Research Area: Cell engineering & therapy
Development Stage: Discovery
Goal: Reveal choice in NK cell therapy by identifying differences resulting from subtle gene edits
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Polyfunctionality and PSI underscore significant differences between gene-edited KO- iPSC-NK cells and wild type cells. The CISH-/- knock- out cells showed enrichment of polyfunctional cell subsets compared to the wild type samples (left).
Similarly, the PSI of the knock-out cells is substantially (10x) higher than of the wild type (right) indicating that CIS plays a key role in regulating NK cell activation-induced exhaustion and that Notch activation prevents this exhaustion and enables production of functionally hyperactive NK cells.1
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At day 35, CISH-/- iPSC-NK demonstrate better anti-tumor activity in vivo. NSG mice were inoculated with the human leukemia cell line Molm13, expressing the firefly luciferase gene. One day after tumor transplant, mice were either left untreated or were treated with either WT-iPSC-NK or KO-iPSC-NK cells.
35 days after inoculation, two out of four untreated mice (left) had died and the other two showed significant tumor load, WT-iPSC- NK mice (middle) showed substantial tumor growth while in CISH KO-iPSC-NK mice (right), tumor growth is nearly absent. These results are consistent with 10x higher in vitro PSI of CISH KO-iPSC-NK cells relative to wild type cells presented in the previous figure.1