γδ T Cell-Mediated Immunotherapy of Malignancies with Zoledronate and IL-2.

Despite major advances in our understanding of the adaptive immunity towards tumors and the introduction of vaccine-based strategies, durable responses are rare and adaptive immunotherapeutic approaches are still not an established treatment modality. Several lines of evidence indicate that MHC-independent effector cells of the innate immune system such as natural killer (NK) cells or γδ T cells significantly contribute to the immune surveillance of tumors. As we have shown previously, aminobisphosphonates (ABP) such as pamidronate or zoledronate are potent γδ T cell stimulatory compounds by inducing secretion of proinflammatory cytokines (i.e. IFN-γ) and cell-mediated cytotoxicity against lymphoma and myeloma cells in vitro. The detection of ABP as γδ T cell stimulating drugs at pharmacologically achievable concentrations in humans opened the possibility to evaluate the consequences of selective γδ T cell stimulation in vivo. The concept of γδ T cell-mediated immunotherapy is currently validated in a Phase II clinical trial with zoledronate (4mg i.v., d 1) and low dose IL-2 (2 x 10⁶ IU/m² s.c., d 1–6) for patients with hematological (NHL, myeloma, AML) and non-hematological malignancies (renal cell carcinoma and malignant melanoma). The results of our first clinical pilot study with pamidronate/IL-2 in patients with lymphoid malignancies showed that selective activation and expansion of γδ T cells can be induced in vivo. However, 50% of patients with hematological malignancies failed to respond to pamidronate/IL-2 in vitro. Therefore, positive in vitro sensitivity testing was an essential inclusion criterion in this trial. Immunomonitoring of the first 12 patients included in the study showed that zoledronate/IL-2 is highly effective in activating and expanding γδ T cells in vivo (104 TCRδ2⁺/HLA-DR⁺ cells/μl (range 11-323) at day 8 of cycle 1 compared to 3 TCRδ2⁺/HLA-DR⁺ cells (range 0-15) before treatment). In addition, IFN-γ serum levels increased from 7 to 110 pg/ml (mean 44, n=6) at day 2 at cycle 1 (day 0: 2, range 0–5). So far, objective tumor responses were observed only in hematological malignancies (updated data will be presented). The application of zoledronate/IL-2 is generally well tolerated. In conclusion, effective γδ T cell activation/expansion can be achieved in vivo by the combination of zoledronate and low dose IL-2. Because of the potent anti-tumor effects of γδ T cells this strategy might be a new attractive immunotherapy approach for malignancies with preserved γδ T cell function.