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148 | Chapter 6 carcinoma when compared to activated and expanded PBNK cells 39,40 . mRNA based genetic engineering has been used to enhance migration of NK cells to tumors. Apart from gene modification, gene editing is also widely used to overexpress or knock out genes of interest to augment NK cell function. Expression of HLA-A on allogeneic NK cells leads to rejection of allogeneic NK cells by the recipient’s T and NK cells. Cooper and colleagues from Ziopharm Oncology, used zinc finger nuclease (ZFN) technology to remove HLA-A sequences from allogeneic NK cells, thus enabling these immune effector cells to escape rejection from recipient T cells. However, in that case there is yet a high probability of being attacked by endogenous NK cells targeting HLA-A negative allogeneic cells. This was further addressed by retaining HLA-B and HLA-C genes in donor NK cells 41-43 . To increase NK cell persistence in vivo, scientists at oNKo-innate identified a group of proteins called suppressor of cytokine signalling (CIS, SOCS 1-7), which negatively regulate cytokine signalling pathways. SOCS1 and SOCS3 bind to JAK1, JAK2 and TYK2 molecules and inhibit JAK activity. Similarly, CIS protein binds to JAK1, and suppresses IL-15 signalling in NK cells. It became evident from in vivo studies in mice with Cish - / - knockout NK cells that loss of CIS led to prolonged IL-15 signalling, resulting in an increased proliferation, survival and functionality of NK cells 44 . Fc optimized monoclonal antibodies The potential of NK cells to mediate ADCC with therapeutic mAbs has been well described over the years 45 . However, concerns have been voiced based on results from certain clinical trials, showing that polymorphisms in NK CD16 (V158V, V158F and F158F) could influence the efficacy of mAb treatment and ADCC 46 . To address this issue and limit the variations between different CD16 sequences, Fc glyco-engineered (defucosylated) mAbs with enhanced binding affinities to NK CD16a were developed. The Fc optimized anti-CCR4 mAb mogamulizumab 47 (Kyowa Hakko Kirin) has entered Phase III clinical testing in patients with adult T cell leukemia, emerging as the lead NK cell ADCC product to reach the market soon. Fc optimized anti-CD20 mAbs obinutuzumab (Genentech) 48 and ocaratuzumab (Mentrik Biotech, LLC) 49 are currently tested in patients with chronic lymphocytic leukemia and follicular lymphoma. Similarly, the Fc optimized anti-EGFR mAb imgatuzumab (Roche Glycart) is tested in phase I/II clinical trials for head and neck cancer and in KRAS mutant colorectal cancer 50,51 . Although Fc engineered mAbs address NK-mAb binding issues, reports of serious side effects, like from the imgatuzumab study 52 , have made the scientists rethink this strategy and call for the careful study of the advantages and disadvantages of this approach.