15353-j-veluchamy

5 Towards UCB-NK cells treatment in colorectal cancer | 129 tumor load or improvement in survival, recapitulating the clinical data from patients bearing RAS mut CRC tumors. Unexpectedly, we failed to demonstrate superior in vivo anti- tumor effects or survival when we combined the transfer of UCB-NK cells with cetuximab infusions. The underlying causes for this latter finding remain obscure but may be related to sub-optimal in vivo upregulation of CD16 in the used mouse model or CD16 polymorphisms in the employed batch of UCB-NK cells, both of which could have hampered efficient ADCC. Taken together, UCB-NK cells displayed significant anti-tumor efficacy, suggesting a potential beneficial role for UCB-NK cells in the treatment of RAS and BRAF mutant CRC. As an important present limitation in treating mCRC patients is related to resistance to anti-EGFR mAbs, adoptive transfer of cytolytic UCB-NK cells could thus constitute a viable treatment option. Our in vitro and in vivo data demonstrating that adoptive transfer of UCB-NK cells alone was as effective as the combination of A-PBNK and cetuximab raises the possibility that UCB-NK administration could obviate the use of cetuximab in RAS wt mCRC. Furthermore, UCB-NK can also lyse RAS mut CRC cells at levels higher than those observed with A-PBNK. Importantly, allogeneic NK cells have demonstrated their safety in clinical trials in several solid tumors 39, 40 , and more specifically, the UCB-NK cell product used in our experiments was found to be safe in a clinical trial in Acute Myeloid Leukemia (AML) patients 41 . Several features make UCB-NK attractive for further clinical development. For example, our GMP based expansion and differentiation protocol reproducibly resulted in a more than 10,000-fold expansion of cytotoxic UCB-NK cells from single donors. Furthermore, UCB- NK cells can be supplied as an “off the shelf” product, stored in large aliquots facilitating multiple infusions. Also, the low immunogenicity by UCB grafts prevents adverse reactions that are prevalent after repeated PBNK transfusions 42 . In this respect, it is relevant to mention that while NK cells in general are often inhibited by recognition of MHC class I molecules on the surface of tumor cells, UCB-NK display relatively low levels of Killer cell - immunoglobulin like receptors (KIRs) supporting their ability to effectively lyse MHC class I expressing tumor cells 29 . Finally, the ability of UCB-NK cells to proliferate and home to liver, lungs, spleen and bone-marrow after adoptive transfer has been previously demonstrated in NSG mice 38 , though additional studies are required to determine whether UCB-NK cells have a similar migratory pattern upon adoptive transfer in solid tumor patients. Together, these features and observations provide UCB-NK cells with several unique advantages for further development as a universal NK cell platform. Considering the size and heterogeneity of the tumor mass in advanced stages of CRC and other types of cancer, UCB-NK may not provide a sufficient therapeutic effect as a single agent. However, rational combinations of UCB-NK cells with existing drugs or drugs that are in clinical development can be envisioned to further increase their efficacy.