Abstract
Therapeutic monoclonal antibodies against the epidermal growth factor receptor (EGFR) act by inhibiting EGFR downstream signaling and by eliciting a natural killer (NK) cell-mediated antitumor response. The IgG1 mAb cetuximab has been used for treatment of RASwt 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., allogeneic 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− RASwt, EGFR+ RASmut, and EGFR+ BRAFmut 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−RASwt (42 ± 8 versus 67 ± 7%), EGFR+ RASmut (20 ± 2 versus 37 ± 6%), and EGFR+ BRAFmut (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 antitumor efficacy of UCB-NK cells against cetuximab-resistant human EGFR+ RASmut colon cancer cells was further confirmed in an in vivo preclinical mouse model where UCB-NK showed enhanced antitumor 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.
Highlights
Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths in the world [1]
Though natural killer (NK) cells of metastatic colorectal cancer (mCRC) patients were capable of antibody-dependent cell-mediated cytotoxicity (ADCC), as evidenced by significant increases in degranulation when target cells were coated with cetuximab (P < 0.05), levels were still low compared to those observed in healthy volunteers (Figure 1B)
Measurements of NK cell degranulation reflected equivalent trends observed for tumor cell lysis (Figures 2D,E,F). These results show that umbilical cord blood stem cell-derived NK cells (UCB-NK) cells have superior cytotoxic efficacy over activated peripheral blood NK cells (A-PBNK) cells against cetuximab-resistant colon cancer cells in vitro
Summary
Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths in the world [1]. Treating mCRC with UCB-NK Cells and cetuximab, are approved for the treatment of patients with advanced CRC either in combination with chemotherapy or, as monotherapy, in chemorefractory conditions [4]. Cetuximab (CET) and panitumumab block the interaction between EGFR and its ligands, inhibiting the downstream RAS-signaling cascade and tyrosine kinase activation [5]. Mutations in tumor suppressor genes and proto-oncogenes in EGFR signaling pathways, such as in RAS, BRAF, and PIK3CA, are common in patients with CRC. These mutations represent a poor prognostic marker and render anti-EGFR mAbs ineffective, leaving 42% of the chemorefractory mCRC population without this standard treatment option [6, 7]
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