From iPSC to manufactured iNK cells using CombiCult® screening platform

Background Allogeneic cell-based immunotherapies generated from pluripotent stem cells show considerable promise for the treatment of oncological, autoimmune, and viral diseases, however discovery platforms for induced pluripotent stem cell (iPSC)-derived cell therapies do not translate well to scalable manufacturing platforms. Methods We applied a high-throughput combinatorial screening platform (CombiCult®) to identify novel, manufacturing-ready, feeder-free protocols for the generation of mature, functional NK cells from human iPSCs. Results We validated seven CombiCult®-derived differentiation protocols for the production of highly cytotoxic, phenotypically mature iPSC-derived NK (iNK) cells, which are comparable to donor-derived NK cells. Translation to a Stirred Tank Bioreactor (STR) system resulted in a 10x increase in productivity, from ∼20 to ∼190 iNK cells per starting iPSC. iNK cells demonstrate mature transcriptomic signatures, retained after translation to bioreactor-based production. Conclusion The three-dimensional, bead-based screening approach enables seamless translation to bioreactor-based production of iNK cells exhibiting high cytotoxic activity against a range of cancer cell types.