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150 | Chapter 6 Tumor disruptive technology aiding NK tumor recognition NOXXON Pharma is targeting the chemokine receptor CXCL12, with the aim of increasing the sensitivity of tumor cells to drugs and immune cells. Their product NOX-A12 functions as a CXCL12 inhibitor and enables the release of CXCL12 from the surface of tumor stromal cells and blocks its interaction with cell surface receptors CXCR4 and CXCR7. This mechanism facilitated the mobilization of CXCR4 expressing tumor cells from their tissue niches to areas, where they become more easily accessible by NK cells or T cells 60,61 . Using tumor spheroids, increased mobilization of T and NK cells towards tumor cells in the tumor microenvironment was demonstrated. NOX-A12 also enhanced NK killing of obinutuzumab coated Raji cells in vitro, mediated by ADCC 62 . NK cells from iPSCs Generally applicableNK cell platforms, likeUCB-NK, are very attractive for clinical therapeutic purposes. In recent years, NK cells generated from induced pluripotent stem cells (iPSC-NK) and human embryonic stem cells (hESC-NK) have been gaining more interest as an NK cell therapeutic product. Fate Therapeutics developed a platform technology to generate NK cells from iPSC. hESC/iPSC were made into aggregates by centrifugation to form so-called embryoid bodies (spin EBs) 63 , giving rise to hematopoietic progenitor cells expressing CD34 and CD45, which were then differentiated into mature NK cells using a specific cytokine cocktail. iPSC/hESC derived NK cells were shown to express common NK cell markers, such as KIRs, CD16, NKp44, NKp46, NKG2D and TRAIL and were cytotoxic against several haematological and solid tumor cells in vitro 64,65 . In the next stage, iPSC/hESC derived NK cells were successfully expanded using IL-2 and K562-based aAPCs with membrane-bound IL-21 to generate sufficiently high numbers for clinical applications 66 . Conclusions From the information obtained from NK cell clinical trials, we conclude that adoptive transfer of allogeneic NK cells in a non-transplant setting is safe and shows early signs of clinical efficacy against haematological and certain solid tumors. Current data are mostly based on phase I clinical trials and hence it is still too early to get an overall picture of NK cell alloreactivity in different kinds of cancer. Most of the clinical studies conducted so far have used primary NK cells but with limited efficacy, pointing to the need to improve the functionality of these NK cells after their transfer to patients. The growing opportunities to augment NK cell functions have attracted several biotech companies to invest in NK cell research, spearheading NK therapy development with different innovative approaches. This also stresses the need for combining adoptive transfer of allogeneic NK cells with NK function-augmenting products to achieve a maximum anti-tumor effect. As NK cells are safe to infuse, the use of CAR-NK cells may be instrumental in providing a much safer but