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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.

Publication ,  Journal Article
Hamilton, EP; Hobeika, AC; Lyerly, HK; Owzar, K; Rocha, G; Kimmick, GG; Marcom, PK; Peppercorn, JM; Morse, MA; Blackwell, KL
Published in: Cancer Research
December 15, 2011

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<0.0003). This was followed by an increase in both effector (CD3+/Vdelta2+/CD45RA-/CD27-) (P<0.005) and central memory GDT (CD3+/Vdelta2+/CD45RA-/CD27+)(P<0.007) and a decrease in naïve GDT (CD3+/Vdelta2+/CD45RA+/CD27+) (P<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<0.003), IL-12 (P<0.0005), MIP-1b (P<0.0005), IP-10 (P<0.00002) and MIG (P<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.

Duke Scholars

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

December 15, 2011

Volume

71

Issue

24_Supplement

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Hamilton, E. P., Hobeika, A. C., Lyerly, H. K., Owzar, K., Rocha, G., Kimmick, G. G., … Blackwell, K. L. (2011). 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. Cancer Research, 71(24_Supplement). https://doi.org/10.1158/0008-5472.sabcs11-p1-13-03
Hamilton, E. P., A. C. Hobeika, H. K. Lyerly, K. Owzar, G. Rocha, G. G. Kimmick, P. K. Marcom, J. M. Peppercorn, M. A. Morse, and K. L. Blackwell. “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.Cancer Research 71, no. 24_Supplement (December 15, 2011). https://doi.org/10.1158/0008-5472.sabcs11-p1-13-03.
Hamilton EP, Hobeika AC, Lyerly HK, Owzar K, Rocha G, Kimmick GG, et al. 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. Cancer Research. 2011 Dec 15;71(24_Supplement).
Hamilton, E. P., et al. “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.Cancer Research, vol. 71, no. 24_Supplement, American Association for Cancer Research (AACR), Dec. 2011. Crossref, doi:10.1158/0008-5472.sabcs11-p1-13-03.
Hamilton EP, Hobeika AC, Lyerly HK, Owzar K, Rocha G, Kimmick GG, Marcom PK, Peppercorn JM, Morse MA, Blackwell KL. 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. Cancer Research. American Association for Cancer Research (AACR); 2011 Dec 15;71(24_Supplement).

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

December 15, 2011

Volume

71

Issue

24_Supplement

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis