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Aminobisphosphonate-pretreated dendritic cells trigger successful Vγ9Vδ2 T cell amplification for immunotherapy in advanced cancer patients

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Abstract

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 Vγ9Vδ2 T lymphocytes represents an attractive strategy. Indeed, Vγ9Vδ2 T cells were shown to exhibit efficient lytic activity against various human tumor cell lines, and in vitro Vγ9Vδ2 T expansion protocol based on single phosphoantigen stimulation could be easily performed for healthy donors. However, a low proliferative response of Vγ9Vδ2 T cells was observed in about half of the cancer patients, leading to an important limitation in the development of Vγ9Vδ2 T cell-based immunotherapy. Here, for the first time in the context of cancer patients, Vγ9Vδ2 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 Vγ9Vδ2 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 Vγ9Vδ2 T cells as measured by IFN-γ production. Moreover, we demonstrated that the cytotoxic level of Vγ9Vδ2 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 Vγ9Vδ2 T cells leads eligible for Vγ9Vδ2 T cell adoptive immunotherapy the HCC and mCRC patients.

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Abbreviations

HCC:

Hepatocellular carcinoma

mCRC:

Colorectal cancer with hepatic metastases

IPP:

Isopentenyl pyrophosphate

ABP:

Aminobisphosphonate

BrHPP:

Bromohydrin pyrophosphate

PBMC:

Peripheral blood mononuclear cell

DC:

Dendritic cell

mAb:

Monoclonal antibody

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

cpm:

Count per minute

P-Ag:

Phosphoantigen

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Acknowledgments

The authors thank C. Guillouzo (INSERM U522, Rennes) for providing HCC cell lines and expert assistance in the culture of normal hepatocytes, L. Jégu (Département de Chirurgie Hépatobiliaire et Digestive, CHU de Rennes) for assistance in patient inclusion and Innate Pharma (Marseille) for providing bromohydrin pyrophosphate (BrHPP, Phosphostim). This study was supported by funds from the Comité Grand Ouest de la Ligue contre le Cancer and the Institut National du Cancer (PL075).

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Correspondence to Florian Cabillic.

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F. Cabillic and O. Toutirais contributed equally to this work.

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Cabillic, F., Toutirais, O., Lavoué, V. et al. Aminobisphosphonate-pretreated dendritic cells trigger successful Vγ9Vδ2 T cell amplification for immunotherapy in advanced cancer patients. Cancer Immunol Immunother 59, 1611–1619 (2010). https://doi.org/10.1007/s00262-010-0887-0

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