Background: CD3+ γδ+ T cells comprise 2 to 5% of the circulating T cells. Vγ9Vδ2+ cells are the dominant circulating γδ T cell and recognize non-peptide phosphoantigens and stress-associated NKG2D ligands expressed on malignant cells. Strategies that incorporate the tumoricidal properties of γδ T cells represent a promising means of harnessing the innate immune system to treat malignancies including neuroblastoma (NB). Indeed, γδ T cells from both healthy volunteers and NB patients exert a potent cytotoxic effect on NB cell lines and autologous NB in vitro following expansion and activation in culture. Vγ9Vδ2+ cells can also be induced to proliferate in vivo. By blocking farnesyl pyrophosphate synthase in the mevalonate pathway of isoprenoid synthesis in monocytes, the aminobisphosphonate zoledronic acid (ZOL) promotes the accumulation of isopentenyl pyrophosphate which is sensed by γδ T cells. IL-2 is also required for robust expansion γδ T cells. Methods: The trial is a prospective, non-randomized trial that assesses two dose levels of recombinant IL-2 (aldesleukin) in combination with ZOL. To be eligible for the study patients must be 2 to 21 years of age with refractory neuroblastoma with no known curative therapeutic options. Patients must also have adequate organ function and performance status. ZOL is given intravenously on day 1, and aldesleukin is given subcutaneously on days 1 to 5 and 15 to 19 of every 28 day cycle. The single-institution study is being conducted at the University of Alabama at Birmingham. Correlative studies include evaluating the absolute count, phenotype, activation, and effector/memory progression of γδ T cells by flow cytometry and the biological function of autologous expanded/activated γδ T cells by in vitro cytotoxicity assays employing established human NB cell lines. In order to determine the ability of in vivo expanded/activated γδ T cells to infiltrate NB tissue, bone marrow core biopsies obtained before and after the first course of therapy from patients with bone marrow metastasis are assayed for T cell infiltration by immunohistochemistry. The study has currently enrolled 1 of the planned 6 patients. Clinical trial information: NCT01404702.