From iPSC to manufactured iNK cells using CombiCult® screening platform

Area of Science:

• Immunology
• Stem Cell Biology
• Biotechnology

Background:

• Allogeneic cell-based immunotherapies, particularly those derived from pluripotent stem cells, hold significant therapeutic potential for oncological, autoimmune, and viral diseases.
• Current discovery platforms for induced pluripotent stem cell (iPSC)-derived cell therapies face challenges in translating to scalable manufacturing processes.

Purpose of the Study:

• To identify novel, manufacturing-ready, feeder-free protocols for generating mature, functional NK cells from human iPSCs.
• To optimize the production of iPSC-derived NK (iNK) cells for therapeutic applications.

Main Methods:

• Utilized a high-throughput combinatorial screening platform (CombiCult®) to discover differentiation protocols.
• Validated seven CombiCult®-derived protocols for iNK cell generation.
• Translated successful protocols to a Stirred Tank Bioreactor (STR) system for scalable production.

Main Results:

• Successfully generated highly cytotoxic, phenotypically mature iNK cells comparable to donor-derived NK cells.
• Achieved a 10-fold increase in iNK cell productivity (from ~20 to ~190 iNK cells per starting iPSC) after translation to STR systems.
• Confirmed that iNK cells retain mature transcriptomic signatures post-bioreactor production.

Conclusions:

• The developed three-dimensional, bead-based screening approach facilitates seamless translation to bioreactor-based production.
• The resulting iNK cells exhibit high cytotoxic activity against various cancer types, demonstrating their therapeutic potential.
• This scalable manufacturing process enhances the feasibility of iPSC-derived NK cell therapies.