Aminobisphosphonate-pretreated dendritic cells trigger successful V gamma 9V delta 2 T cell amplification for immunotherapy in advanced cancer patients

作者：Cabillic Florian^*; Toutirais Olivier; Lavoue Vincent; de La Pintiere Cecile Thomas; Daniel Pascale; Rioux Leclerc Nathalie; Turlin Bruno; Monkkonen Hannu; Monkkonen Jukka; Boudjema Karim; Catros Veronique; Bouet Toussaint Francoise

来源：Cancer Immunology, Immunotherapy, 2010, 59(11): 1611-1619.

DOI：10.1007/s00262-010-0887-0

• Colorectal carcinoma
• Hepatocarcinoma
• Immunotherapy
• Aminobisphosphonate
• gamma delta T cell
• Isopentenyl pyrophosphate

Hepatocellular carcinoma (HCC) and colorectal carcinoma with hepatic metastases (mCRC) are cancers with poor prognosis and limited therapeutic options. New approaches are needed and adoptive immunotherapy with V gamma 9V delta 2 T lymphocytes represents an attractive strategy. Indeed, V gamma 9V delta 2 T cells were shown to exhibit efficient lytic activity against various human tumor cell lines, and in vitro V gamma 9V delta 2 T expansion protocol based on single phosphoantigen stimulation could be easily performed for healthy donors. However, a low proliferative response of V gamma 9V delta 2 T cells was observed in about half of the cancer patients, leading to an important limitation in the development of V gamma 9V delta 2 T cell-based immunotherapy. Here, for the first time in the context of cancer patients, V gamma 9V delta 2 T cell expansions were performed by co-culturing peripheral blood mononuclear cell (PBMCs) with autologous dendritic cells (DCs) pretreated with aminobisphosphonate zoledronate. For patients not responding to the conventional culture protocol, co-culture of PBMC with zoledronate-pretreated DCs induced strong cell expansion and allowed reaching a minimal rate of purity of 70% of V gamma 9V delta 2 T cells. The potent immunostimulatory activity of zoledronate-treated DCs was associated with higher amount of isopentenyl pyrophosphate (IPP) in the culture and was correlated with better ability to activate V gamma 9V delta 2 T cells as measured by IFN-gamma production. Moreover, we demonstrated that the cytotoxic level of V gamma 9V delta 2 T cells against freshly autologous tumor cells isolated from patients could be significantly increased by pretreating the tumor cells with zoledronate. Thus, this method of generating V gamma 9V delta 2 T cells leads eligible for V gamma 9V delta 2 T cell adoptive immunotherapy the HCC and mCRC patients.

• 出版日期2010-11