Effect of Aminobiphosphonates and Statins on Circulating Vgamma9Vdelta2-T Cells
Effect of Aminobiphosphonates and Statins on Circulating Vgamma9Vdelta2-T Cells
The purpose of this study is to investigate the effects of aminobiphosphonate treatment on
 the phenotype and function of circulating Vgamma9Vdelta2-T cells and to determine whether
 these effects are inhibited by simultaneous treatment with statins.
A total of 40 patients will be entered in this study. Half of the patients will receive
 standard intravenous treatment with aminobsiphosphonates, the other half will be additionally
 be treated with a statin. Patients already receiving statin treatment will continue this
 treatment, other patients will be asked whether they are willing to be treated with a statin
 for a maximum of 5 weeks. Consenting patients will be randomized to receive i.v.
 aminobisphosponates plus or minus simvastatin 40 mg once daily. Simvastatin will be started
 one week prior to the first administration of aminobisphosphonates and continued for a
 maximum of 5 weeks. In each patient 10 ml peripheral blood will be drawn (t=0, t=24 hr, t=1
 week, t=3-4 weeks (prior to the 2nd aminobisphosphonate administration). In addition,
 patients will be requested to measure their temperature thrice daily during the 2 days
 following the first aminobisphosponate administration. This, because a relation between the
 occurrence of a febrile response upon aminobisphosponate administration and an activation and
 expansion of Vy9Vd2-T cells has been suggested. Peripheral blood mononuclear cells will be
 isolated from the drawn peripheral blood. Using intra- and extracellular flowcytometry
 Vy9Vd2-T cells will be characterized phenotypically (APC markers: CD1d, CD40, CD80, CD83,
 CD86, HLA-DR; activation/memory markers: CD25, CD27, CD45RA, CD45RO, CCR7) and functionally
 (IFN-γ, TNF-α, granzyme B). In addition, the frequency of CD3+, CD4+, CD8+ T cells, NK cells,
 B cells, iNKT cells, CD4+CD25+ regulatory T cells, and circulating dendritic cells will be
 assessed.
Inclusion Criteria:

 -  Patients with an indication for intravenous treatment with an aminobiphosphonate
 because of a malignant tumor

 -  WHO 0,1,2 performance score

 Exclusion Criteria:

 -  WHO 3, 4 performance score

 -  prior or current use of aminobisphosphonates -immunosuppressive medication (NSAID
 allowed)

 -  chemotherapy and/or radiotherapy in 4 weeks prior to start of aminobisphosphonate
 administration

 -  renal insufficiency (creatinine clearance < 30 ml/min)

 -  liver enzyme abnormalities:

 -  bilirubin > 1.5 times ULN (upper limit of normal)

 -  ASAT or ALAT > 2.5 times ULN (in absence of liver metastases)

 -  ASAT or ALAT > 5 times ULN (in presence of liver metastases)

 -  concomitant use of strong inhibitors of CYP3A4, such as itraconazole, ketoconazole,
 erytromycin, clarithromycin, hiv-protease inhibitors or grapefruit juice is
 contra-indicated.