title: Adoptive transfer of ex vivo expanded Vγ9Vδ2 T cells in combination with zoledronic acid inhibits cancer growth and limits osteolysis in a murine model of osteolytic breast cancer.
abstract: Bone metastases occur in over 75% of patients with advanced breast cancer and are responsible for high levels of morbidity and mortality. In this study, ex vivo expanded cytotoxic Vγ9Vδ2 T cells isolated from human peripheral blood were tested for their anti-cancer efficacy in combination with zoledronic acid (ZOL), using a mouse model of osteolytic breast cancer. In vitro, expanded Vγ9Vδ2 T cells were cytotoxic against a panel of human breast cancer cell lines, and ZOL pre-treatment further sensitised breast cancer cells to killing by Vγ9Vδ2 T cells. Vγ9Vδ2 T cells adoptively transferred into NOD/SCID mice localised to osteolytic breast cancer lesions in the bone, and multiple infusions of Vγ9Vδ2 T cells reduced tumour growth in the bone. ZOL pre-treatment potentiated the anti-cancer efficacy of Vγ9Vδ2 T cells, with mice showing further reductions in tumour burden. Mice treated with the combination also had reduced tumour burden of secondary pulmonary metastases, and decreased bone degradation. Our data suggests that adoptive transfer of Vγ9Vδ2 T cell in combination with ZOL may prove an effective immunotherapeutic approach for the treatment of breast cancer bone metastases.
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Aneta
authors.initials: A
authors.lastname: Zysk
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Mark O
authors.initials: MO
authors.lastname: DeNichilo
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Panagopoulos
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Irene
authors.initials: I
authors.lastname: Zinonos
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Liapis
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Shelley
authors.initials: S
authors.lastname: Hay
authors.affiliation: Discipline of Surgery, Breast Biology Cancer Unit, Basil Hetzel Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Wendy
authors.initials: W
authors.lastname: Ingman
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Centre, New York, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ponomarev
authors.affiliation: Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Gerald
authors.initials: G
authors.lastname: Atkins
authors.affiliation: Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Findlay
authors.affiliation: School of Medical Sciences, Myeloma Research Laboratory Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Faculty of Health Science, University of Adelaide, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zannettino
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute, University of Adelaide, Adelaide, South Australia, Australia. Electronic address: andreas.evdokiou@adelaide.edu.au.
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D008213:Lymphocyte Activation; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010014:Osteolysis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D010641:Phenotype; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000077211:Zoledronic Acid
keywords: Bisphosphonate; Immunotherapy; Metastasis; Osteoclast; Tumour associated macrophage