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106 | Chapter 4 From the data obtained using primary colon cancer cells as target cells, it was evident that NK cells could kill primary tumor cells and that while cetuximab monotherapy was effective only in RAS wt tumor samples, NK cell cytotoxicity could be increased by cetuximab irrespective of RAS mutational status, making these primary tumor cells ideal targets for observing the potentiating effect of cetuximab induced ADCC on NK cell natural cytotoxicity against EGFR low primary tumors (Figure 5A and B) 32 . Menon et al, showed that HLA Class-I was down-regulated in 72% of patients with CRC 33 , thereby making the majority of CRC cells highly susceptible to NK cell mediated killing. The clinical relevance of FcR polymorphisms and NK ADCC influencing the treatment of RAS mutated mCRC patients have been studied by Bibeau and his team reporting disease stabilization in 10 out of 27 patients with RAS mutant tumors following cetuximab monotherapy 34 . In accordance with their findings, our in vitro data support the notion that NK cell ADCC could exert relevant cytotoxicity in this setting. Of note, clinical studies point out that most of the cancer patients present with an imbalance in their immune subsets, which tilts the balance towards tumor progression. Additionally, adoptive transfer of ex vivo activated autologous NK cells has failed to demonstrate clinical responses in mCRC patients 35-37 . Combining all these factors, allogeneic NK cell transplantation might be the preferred choice to treat solid tumors and hence support the immune systemof the patient with sufficient cytolytic NK cells tomount a strong anti-tumor attack. Furthermore, adoptive transfer of large number of allogeneic cytolytic NK cells could be an option to strengthen tumor eradication in combination with cetuximab on RAS mutated tumors via ADCC. Allogeneic NK cell therapies are widely explored over recent years due to their cytotoxic nature providing a window to induce a HLA-mismatch setting to efficiently target tumor cells 38 . Different sources of allogeneic NK cell products are currently in use for clinical applications from adult PBNK cells 39 , umbilical cord blood stem cell derived NK cells 40,41 and engineered NK cell lines 42 . Adoptive transfer of large number of allogeneic NK cells could repopulate the immune system, providing sufficient numbers of cytolytic NK cells to support ADCC with cetuximab. An increased number of NK cells in the blood stream could also target circulating tumor cells preventing metastasis and with a further role in decreasing or removing residual tumor load 43 . Further clinical confirmation of NK cell adoptive transfer advantages in combination with cetuximab on RAS mut or BRAF mut mCRC tumors is warranted and calls for clinical trials. In conclusion, the ability of functional NK cells to overcome the limitations of anti-EGFR therapy has been clearly demonstrated. The availability of allogeneic NK cells, combined with cetuximab could pave the way to demonstrate the therapeutic efficacy of this approach in patients with RAS mut , BRAF mut and EGFR low/- CRC.