title: In VivoEfficacy of Umbilical Cord Blood Stem Cell-Derived NK Cells in the Treatment of Metastatic Colorectal Cancer.
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 IgG1mAb cetuximab has been used for treatment of RASwtmetastatic 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+BRAFmutcells, 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+RASmutcolon cancer cells was further confirmed in anin vivopreclinical 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.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands; Glycostem Therapeutics, Oss, Netherlands.
authors.forename: John P
authors.initials: JP
authors.lastname: Veluchamy
authors.affiliation: Innate Immunity Unit, Institut Pasteur, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1223, Paris, France; Université Paris-Sud (Paris-Saclay), Paris, France.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lopez-Lastra
authors.affiliation: Glycostem Therapeutics , Oss , Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Spanholtz
authors.affiliation: Glycostem Therapeutics , Oss , Netherlands.
authors.forename: Fenna
authors.initials: F
authors.lastname: Bohme
authors.affiliation: Glycostem Therapeutics , Oss , Netherlands.
authors.forename: Nina
authors.initials: N
authors.lastname: Kok
authors.affiliation: Department of Pathology, VU University Medical Center , Amsterdam , Netherlands.
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam , Amsterdam , Netherlands.
authors.forename: Henk M W
authors.initials: HM
authors.lastname: Verheul
authors.affiliation: Innate Immunity Unit, Institut Pasteur, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1223, Paris, France.
authors.forename: James P
authors.initials: JP
authors.lastname: Di Santo
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam , Amsterdam , Netherlands.
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam , Amsterdam , Netherlands.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: van der Vliet
keywords: A-PBNK; EGFR; RAS mutation; UCB-NK; allogeneic NK cell immunotherapy; cetuximab; metastatic colorectal cancer