15353-j-veluchamy

120 | Chapter 5 Abstract Therapeutic monoclonal antibodies (mAbs) against the epidermal growth factor receptor (EGFR) act by inhibiting EGFR downstreamsignaling and by eliciting anNK cell-mediated anti- tumor response. The IgG 1 mAb cetuximab has been used for treatment of RAS wt metastatic colorectal cancer (mCRC) patients, showing limited efficacy. In the present study, we address the potential of adoptive NK cell therapy to overcome these limitations investigating two allogeneic NK cell products, i.e. activated peripheral blood NK cells (A-PBNK) and umbilical cord blood stem cell derived NK cells (UCB-NK). While cetuximab monotherapy was not effective against EGFR - RAS wt , EGFR + RAS mut and EGFR + BRAF mut cells, A-PBNK were able to initiate lysis of EGFR + colon cancer cells irrespective of RAS or BRAF status. Cytotoxic effects of A-PBNK (but not UCB-NK) were further potentiated significantly by coating EGFR + colon cancer cells with cetuximab. Of note, a significantly higher cytotoxicity was induced by UCB- NK in EGFR - RAS wt (42 ± 8% versus 67 ± 7%), EGFR + RAS mut (20 ± 2% versus 37 ± 6%) and EGFR + BRAF mut (23 ± 3% versus 43 ± 7%) colon cancer cells compared to A-PBNK and equaled the cytotoxic efficacy of the combination of A-PBNK and cetuximab. The anti-tumor efficacy of UCB-NK cells against cetuximab resistant human EGFR + RAS mut colon cancer cells was further confirmed in an in vivo preclinical mouse model where UCB-NK showed enhanced anti-tumor cytotoxicity against colon cancer independent of EGFR and RAS status. As UCB- NK have been proven safe in a recently conducted phase I clinical trial in acute myeloid leukemia, a fast translation into clinical proof of concept for mCRC could be considered.