title: A combination of an anti-SLAMF6 antibody and ibrutinib efficiently abrogates expansion of chronic lymphocytic leukemia cells.
abstract: The signaling lymphocyte activation molecule family [SLAMF] of cell surface receptors partakes in both the development of several immunocyte lineages and innate and adaptive immune responses in humans and mice. For instance, the homophilic molecule SLAMF6 (CD352) is in part involved in natural killer T cell development, but also modulates T follicular helper cell and germinal B cell interactions. Here we report that upon transplantation of a well-defined aggressive murine B220+CD5+ Chronic Lymphocytic Leukemia (CLL) cell clone, TCL1-192, into SCID mice one injection of a monoclonal antibody directed against SLAMF6 (αSlamf6) abrogates tumor progression in the spleen, bone marrow and blood. Similarly, progression of a murine B cell lymphoma, LMP2A/λMyc, was also eliminated by αSlamf6. But, surprisingly, αSLAMF6 neither eliminated TCL1-192 nor LMP2A/λMyc cells, which resided in the peritoneal cavity or omentum. This appeared to be dependent upon the tumor environment, which affected the frequency of sub-populations of the TCL1-192 clone or the inability of peritoneal macrophages to induce Antibody Dependent Cellular Cytotoxicity (ADCC). However, co-administering αSlamf6 with the Bruton tyrosine kinase (Btk) inhibitor, ibrutinib, synergized to efficiently eliminate the tumor cells in the spleen, bone marrow, liver and the peritoneal cavity. Because an anti-human SLAMF6 mAb efficiently killed human CLL cells in vitro and in vivo, we propose that a combination of αSlamf6 with ibrutinib should be considered as a novel therapeutic approach for CLL and other B cell tumors.
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Burcu
authors.initials: B
authors.lastname: Yigit
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Halibozek
authors.affiliation: Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Shih-Shih
authors.initials: SS
authors.lastname: Chen
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: O'Keeffe
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Arnason
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Avigan
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Italy.
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Atul
authors.initials: A
authors.lastname: Bhan
authors.affiliation: Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Osman
authors.initials: O
authors.lastname: Cen
authors.affiliation: Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Longnecker
authors.affiliation: Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Ninghai
authors.initials: N
authors.lastname: Wang
authors.affiliation: Immunology Unit, Department of Cell Biology, Immunology and Neurosciences, Medical School, University of Barcelona, Barcelona, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Engel
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D010880:Piperidines; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D000071176:Signaling Lymphocytic Activation Molecule Family / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C000604060:SLAMF6 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family; C000604063:Slamf6 protein, mouse; C551803:ibrutinib; D000225:Adenine
keywords: BCR; CLL; SLAMF6; TCL1-192; ibrutinib