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Monoclonal antibodies (mAbs) constitute the most rapidly growing class of human therapeutics and the second largest class of drugs after vaccines. The treatment of B-cell malignancies and HER2/Neu(+) breast cancer has benefited considerably from the use of therapeutic mAbs, either alone or in combination with standard chemotherapy. Frequent relapses, however, demonstrate that the bioactivity of these mAbs is still suboptimal. The concept of improving the anti-tumor activity of mAbs is well established and potentiating the cytotoxicity induced by anticancer mAbs can be achieved by strategies that target the downstream cytolytic effector cells. The recruitment of Fcγ receptor-dependent functions appears well suited in this regard, because several lines of evidence suggest that enhancing antibody-dependent cellular cytotoxicity (ADCC) induced by therapeutic mAbs may directly improve their clinical efficacy. The cytolytic effector cells involved in ADCC are FcγR-expressing natural killer (NK) cells, but also γδ T cells can be amplified and finetuned for stronger ADCC activity. γδ T cells are raising a considerable interest in the immunotherapy community given their intrinsic antitumor activity that can be boosted by stimulation with synthetic phosphoantigens (PAgs), or with drugs that cause their accumulation into target cells, like aminobisphosphonates (N-BPs), and low doses interleukin (IL)-2. The field is interesting, and several papers have already explored this approach in solid and haematological malignancies. Thus, we propose that enhancing the efficacy of mAbs by combination with γδ T cell activation may have considerable therapeutic potential for a variety of malignancies, most especially for patients whose FcγR alleles impair ADCC.

BACKGROUND: Activated V gamma 9 V delta 2 T cells are able to kill most tumour cells because of recognition by T cell receptor and natural killer receptors. OBJECTIVE: We discuss the possibility that the intentional activation of gammadelta T cells in vivo by aminobisphosphonates may represent a promising target for the design of novel and highly innovative immunotherapy in cancer patients. METHODS: The antitumoral effects of gammadelta T cells both in vitro and in vivo have been demonstrated suggesting a new therapeutic approach for translation into the clinical setting. RESULTS/CONCLUSION: V gamma 9 V delta 2 T lymphocytes represent a particularly interesting target for immunotherapeutic protocols based on N-aminobisphosphonate administration and several Phase I-II trials are ongoing investigating the activity of zoledronic acid plus IL-2 in solid tumours.