This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dieli, F. Articles by Hayday, A. C. Search for Related Content PubMed PubMed Citation Articles by Dieli, F. Articles by Hayday, A. C.

Targeting Human T Cells with Zoledronate and Interleukin-2 for Immunotherapy of Hormone-Refractory Prostate Cancer

¹ Dipartimento di Biopatologia e Metodologie Biomediche, and ² Section of Medical Oncology, Dipartimento di Chirurgia ed Oncologia, Università di Palermo, Palermo, Italy; ³ Peter Gorer Department of Immunobiology, The Medical School of King's College at Guy's and St. Thomas' Hospitals, London, United Kingdom; ⁴ Institute of Cell Biology, University of Bern, Bern, Switzerland; and ⁵ Department of Medical Biochemistry and Immunology, Cardiff University School of Medicine, Cardiff, United Kingdom

Requests for reprints: Francesco Dieli, Dipartimento di Biopatologia e Metodologie Biomediche, Università di Palermo, Corso Tukory 211, Palermo 90134, Italy. Phone: 39-091-6555916; Fax: 39-091-6555924; E-mail: dieli{at}unipa.it.

The increasing evidence that T cells have potent antitumor activity suggests their value in immunotherapy, particularly in areas of unmet need such as metastatic carcinoma. To this end, we initiated a phase I clinical trial in metastatic hormone-refractory prostate cancer to examine the feasibility and consequences of using the T-cell agonist zoledronate, either alone or in combination with low-dose interleukin 2 (IL-2), to activate peripheral blood cells. Nine patients were enlisted to each arm. Neither treatment showed appreciable toxicity. Most patients were treated with zoledronate + IL-2, but conversely only two treated with zoledronate displayed a significant long-term shift of peripheral cells toward an activated effector-memory–like state (T_EM), producing IFN- and perforin. These patients also maintained serum levels of tumor necrosis factor–related apoptosis inducing ligand (TRAIL), consistent with a parallel microarray analysis showing that TRAIL is produced by cells activated via the T-cell receptor and IL-2. Moreover, the numbers of T_EM cells showed a statistically significant correlation with declining prostate-specific antigen levels and objective clinical outcomes that comprised three instances of partial remission and five of stable disease. By contrast, most patients treated only with zoledronate failed to sustain either cell numbers or serum TRAIL, and showed progressive clinical deterioration. Thus, zoledronate + IL-2 represents a novel, safe, and feasible approach to induce immunologic and clinical responses in patients with metastatic carcinomas, potentially providing a substantially increased window for specific approaches to be administered. Moreover, cell phenotypes and possibly serum TRAIL may constitute novel biomarkers of prognosis upon therapy with zoledronate + IL-2 in metastatic carcinoma. [Cancer Res 2007;67(15):7450–7]

This article has been cited by other articles:

				G. Sarikonda, H. Wang, K.-J. Puan, X.-h. Liu, H. K. Lee, Y. Song, M. D. Distefano, E. Oldfield, G. D. Prestwich, and C. T. Morita Photoaffinity Antigens for Human {gamma}{delta} T Cells J. Immunol., December 1, 2008; 181(11): 7738 - 7750. [Abstract] [Full Text] [PDF]

				H. Wei, D. Huang, X. Lai, M. Chen, W. Zhong, R. Wang, and Z. W. Chen Definition of APC Presentation of Phosphoantigen (E)-4-Hydroxy-3-methyl-but-2-enyl Pyrophosphate to V{gamma}2V{delta}2 TCR J. Immunol., October 1, 2008; 181(7): 4798 - 4806. [Abstract] [Full Text] [PDF]

				Z. Liu, I.-E. A. Eltoum, B. Guo, B. H. Beck, G. A. Cloud, and R. D. Lopez Protective Immunosurveillance and Therapeutic Antitumor Activity of {gamma}{delta} T Cells Demonstrated in a Mouse Model of Prostate Cancer J. Immunol., May 1, 2008; 180(9): 6044 - 6053. [Abstract] [Full Text] [PDF]

				M. Takahara, M. Miyai, M. Tomiyama, M. Mutou, A. J. Nicol, and M. Nieda Copulsing tumor antigen-pulsed dendritic cells with zoledronate efficiently enhance the expansion of tumor antigen-specific CD8+ T cells via V{gamma}9{gamma}{delta} T cell activation J. Leukoc. Biol., March 1, 2008; 83(3): 742 - 754. [Abstract] [Full Text] [PDF]