approximately 1 - 5% of peripheral blood t cells express the  t - cell receptor instead of the conventional  t - cell receptor . the  versus  t - cell lineage commitment during intrathymic t - cell development seems to be controlled by the signal strength provided to the  t - cell receptor . in healthy donors , most blood  t cells carry a specific t - cell receptor composed of v9 and v2 elements . in addition to effector functions shared with  t cells , the v9v2 t cells can acquire professional antigen - presenting capacity characteristic of dendritic cells . in contrast to  t cells , v9v2 t cells do not see processed antigenic peptides presented by major histocompatibility complex molecules , but rather recognize small phosphorylated non - peptide molecules (  phosphoantigens ) produced by many microorganisms but also by transformed eukaryotic cells . while microbial phosphoantigens are active at pico- to nanomolar concentrations , micromolar concentrations of the eukaryotic phosphoantigen isopentenyl pyrophosphate ( ipp ) are required for  t - cell activation . such high concentrations are not achieved in the mevalonate pathway of isoprenoid synthesis used in non - transformed cells . interestingly , human v9v2 t cells can kill a broad variety of epithelial tumor and leukemia / lymphoma cells . the sensitivity of tumor cells to  t - cell - mediated killing is increased upon treatment of tumor cells with aminobisphosphonates ( n - bps ) , drugs that are used in clinical practice for the treatment of osteoporosis and bone metastasis in cancer patients . n - bps inhibit the ipp - processing enzyme farnesyl diphosphate synthase ( fpps ) , thereby leading to an accumulation of ipp , which is then sensed by the  t cells . t cells are poor producers of interleukin-2 ( il-2 ) , which is required for expansion of  t cells . therefore , attempts to activate tumor - reactive  t cells endogenously by treating patients with n - bps must take into consideration an appropriate supply of il-2 . alternative strategies consider the adoptive transfer of in vitro expanded tumor - reactive  t cells [ 10 - 14 ] . the critical role of fpps in the control of intracellular ipp levels , and thus of the sensitivity of tumor cells toward  t - cell killing , has been recently demonstrated using short hairpin rna - mediated knock - down of fpps . knock - down of fpps caused tumor cells , which otherwise were not recognized by  t cells , to be susceptible to  t - cell killing . therefore , v9v2 t cells recognize and kill tumor cells on the basis of the unbalanced isoprenoid metabolic pathway in transformed cells , a pathway that is stable in non - malignant cells . the discovery that n - bps activate  t cells by inhibiting fpps , thereby leading to accumulation of ipp , has paved the way for proof - of - principle studies to activate  t cells in patients with advanced cancer . in a phase i clinical trial , dieli and colleagues   treated patients with hormone - refractory prostate cancer with a standard application of the n - bp zoledronate ( 4 mg intravenous infusion every 21 days ) either with or without additional low - dose ( 6  10 iu ) subcutaneous application of il-2 . various parameters , including subset analysis of  t cells , and serum levels of prostate - specific antigen and cytokines , were monitored over time . although the two cohorts comprised only a few patients , statistically significant effects of zoledronate plus il-2 on the mobilization and effector cell maturation of  t cells were recorded . very importantly , the two cohorts showed distinct clinical outcomes , with clinical responses seen in six of nine patients treated with zoledronate plus il-2 but only in one of nine patients treated with zoledronate alone . interestingly , a correlation between favorable outcome at 12 months and  t - cell numbers or functional status ( or both ) was observed . similarly , wilhelm and colleagues had previously shown that the combined application of n - bp plus low - dose il-2 can induce objective tumor responses in patients with lymphoid malignancies . together , these studies support the view that application of n - bps plus il-2 is safe , induces in vivo activation / maturation of  t cells , and may have beneficial effects in advanced cancer ( figure 1a ) . ( a ) n - bps inhibit farnesyl diphosphate synthase ( fpps ) , thus preventing processing of isopentenyl pyrophosphate ( ipp ) to farnesyl diphosphate ( fpp ) . the combined application of n - bp plus il-2 leads to in vivo activation of  t cells . ( b ) alternatively ,  t cells can be activated in vitro with n - bp or synthetic phosphoantigens in the presence of antigen - presenting cells ( apc ) and can be subsequently expanded to large cell numbers by an exogenous supply of il-2 for subsequent adoptive transfer into cancer patients . the cell preparation can be performed under gmp ( good manufacturing practice ) conditions . in a case study reported by laggner et al . , regression of lung and bone metastases was observed in a patient with advanced stage melanoma upon systemic treatment with zoledronate and localized radiotherapy . although  t - cell subsets were analyzed , it is difficult to ascertain a substantial role of  t - cell activation in the resolution of metastases in this single case , particularly since il-2 was omitted in the treatment of this patient . in addition to their  t - cell activating properties , n - bps also exhibit direct anti - tumor activities by both inhibiting proliferation and inducing apoptosis in tumor cells . while zoledronate seems to be the most potent  t - cell - activating substance among the n - bps licensed for clinical application , derivatives of zoledronate with further improved  t - cell - stimulating capacity and enhanced direct anti - tumor activity are under development . such modified n - bps might also exert improved in vivo activation of  t cells when given to patients together with il-2 . t - cell - based immunotherapeutic strategy is the adoptive transfer of in vitro expanded v9v2 t cells from tumor patients ( figure 1b ) . recently , efficient protocols for the large - scale in vitro expansion of v9v2 t cells based on stimulation with synthetic phosphoantigens   or zoledronate   have been established . first results indicate that the repetitive adoptive transfer of in vitro expanded  t cells is well tolerated and may induce anti - tumor responses in patients with solid tumors , including renal cell carcinoma   and myeloma . the protocol developed by dieli et al .   for the in vivo activation of  t cells based on zoledronate plus low - dose il-2 application is ready to be explored in larger clinical trials and in other tumor entities with poor prognosis , for example , pancreatic ductal adenocarcinoma where it might be combined with standard regimens such as gemcitabine . it is conceivable that this protocol can be further improved , for instance , by combination with tumor - targeting monoclonal antibodies . along this line , it has been shown that b - cell lymphoma or breast tumor cell killing by fc receptor - expressing  t cells is enhanced in the presence of targeting antibodies rituximab ( cd20 ) or trastuzumab ( her2/neu ) , respectively . moreover , a  t - cell - stimulating synthetic phosphoantigen was found to enhance the depletion of cd20 b cells by rituximab in a non - human primate model in vivo , pointing to the possible use of phosphoantigen plus anti - cd20 antibodies in the treatment of cd20 leukemias and lymphomas . furthermore , cytokines promoting homeostatic proliferation and survival of t cells , such as il-15 , or cytokines potentiating the cytolytic activity and pro - inflammatory response , such as il-21 , might be combined with il-2 or used instead of il-2 . this could be considered both for in vivo application together with n - bps and for optimization of in vitro expansion of  t cells . in addition , future study protocols might include the combination of in vivo activation of  t cells ( by n - bp or phosphoantigen plus il-2 ) followed by the adoptive transfer of in vitro expanded  t cells , finally , it should be stressed that  t - cell - based immunotherapy is not expected to replace established therapeutic protocols . rather , it might offer additional benefit to the patient , for instance , in combination with conventional chemotherapy .
t lymphocytes are a numerically small subset of t cells with potent cytotoxic activity against a variety of tumor cells . 
 human  t cells expressing the v9v2 t cell antigen receptor recognize endogenous pyrophosphate molecules that are overproduced in transformed cells . moreover , the intracellular accumulation of such pyrophosphates is strongly enhanced by aminobisphosphonates used in the treatment of osteoporosis and bone metastasis in certain cancer patients . 
 a new concept of cancer immunotherapy is based on the endogenous activation of  t cells with aminobisphosphonates plus low - dose interleukin-2 .