Adoptive transfer of ex vivo expanded gamma delta T cells targeting osteolytic cancer in the bone

Abstract

Bone metastases occur in more than 75% of patients with advanced breast cancer. Cancer in bone is associated with bone destruction and is responsible for high levels of morbidity and mortality but is notoriously difficult to treat. Bone destruction is also the primary cause of morbidity in patients with primary bone cancer, such as osteosarcoma, with metastatic spread to the lungs correlating with poor survival. Therefore, clearly new therapies are desperately required to target cancers in the bone. This study explored the therapeutic potential of gamma delta (Vγ9Vδ2) T cell based adoptive transfer using animal models of osteolytic breast cancer and osteosarcoma. Cytotoxic Vγ9Vδ2 T cells were expanded ex vivo from peripheral blood using IL-2 and zoledronic acid (ZOL). In vitro, expanded Vγ9Vδ2 T cells were cytotoxic against a panel of breast cancer and osteosarcoma cell lines and pre-treatment with ZOL sensitised all cancer cells to rapid killing by Vγ9Vδ2 T cells. Adoptive transfer of fluorescently labelled ex vivo expanded Vγ9Vδ2 T cells into NOD/SCID mice localised to cancer lesions in bone. Multiple infusions of Vγ9Vδ2 T cells reduced breast cancer growth, but had no effect on osteosarcoma growth in the bone marrow. However, in both cases, ZOL pre-treatment potentiated the anti-cancer efficacy of Vγ9Vδ2 T cells in bone, protected the bone from cancer-induced osteolysis and decreased the incidence of pulmonary metastases. Collectively these studies suggest this treatment regimen to be an effective immunotherapeutic approach for the treatment of primary and metastatic bone cancers.