KOBAYASHI Hirohito    Department   School of Medicine(Tokyo Women's Medical University Adachi Medical Center), School of Medicine    Position   Associate Professor
Article types	Original article
Language	English
Peer review	Peer reviewed
Title	Expansion of human γδ T cells for adoptive immunotherapy using a bisphosphonate prodrug.
Journal	Formal name：Cancer science Abbreviation：Cancer Sci ISSN code：13497006/13479032
Domestic / Foregin	Foregin
Volume, Issue, Page	109(3),pp.587-599
Author and coauthor	Tanaka Yoshimasa, Murata-Hirai Kaoru, Iwasaki Masashi, Matsumoto Kenji, Hayashi Kosuke, Kumagai Asuka, Nada Mohanad H, Wang Hong, Kobayashi Hirohito, Kamitakahara Hiroshi, Okamura Haruki, Sugie Tomoharu, Minato Nagahiro, Toi Masakazu, Morita Craig T
Publication date	2018/03
Summary	Cancer immunotherapy with human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) has shown promise because of their ability to recognize and kill most types of tumors in a major histocombatibility complex (MHC) -unrestricted fashion that is independent of the number of tumor mutations. In clinical trials, adoptive transfer of Vγ2Vδ2 T cells has been shown to be safe and does not require preconditioning. In this report, we describe a method for preparing highly enriched human Vγ2Vδ2 T cells using the bisphosphonate prodrug, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA). PTA stimulated the expansion of Vγ2Vδ2 cells to purities up to 99%. These levels were consistently higher than those observed after expansion with zoledronic acid, the most commonly used stimulator for clinical trials. Cell numbers also averaged more than those obtained with zoledronic acid and the expanded Vγ2Vδ2 cells exhibited high cytotoxicity against tumor cells. The high purity of Vγ2Vδ2 cells expanded by PTA increased engraftment success in immunodeficient NOG mice. Even low levels of contaminating αβ T cells resulted in some mice with circulating human αβ T cells rather than Vγ2Vδ2 cells. Vγ2Vδ2 cells from engrafted NOG mice upregulated CD25 and secreted tumor necrosis factor-α and interferon-γ in response to PTA-treated tumor cells. Thus, PTA expands Vγ2Vδ2 T cells to higher purity than zoledronic acid. The high purities allow the successful engraftment of immunodeficient mice without further purification and may speed up the development of allogeneic Vγ2Vδ2 T cell therapies derived from HLA-matched normal donors for patients with poor autologous Vγ2Vδ2 T cell responses.
DOI	10.1111/cas.13491
PMID	29288540