Adoptive Immunotherapy for Advanced Non-small Cell Lung Cancer Using Zoledronate-expanded γδ T Cells: A Phase I Clinical Study

Human gamma delta T cells can recognize and kill non-small cell lung cancer (NSCLC) cells using the V gamma 9V delta 2 T-cell receptor and/or NKG2D. We have established clinical grade large-scale ex vivo expansion of gamma delta T cells from peripheral blood mononuclear cells by culturing with zoledronate and interleukin-2 (IL-2). A phase I study was conducted to evaluate safety and potential antitumor effects of re-infusing ex vivo expanded gamma delta T cells in patients with recurrent or advanced NSCLC. Patient's peripheral blood mono-nuclear cells were stimulated with zoledronate (5 mu M) and IL-2 (1000 IU/mL) for 14 days. Harvested cells, mostly gd T cells, were given intravenously every 2 weeks without additional IL-2, a total of 6 times. The cumulative number of transferred gamma delta T cells ranged from 2.6 to 45.1 x 10(9) (median, 15.7 x 10(9)). Fifteen patients underwent adoptive immunotherapy with these gamma delta T cells. There were no severe adverse events related to the therapy. Immunomonitoring data showed that with increasing numbers of infusions, the number of peripheral gamma delta T cells gradually increased. All patients remained alive during the study period with a median survival of 589 days and median progression-free survival of 126 days. According to the Response Evaluation Criteria In Solid Tumors, there were no objective responses. Six patients had stable disease, whereas the remaining 6 evaluable patients experienced progressive disease 4 weeks after the sixth transfer. We conclude that adoptive transfer of zoledronate-expanded gamma delta T cells is safe and feasible in patients with NSCLC, refractory to other treatments.