Adoptive Immunotherapy of Epithelial Ovarian Cancer with Vγ9Vδ2 T Cells, Potentiated by Liposomal Alendronic Acid

Ana C. Parente-Pereira, Hilary Shmeeda, Lynsey M. Whilding, Constantinos P. Zambirinis, Julie Foster, Sjoukje J C Van Der Stegen, Richard Beatson, Tomasz Zabinski, Nancy Brewig, Jane K. Sosabowski, Stephen Mather, Sadaf Ghaem-Maghami, Alberto Gabizon, John Maher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

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 gd T cells are targeted using liposomal alendronic acid.

Original languageEnglish
Pages (from-to)5557-5566
Number of pages10
JournalJournal of Immunology
Volume193
Issue number11
Early online date19 Nov 2014
DOIs
Publication statusPublished - 1 Dec 2014

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