P1-13-03: Zoledronic Acid Induces an Immune Response in Breast Cancer Patients through Stimulation of Central Memory and Effector Memory gamma/delta T-Cells.
Authors: Hamilton EP , Hobeika AC , Lyerly HK , Owzar K , Rocha G , Kimmick GG , Marcom PK , Peppercorn JM , Morse MA , Blackwell KL 
Published: June 2012

Abstract
Background Zoledronic acid (ZA) in combination with endocrine therapy (ET) and ovarian ablation (OA) reported a DFS advantage in premenopausal women with early stage breast cancer (EBC) in ABCSG-12. Emerging evidence from pre-clinical studies suggests that ZA increases gamma/delta T-cells (GDT), an immune cell population with anti-tumor activity. This study examined immune responses to a single dose of ZA in patients with either EBC or metastatic breast cancer (MBC) through sequential measurement of T-cells and immune regulatory cytokines.
Methods Women with EBC/MBC, both pre- and post-menopausal, and no history of immune dysregulation who were scheduled to receive their first-ever dose of ZA were eligible. Blood was collected for serum and blood mononuclear cells at Day 0 (pre-ZA), Day 1 (18-48 hours post-ZA), Day 7 (Day 5–8 post ZA), and Day 28 (Day 25–32 post-ZA). GDT populations and cytokine responses were assayed using flow cytometry and multi-analyte profiling beads (Luminex), respectively. Relative changes from baseline at days 1, 7 and 18 were quantified using log-ratios and analyzed using the Wilcoxon signed-rank test.
Results 24 patients were enrolled from Oct 2009 to Mar 2011. 75% of pts had MBC, and 25% had EBC, while 75% received ET, 17% received chemo (C), and 8% received other. Following ZA administration, a transient decrease in total GDT (CD3+/Vdelta2+) at Day 1 was seen (p&lt;0.0003). This was followed by an increase in both effector (CD3+/Vdelta2+/CD45RA-/CD27-) (P&lt;0.005) and central memory GDT (CD3+/Vdelta2+/CD45RA-/CD27+)(P&lt;0.007) and a decrease in naïve GDT (CD3+/Vdelta2+/CD45RA+/CD27+) (P&lt;0.006) at day 7; total GDT unchanged. The change in naïve GDT and effector GDT appeared to persist at Day 28. IL-1RA (P&lt;0.003), IL-12 (P&lt;0.0005), MIP-1b (P&lt;0.0005), IP-10 (P&lt;0.00002) and MIG (P&lt;0.00006), were increased at Day 1 compared to baseline. By day 28, these cytokine levels returned to baseline except IP-10 which appeared to remain elevated. In this limited patient sample, no differences were observed between patients with EBC vs. MBC, ET vs. C, and pre- vs. post-menopausal.
Conclusion: ZA appears to induce a highly significant change in immune effector cells in both EBC and MBC patients receiving ET or C. Mobilization of anti-tumor T-cells with a decrease in total (non-specific) GDT followed by a marked increase post-ZA in specific central and effector memory GDT was seen at day 7. Significant increases in cytokine levels, like those seen in this study including those associated with Th1 responses or cell-mediated immunity, as well as IL-12 levels, have been implicated in direct anti-tumor activity. This apparent cytokine and cellular response to ZA could offer an important biologic mechanism for the anti-cancer activity reported in ABCSG-12. Further studies should be performed to determine which subsets of BC patients might achieve these described immune benefits from ZA.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-13-03.