title: Adoptive immunotherapy of epithelial ovarian cancer with Vγ9Vδ2 T cells, potentiated by liposomal alendronic acid.
abstract: Adoptive immunotherapy using γδ T cells harnesses their natural role in tumor immunosurveillance. The efficacy of this approach is enhanced by aminobisphosphonates such as zoledronic acid and alendronic acid, both of which promote the accumulation of stimulatory phosphoantigens in target cells. However, the inefficient and nonselective uptake of these agents by tumor cells compromises the effective clinical exploitation of this principle. To overcome this, we have encapsulated aminobisphosphonates within liposomes. Expanded Vγ9Vδ2 T cells from patients and healthy donors displayed similar phenotype and destroyed autologous and immortalized ovarian tumor cells, following earlier pulsing with either free or liposome-encapsulated aminobisphosphonates. However, liposomal zoledronic acid proved highly toxic to SCID Beige mice. By contrast, the maximum tolerated dose of liposomal alendronic acid was 150-fold higher, rendering it much more suited to in vivo use. When injected into the peritoneal cavity, free and liposomal alendronic acid were both highly effective as sensitizing agents, enabling infused γδ T cells to promote the regression of established ovarian tumors by over one order of magnitude. Importantly however, liposomal alendronic acid proved markedly superior compared with free drug following i.v. delivery, exploiting the "enhanced permeability and retention effect" to render advanced tumors susceptible to γδ T cell-mediated shrinkage. Although folate targeting of liposomes enhanced the sensitization of folate receptor-α(+) ovarian tumor cells in vitro, this did not confer further therapeutic advantage in vivo. These findings support the development of an immunotherapeutic approach for ovarian and other tumors in which adoptively infused γδ T cells are targeted using liposomal alendronic acid.
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre, London SE1 9RT, United Kingdom;
authors.forename: Ana C
authors.initials: AC
authors.lastname: Parente-Pereira
authors.affiliation: Shaare Zedek Medical Center, Department of Oncology, Jerusalem 91031, Israel;
authors.forename: Hilary
authors.initials: H
authors.lastname: Shmeeda
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre, London SE1 9RT, United Kingdom; Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London W12 0HS, United Kingdom;
authors.forename: Lynsey M
authors.initials: LM
authors.lastname: Whilding
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre, London SE1 9RT, United Kingdom;
authors.forename: Constantinos P
authors.initials: CP
authors.lastname: Zambirinis
authors.affiliation: Centre for Molecular Oncology and Imaging, John Vane Science Centre, Institute of Cancer, Barts and the London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom;
authors.forename: Julie
authors.initials: J
authors.lastname: Foster
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre, London SE1 9RT, United Kingdom;
authors.forename: Sjoukje J C
authors.initials: SJ
authors.lastname: van der Stegen
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre, London SE1 9RT, United Kingdom;
authors.forename: Richard
authors.initials: R
authors.lastname: Beatson
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre, London SE1 9RT, United Kingdom;
authors.forename: Tomasz
authors.initials: T
authors.lastname: Zabinski
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London W12 0HS, United Kingdom;
authors.forename: Nancy
authors.initials: N
authors.lastname: Brewig
authors.affiliation: Centre for Molecular Oncology and Imaging, John Vane Science Centre, Institute of Cancer, Barts and the London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom;
authors.forename: Jane K
authors.initials: JK
authors.lastname: Sosabowski
authors.affiliation: Centre for Molecular Oncology and Imaging, John Vane Science Centre, Institute of Cancer, Barts and the London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom;
authors.forename: Stephen
authors.initials: S
authors.lastname: Mather
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London W12 0HS, United Kingdom;
authors.forename: Sadaf
authors.initials: S
authors.lastname: Ghaem-Maghami
authors.affiliation: Shaare Zedek Medical Center, Department of Oncology, Jerusalem 91031, Israel; Hebrew University School of Medicine, Jerusalem 91905, Israel;
authors.forename: Alberto
authors.initials: A
authors.lastname: Gabizon
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre, London SE1 9RT, United Kingdom; Department of Immunology, Barnet Hospital, Barnet, Hertfordshire EN5 3DJ, United Kingdom; and Department of Clinical Immunology and Allergy, King's College Hospital National Health Service Foundation Trust, London SE5 9RS, United Kingdom john.maher@kcl.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Maher
mesh_terms: D019386:Alendronate / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D002277:Carcinoma / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D007114:Immunization; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D008081:Liposomes; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521523:T-cell receptor Vdelta2, human; C521522:T-cell receptor Vgamma9, human; D019386:Alendronate