Over the past 15 years, immunotherapy, represented by checkpoint inhibitors, has led to significant changes in cancer treatment, but the effectiveness of such therapies remains limited.
for example, most patients treated with PD-1/L1 inhibitors did not receive complete remission, and only a few patients had a persistent subsidion of the tumor after treatment.
to enhance immuno-checkpoint blocking therapy, scientists are developing a variety of combination therapy strategies.
, in combination with the over-transfer of NK cells, is a promising path.
NK cells can mediate direct tumor lysis and the activity and collection of T cells, but the number of NK cells that can be isolated during a single blood collection process is limited, and there are significant differences in the number and quality of NK cells between the donor.
In a new study published in Science Translational Medicine on November 4, researchers from the University of Minnesota and Fat Therapeutics developed a robust and efficient production system to overcome this barrier, and demonstrated that NK cells from induced omnipotent stem cells (iPSCs) can produce inflammatory cytokines that work in synergy with T cells and PD-1 antibodies to further enhance the anti-tumor response.
source: Science Translational Medicine, an NK cell derived from iPSC, is called iNK cells and is produced by mass amplification as shown in the figure below.
data showed that iNK cells had a consistently high amplification rate throughout culture and were trouted similar to primary exogenally NK cells.
The amplification and performance of iNK cells (Source: Science Translational Medicine) In mouse models of ovarian cancer allogeneic transplantation, iNK cells exhibited strong anti-tumor function, and after treatment in mice, the tumor burden was significant and decreased continuously.
the treatment group had a longer medium survival time (53 vs. 35 days) than the control group, and iNK cells were able to maintain strong anti-tumor function after freezing/thawing cycles.
The over-transfer of iNK cells slowed tumor progression in mice (Source: Science Translational Medicine) Next, the researchers assessed whether the combination of iNK cells over-transfer could improve immunotherapy that relies on T-cells and overcome resistance to checkpoint inhibitors.
, the researchers tested the recruitment role of iNK, which they found promoted the collection of CD4 and CD8 T cells both in vitro and in vivo.
iNK cells recruit exosome t-cells in vitro and in vivo (Source: Science Translational Medicine) and, when used in union with T cells and PD-1 antibodies, can enhance the secretion of inflammatory cytokines and tumor cleavage.
in-body experiments, the number of tumor cells decreased by 99% in the co-existence of iNK cells, active T cells and PD-1 antibodies, while in the presence of iNK cells and active T cells, without PD-1 antibodies, the number of tumor cells decreased by 60%.
results were validated in mouse models where iNK cells worked in synergy with T cells and anti-PD-1 antibodies (Source: Science Translational Medicine).
After the 35th day of the trial, mice receiving triple therapy (iNK cells, active T cells, and PD-1 antibodies) had significantly smaller tumors than other mice receiving active T cells, iNK cells, PD-1 antibodies treated alone or in two combinations.
iNK cells bind to T cells and PD-1 antibodies to promote long-lasting tumor control in the body (Source: Science Translational Medicine) Because iNK cells come from renewable raw materials (iPSCs) and can produce large doses of drugs at once, iNK cells represent a "spot" cell source for immunotherapy.
iNK cells enhance the efficacy of immunosuppressants, which has great potential to make "cold" tumors "hot".
: 1 s Frank Cichocki, Ryan Bjordahl, Svetlana Gaidarova et al. iPSC-derived NK cells maintain high cytotoxicity and enhance in vivo tumor control in concert with T cells and anti-PD-1 therapy. Science Translational Medicine (2020)