title: Induction of potent NK cell-dependent anti-myeloma cytotoxic T cells in response to combined mapatumumab and bortezomib.
abstract: There is increasing evidence that some cancer therapies can promote tumor immunogenicity to boost the endogenous antitumor immune response. In this study, we used the novel combination of agonistic anti-TRAIL-R1 antibody (mapatumumab, Mapa) with low dose bortezomib (LDB) for this purpose. The combination induced profound myeloma cell apoptosis, greatly enhanced the uptake of myeloma cell apoptotic bodies by dendritic cell (DC) and induced anti-myeloma cytotoxicity by both CD8+T cells and NK cells. Cytotoxic lymphocyte expansion was detected within 24 h of commencing therapy and was maximized when myeloma-pulsed DC were co-treated with low dose bortezomib and mapatumumab (LDB+Mapa) in the presence of NK cells. This study shows that Mapa has two distinct but connected modes of action against multiple myeloma (MM). First, when combined with LDB, Mapa produced powerful myeloma cell apoptosis; secondly, it promoted DC priming and an NK cell-mediated expansion of anti-myeloma cytotoxic lymphocyte (CTL). Overall, this study indicates that Mapa can be used to drive potent anti-MM immune responses.
authors.affiliation: Cancer Immunology Research; Peter MacCallum Cancer Center ; East Melbourne, VIC, Australia ; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia ; The University of Melbourne ; Parkville, VIC, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Neeson
authors.affiliation: Cancer Immunology Research; Peter MacCallum Cancer Center ; East Melbourne, VIC, Australia ; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia.
authors.forename: Andy K
authors.initials: AK
authors.lastname: Hsu
authors.affiliation: Cancer Immunology Research; Peter MacCallum Cancer Center ; East Melbourne, VIC, Australia ; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia.
authors.forename: Yin R
authors.initials: YR
authors.lastname: Chen
authors.affiliation: Cancer Immunology Research; Peter MacCallum Cancer Center ; East Melbourne, VIC, Australia ; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia.
authors.forename: Heloise M
authors.initials: HM
authors.lastname: Halse
authors.affiliation: Cancer Immunology Research; Peter MacCallum Cancer Center ; East Melbourne, VIC, Australia ; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia.
authors.forename: Joanna
authors.initials: J
authors.lastname: Loh
authors.affiliation: Cancer Immunology Research; Peter MacCallum Cancer Center ; East Melbourne, VIC, Australia ; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia.
authors.forename: Reece
authors.initials: R
authors.lastname: Cordy
authors.affiliation: Cancer Immunology Research; Peter MacCallum Cancer Center ; East Melbourne, VIC, Australia ; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Fielding
authors.affiliation: Cancer Immunology Research; Peter MacCallum Cancer Center ; East Melbourne, VIC, Australia ; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia ; The University of Melbourne ; Parkville, VIC, Australia ; The ACRF Translational Research Laboratory; Royal Melbourne Hospital ; Parkville, VIC, Australia.
authors.forename: Joanne
authors.initials: J
authors.lastname: Davis
authors.affiliation: Cancer Immunology Research; Peter MacCallum Cancer Center ; East Melbourne, VIC, Australia ; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia.
authors.forename: Josh
authors.initials: J
authors.lastname: Noske
authors.affiliation: Cancer Immunology Research; Peter MacCallum Cancer Center ; East Melbourne, VIC, Australia ; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia ; The ACRF Translational Research Laboratory; Royal Melbourne Hospital ; Parkville, VIC, Australia.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Davenport
authors.affiliation: Cancer Immunology Research; Peter MacCallum Cancer Center ; East Melbourne, VIC, Australia ; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia ; The ACRF Translational Research Laboratory; Royal Melbourne Hospital ; Parkville, VIC, Australia.
authors.forename: Camilla A
authors.initials: CA
authors.lastname: Lindqvist-Gigg
authors.affiliation: Human Genome Sciences Inc. ; Rockville, MD, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Humphreys
authors.affiliation: Cancer Immunology Research; Peter MacCallum Cancer Center ; East Melbourne, VIC, Australia ; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia.
authors.forename: Tsin
authors.initials: T
authors.lastname: Tai
authors.affiliation: Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia ; Department of Cancer Medicine; Peter MacCallum Cancer Center ; East Melbourne, VIC, Australia.
authors.forename: H Miles
authors.initials: HM
authors.lastname: Prince
authors.affiliation: Cancer Immunology Research; Peter MacCallum Cancer Center ; East Melbourne, VIC, Australia ; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia ; The University of Melbourne ; Parkville, VIC, Australia.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
authors.affiliation: Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia ; Immunology in Cancer and Infection Laboratory; Queensland Institute of Medical Research ; Herston, QLD, Australia ; School of Medicine; University of Queensland ; Herston, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: Cancer Immunology Research; Peter MacCallum Cancer Center ; East Melbourne, VIC, Australia ; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, VIC, Australia ; The University of Melbourne ; Parkville, VIC, Australia ; The ACRF Translational Research Laboratory; Royal Melbourne Hospital ; Parkville, VIC, Australia ; Department of Clinical Hematology and Bone Marrow Transplantation; Royal Melbourne Hospital ; Parkville, VIC, Australia.
authors.forename: David S
authors.initials: DS
authors.lastname: Ritchie
keywords: T cell; dendritic cell; multiple myeloma; natural killer cell; proteasome inhibitor; tumor necrosis factor apoptosis inducing ligand and receptor