sources of NK cells. Priming the cells consistently led to higher levels of killing of patient leukaemic blasts and solid tumour cell lines in vitro, however this activation step was not required to observe killing of patient AML blasts in vivo. This implies that the cells might not require prior activation before infusion resulting in a more economical cellular therapy that is more easily translatable to the clinic. We are therefore able to generate and cryopreserve NK cells differentiated from CB CD34+ cells in high numbers allowing for multiple infusions of highly cytotoxic NK 5 cells that have potential to further proliferate in vivo and have a clear survival advantage over other sources of NK cells.

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