Identifying the optimal donor for natural killer cell adoptive therapy to treat paediatric B‐ and T‐cell acute lymphoblastic leukaemia

Abstract

Objectives. Natural killer (NK) cells are an attractive source of cells for an 'off the shelf' cellular therapy because of their innate capacity to target malignant cells, and ability to be transferred between donors and patients. However, since not all NK cells are equally effective at targeting cancer, selecting the right donor for cellular therapy is critical for the success of the treatment. Recently, cellular therapies utilising NK cells from cytomegalovirus (CMV)seropositive donors have been explored. However, whether these NK cells are the best source to treat paediatric acute lymphoblastic leukaemia (ALL) remains unclear. Methods. Using a panel of patient-derived paediatric Band TALL , we assessed the ability of NK cells from 49 healthy donors to mount an effective functional response against these two major subtypes of ALL. Results. From this cohort, we have identified a pool of donors with superior activity against multiple ALL cells. While these donors were more likely to be CMV + , we identified multiple CMV neg donors within this group. Furthermore, NK cells from these donors recognised Band TALL through different activating receptors. Dividing functional NK cells into 29 unique subsets, we observed that within each individual the same NK cell subsets dominated across all ALL cells. Intriguingly, this occurred despite the ALL cells in our panel expressing different combinations of NK cell ligands. Finally, we can demonstrate that cellular therapy products derived from these superior donors significantly delayed leukaemia progression in preclinical models of ALL. Conclusions. We have identified a pool of superior donors that are effective against a range of ALL cells, representing a potential pool of donors that can be used as an adoptive NK cell therapy to treat paediatric ALL.

Deciphering the Immunological Phenomenon of Adaptive Natural Killer (NK) Cells and Cytomegalovirus (CMV)

“…This suggests that while NKG2C marks adaptive NK cells, its contribution to the recognition and elimination of cancer cells remains unclear. In support of this we have recently demonstrated that while NKG2C + adaptive NK cells were associated with increased effector function against B cell ALL, NKG2C recognition of HLA-E was not involved in this increased function [ 100 ]. There is also rationale to exploit the enhanced ADCC potential of adaptive NK cells to generate improved responses against cancer when using monoclonal, bispecific and trispecific antibodies [ 96 ].…”

Making a Killer: Selecting the Optimal Natural Killer Cells for Improved Immunotherapies

“…Despite the existence of a plethora of strategies to enhance the cytotoxicity and persistence of therapeutic NK cells in vivo, the initial selection of highly functional cells with strong innate potency is essential for the widespread success of NK cell therapies. Over the past decade it has become increasingly evident that not all NK cells have the same baseline capacity to eradicate leukaemic cells (33)(34)(35)(36)(37). In addition to the functional differences between traditional NK cell subsets (33)(34)(35), variability also exists in the functional capacity of NK cells derived from different individuals (36,37).…”

“…Over the past decade it has become increasingly evident that not all NK cells have the same baseline capacity to eradicate leukaemic cells (33)(34)(35)(36)(37). In addition to the functional differences between traditional NK cell subsets (33)(34)(35), variability also exists in the functional capacity of NK cells derived from different individuals (36,37). However, relatively little attention has been given to optimizing the particular subset or donor from which these cells are derived.…”

“…However, relatively little attention has been given to optimizing the particular subset or donor from which these cells are derived. We have recently reported that resting donor-derived pb-NK cells display marked variability in their capacity to mount an effector response against leukaemic target cells ( 36 ). Intriguingly, we identified a pool of donors with strong activity against multiple leukaemic cells, representing ideal candidates for the development of efficacious “off-the-shelf” NK cellular therapies.…”

“…While KIR2DS1 has been shown to recognize HLA-C2 and mediate alloreactivity against cancer cells ( 58 – 61 ), a direct role for KIR2DS2 is harder to decipher ( 62 ). KIR2DS2 can recognize HLA-C in combination with specific peptides ( 63 , 64 ) and may potentially interact with certain HLA-A alleles ( 36 , 65 , 66 ) or non-HLA ligands ( 48 , 67 ) suggesting many mechanisms for KIR2DS2 + NK cells to target cancer cells post-HSCT. Gaining a better understanding of how associations with activating KIR result in improved responses and this information will allow us to not only better select donors for HSCT, but also to consider additional ways we may be able to exploit these findings to enhance NK cell anti-leukaemic responses.…”