a Peripheral blood cells serve as a primary source to generate iPSC lines by non-integrating delivery of reprogramming transcription factors. 
b Generation of iPSC-derived off-the-shelf tumor-specific T cells. iPSCs are genetically modified to bear desirable immunotherapeutic properties. The expression of TCR and HLA is knocked out or silenced to prevent alloreactivity and graft rejection respectively. HLA-E/G molecules can be overexpressed to avoid NK cell–mediated transplant rejection, whereas antigen-specific TCR/CARs can direct anti-tumor activity. Further, introduction of the expression of immune receptors, cytokines, chemokines, or other immune regulatory factors may enhance anti-tumor function. Genome-edited master iPSC lines are differentiated under GMP-grade conditions to fully functional histocompatible tumor-targeting T cells accessible to all patients regardless of their HLA haplotype

The advancement of adoptive cell immunotherapy and the impressive clinical outcomes obtained targeting hematologic malignancies with CAR-T cells dictate for further developments towards a broader use of cellular therapeutics for more patients and more types of malignancy. The advent of iPSC technology provides new perspectives for the manufacturing of customized, tumor-targeting T/NK cells, with improved immunotherapeutic properties and the potential of universal “off-the-shelf” use.

Rapid progress in the field of lymphoid differentiation of iPSC has brought the clinical application of iPSC-derived adoptive immunotherapy from theory to reality. Indeed, the first clinical trial testing an off-the-shelf, iPSC-derived NK cell product against advanced solid tumors started recruiting in 2019 (ClinicalTrials.gov Identifier: NCT03841110). In addition, the production of iPSC-derived T cells and TCR/CAR-engineered T cells is already in pre-clinical development.

Fate Therapeutics is developing TCR-less T-iPSC–derived CD19-CAR-T cells where the CD19CAR is expressed from the TCR α chain constant region (TRAC) locus, while Adaptimmune aims to develop off-the-shelf anti-tumor T cells from TCR-engineered iPSC.

However, there are still several challenges to be pre-clinically addressed before the first clinical application of iPSC-derived T cells. As mentioned above, the phenotypic and functional maturity of the generated T cell effectors has to be ensured as well as an anti-tumor potential comparable with natural T cells. Further, manufacturing protocols should be established which would allow for the efficient, GMP-grade, and clinical scale production of iPSC-derived T cell products. Finally, as with all iPSC-derived cellular products, the potential risk of malignant transformation due to contamination with undifferentiated iPSC has to be minimized, for example with the use of suicide genes such as the iC9/CID system.

Further future advances in iPSC and genome editing technologies in combination with in-depth knowledge of the fundamental mechanisms of T/NK cell function and the regulation of lymphoid development will provide the tools for the generation of iPSC-derived T/NK cell products with improved therapeutic anti-tumor function, better homing, persistence, and applicable across histocompatibility barriers.

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