Zoledronate Enhances the Cytotoxicity of Gamma Delta T Cell Immunotherapy in an Orthotopic Mouse Model of Osteolytic Osteosarcoma

Aneta Zysk, Mark Denichilo, Irene Zinonos, Shelley Hay, Vasilios Liapis, Vladimir Ponomarev, Andrew Zannettino, Andreas Evdokiou, Vasilios Panagopoulos

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Objective: Osteosarcoma is the most common primary tumor of the bone, predominantly affecting children and adolescents. While localized osteosarcoma can be readily treated with the use of pre-operative chemotherapy in combination with surgery, patients who develop metastatic disease and tumor-induced osteolysis continue to have a poor prognosis. Many cancer cells express tumor-specific antigens, rendering them vulnerable to immune effector T cell killing. There is increasing evidence that highly cytotoxic gamma delta (Vγ9Vδ2) T cells together with the bone anti-resorptive drug zoledronate may hold significant clinical benefit in the treatment of a variety of tumor types.
Methods: Ex vivo expanded Vγ9Vδ2 T cells were used to assess effector-mediated killing of osteosarcoma cells (BTK-143 and K-HOS) in response to zoledronate pre-treatment. An orthotopic mouse model of osteolytic osteosarcoma was used to verify Vγ9Vδ2 T cell cytotoxicity in combination with zoledronate on tumor growth, osteolysis and metastasis.
Results: Pre-treatment of osteosarcoma cells with zoledronate enhanced Vγ9Vδ2 T cell rapid killing compared to untreated cells in vitro via blockade of the mevalonate pathway. When adoptively transferred into osteosarcoma bearing NOD/SCID mice in vivo, Vγ9Vδ2 T cells in combination with zoledronate potentiated the anti-cancer efficacy of Vγ9Vδ2T cells and inhibited tumor induced osteolysis. Importantly, Vγ9Vδ2 T cells alone reduced both the incidence and burden of lung metastases.
Conclusion: This study demonstrated the dual-action of zoledronate to enhance the immunogenicity of osteosarcoma cells to Vγ9Vδ2 T cell cytotoxicity and provide protection against tumor-induced osteolysis.
Original languageEnglish
JournalJournal of Cancer Science & Therapy
Publication statusPublished or Issued - 12 Sep 2018


  • Gamma delta T cell
  • immunotherapy
  • osteolysis
  • Osteosarcoma
  • Zoledronte

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