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Cancer Research 67, 7450, August 1, 2007. doi: 10.1158/0008-5472.CAN-07-0199
© 2007 American Association for Cancer Research
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Immunology

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

Francesco Dieli1, David Vermijlen3, Fabio Fulfaro2, Nadia Caccamo1, Serena Meraviglia1, Giuseppe Cicero2, Andrew Roberts3, Simona Buccheri1, Matilde D'Asaro1, Nicola Gebbia2, Alfredo Salerno1, Matthias Eberl4,5 and Adrian C. Hayday3

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 {gamma}{delta} 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 {gamma}{delta} T-cell agonist zoledronate, either alone or in combination with low-dose interleukin 2 (IL-2), to activate peripheral blood {gamma}{delta} 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 {gamma}{delta} cells toward an activated effector-memory–like state (TEM), producing IFN-{gamma} 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 {gamma}{delta} cells activated via the T-cell receptor and IL-2. Moreover, the numbers of TEM {gamma}{delta} 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 {gamma}{delta} 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, {gamma}{delta} 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]




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Copyright © 2007 by the American Association for Cancer Research.