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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dieli, F. Articles by Salerno, A. Search for Related Content PubMed PubMed Citation Articles by Dieli, F. Articles by Salerno, A. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 September 2003, Vol. 102, No. 6, pp. 2310-2311 CORRESPONDENCE To the editor: Induction of T-lymphocyte effector functions by bisphosphonate zoledronic acid in cancer patients in vivo Bisphosphonates are analogues of endogenous pyrophosphate in which a carbon atom replaces the central atom of oxygen. This carbon substitution makes these compounds resistant to hydrolysis and allows 2 additional chains of variable structure. One of these side chains usually contains a hydroxyl moiety that allows high affinity for calcium crystals and bone mineral. The differences at the other side chain produce marked differences in the antiresorptive potency of different bisphosphonates. In fact, the newer bisphosphonates, such as ibandronate and zoledronic acid, show 10 000- to 100 000-fold more potency than the older agents such as etidronate.1 Exposure to bisphosphonates may not only reduce bone loss but may also have an antimyeloma effect. Recent animal studies have shown that the aminobisphosphonates also have potent antiangiogenic activity that may contribute to these drugs' antibone resorptive effect as well as provide additional mechanisms by which these drugs may have antimyeloma effects as well.1 A new potential antitumor mechanism for these compounds was recently reported for aminobisphosphonates.2 These drugs were shown to induce expansion of V9V2 T cells in peripheral blood mononuclear cell cultures and enhance cytotoxicity of malignant plasma cells in bone marrow cultures by these V9V2 T lymphocytes. Thus, there is increasing evidence that bisphosphonates, especially the nitrogen-containing compounds, can lead to direct and indirect effects that result not only in less bone loss but less tumor burden as well. In support of this, Wilhelm et al3 now report the results of a pilot study of low-dose interleukin-2 (IL-2) in combination with pamidronate in patients with low-grade non-Hodgkin lymphoma or multiple myeloma. They selected 9 patients by positive in vitro proliferation of V9V2 T cells in response to pamidronate and IL-2, and show that 5 of the patients had significant in vivo activation/proliferation of V9V2 T cells. Three patients also achieved objective responses, indicating that V9V2 T cells might contribute to this antilymphoma effect. To evaluate the antitumor activity of V9V2 T cells in vivo, we initiated a pilot study of low-dose zoledronic acid in 9 cancer patients with bone metastases (3 females affected by breast cancer; 6 males affected by prostate cancer; median age, 66 years [range, 54-83 years]). The objective of this study was to evaluate the in vivo effect of zoledronic acid on recently identified subsets of V9V2 cells that display different functional activities: CD45RA+CD27+ naive and CD45RA–CD27+ memory V9V2 cells strongly proliferate but lack immediate effector functions, while CD45RA–CD27– V9V2 cells proliferate poorly but produce interferon (IFN) and exert cytotoxicity.4 Both of these functions are strictly involved in their antitumor activity. Patients were treated with 4 mg zoledronic acid via 15-minute intravenous infusion every 3 weeks. Peripheral blood mononuclear cells (PBMCs) were collected before treatment (time 0), and 1 month (time 1) and 3 months (time 2) after the first administration. PBMCs were also taken from 15 age- and sex-matched healthy control subjects. Preliminary experiments (Figure 1A) showed that zoledronic acid was as able as the phosphoantigen isopentenylpyrophosphate (IPP) to induce expansion of V9V2+ T cells upon culture in vitro in the presence of IL-2. The relative percentages of naive, memory, and effector subsets of V9V2 cells were comparable in control and cancer patients before treatment with zoledronic acid (data not shown). However, treatment with zoledronic acid caused a decrease in the percentages of naive and memory V9V2 cells, which was evident 1 month after the initial treatment and dramatic after 3 months (Figure 1B): in fact, at this stage, naive and memory cell subsets were less than 10% of the whole V9V2 population, while in control subjects these 2 subsets usually account for about 70% of V9V2 cells. The decrease of naive and V9V2 cells was paralleled by an increase in the percentage of the effector subset, which accounted for about 80% of the whole V9V2 population after 3 months from the initial treatment with zoledronic acid. As the percentage and absolute numbers of V9V2 cells in PBMCs were not modified during treatment, we interpret these results to indicate that zoledronic acid in vivo expands a subset of effector V9V2 cells, while decreasing the naive and memory subsets. View larger version (20K): [in this window] [in a new window]   Figure 1.. Zoledronic acid activates in vitro V9V2 cells and induces subset distribution in cancer patients in vivo. (A) PBMCs were incubated in vitro with IPP () or zoledronic acid () at the indicated final concentrations and 10 U/mL IL-2. Then, 7 days later, cells were collected and the percentage of V9V2+ cells within the CD3+ population was assessed. (B) V9V2 T-cell subsets were analyzed by 3-color fluorescence-activated cell-sorter (FACS) analysis before or after in vivo treatment with zoledronic acid. The following antibodies were used in different combinations: anti-V2 fluorescein isothiocyanate (FITC, IMMU389; Coulter, Miami, FL), anti-CD27 phycoerythrin (PE) (M-T271; BD Pharmingen, San Diego, CA), and anti-CD45RA PE–cytochrome 5 (Cy5, 2H4; Coulter). Data were acquired on a FACSCalibur instrument (BD Biosciences, San Diego, CA) and analyzed using CellQuest software (BD Immunocytometry Systems, San Jose, CA). Error bars indicate standard deviation.   Different subsets of V9V2 cells have been reported to exert different functions.4 Therefore, we assessed whether modification of V9V2 cell subset distribution was accompanied by alterations in the functions they usually perform. As shown in Figure 2A, proliferative activity of V9V2 cells upon in vitro stimulation with IPP, which is a property of naive and memory cells, strongly decreased upon in vivo treatment with zoledronic acid. Conversely, production of IFN by V9V2 cells upon in vitro stimulation with IPP, which is a property of effector cells, consistently increased upon in vivo treatment with zoledronic acid. View larger version (16K): [in this window] [in a new window]   Figure 2.. Proliferation and IFN production by V9V2 cells from cancer patients before and after treatment with zoledronic acid. PBMCs were cultured at 37°C, in the presence of 5% CO2, at 106/mL in 96-well flat-bottomed plates (0.2 mL/well), with isopentenylpyrophosphate (IPP; Sigma Chemical, St Louis, MO; 100 µM/mL final concentration) and 20 U/mL final concentration human recombinant IL-2 () or with IL-2 alone as a control (). Proliferation (A) was measured 7 days later by adding 1 µCi/well (0.037 MBq) [3H]thymidine (Amersham, Arlington Heights, IL) during the last 6 hours of culture. Cells were then harvested and [3H]thymidine incorporation was measured with a liquid scintillation -counter. Results are expressed as mean counts per minute (cpm) of triplicate wells ± standard deviation (SD). IFN levels in the 48-hour culture supernatants (B) were assessed by 2 monoclonal antibodies (mAbs) sandwich enzyme-linked immunosorbent assay (ELISA) assay following the manufacturer's recommendations (R&D Systems, Minneapolis, MN).   Although the data here reported strengthen the results of Wilhelm et al3 (ie, the high IFN concentrations in serum and the slow response profiles of most of lymphoma patients), a major difference to the study by Wilhelm et al is that they used a combination of pamidronate and low-dose IL-2 in vivo. In principle, IL-2 application in vivo might not have influenced their results, as indicated by the findings that aminobisphosphonate-induced V9V2 T-cell activation and IFN production is strictly dependent on the presence of monocytes,5 and that V9V2 T cells can be quickly and antigen-nonspecifically activated, even in the absence of IL-2, by monocyte-derived IL-12 and tumor necrosis factor (TNF).6 All together, our results indicate that in vivo treatment with zoledronic acid induces V9V2 cells to mature toward an IFN-producing effector phenotype, which may induce more effective antitumor responses. Francesco Dieli, Nicola Gebbia, Fabrizio Poccia, Nadia Caccamo, Carla Montesano, Fabio Fulfaro, Carlo Arcara, Maria R. Valerio, Serena Meraviglia, Caterina Di Sano, Guido Sireci, and Alfredo Salerno Correspondence: Francesco Dieli, Dipartimento di Biopatologia, University of Palermo, Corso Tukory, 211, Palermo 90134, Italy; e-mail: dieli{at}unipa.it. References Anderson KC, Kyle RA, Dalton WS, et al. Multiple myeloma: new insights and therapeutic approaches. Hematology. 2000; 147-165. Kunzmann V, Bauer E, Feurle J, Weissinger F, Tony HP, Wilhelm M. Stimulation of gammadelta T cells by aminobisphosphonates and induction of anti-plasma cell activity in multiple myeloma. Blood. 2000;96: 384-392.[Abstract/Free Full Text] Wilhelm M, Kunzmann V, Eckstein S, et al. T cells for immune therapy of patients with lymphoid malignancies. Blood. 2003;102; 200-206.[Abstract/Free Full Text] Gioia C, Agrati C, Casetti R, et al. Lack of CD27–CD45RA– V9V2+ T cell effectors in immunocompromised hosts and during active pulmonary tuberculosis. J Immunol. 2002;168: 1484-1489.[Abstract/Free Full Text] Miyagawa F, Tanaka Y, Yamashita S, Minato N. Essential requirement of antigen presentation by monocyte lineage cells for the activation of primary human T cells by aminobisphosphonate antigen. J Immunol. 2001;166: 5508-5514.[Abstract/Free Full Text] Ueta C, Kawasumi H, Fujiwara H, et al. Interleukin-12 activates human T cells: synergistic effect of tumor necrosis factor-. Eur J Immunol. 1996;26: 3066-3073.[Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Todaro, M. D'Asaro, N. Caccamo, F. Iovino, M. G. Francipane, S. Meraviglia, V. Orlando, C. La Mendola, G. Gulotta, A. Salerno, et al. Efficient Killing of Human Colon Cancer Stem Cells by {gamma}{delta} T Lymphocytes J. Immunol., June 1, 2009; 182(11): 7287 - 7296. [Abstract] [Full Text] [PDF] J. Gertner-Dardenne, C. Bonnafous, C. Bezombes, A.-H. Capietto, V. Scaglione, S. Ingoure, D. Cendron, E. Gross, J.-F. Lepage, A. Quillet-Mary, et al. Bromohydrin pyrophosphate enhances antibody-dependent cell-mediated cytotoxicity induced by therapeutic antibodies Blood, May 14, 2009; 113(20): 4875 - 4884. 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