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Title: Expansion of human γδ T cells for adoptive immunotherapy using a bisphosphonate prodrug
Authors: Tanaka, Yoshimasa
Murata-Hirai, Kaoru
Iwasaki, Masashi
Matsumoto, Kenji
Hayashi, Kosuke
Kumagai, Asuka
Nada, Mohanad H.
Wang, Hong
Kobayashi, Hirohito
Kamitakahara, Hiroshi  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0002-0130-1919 (unconfirmed)
Okamura, Haruki
Sugie, Tomoharu
Minato, Nagahiro
Toi, Masakazu  kyouindb  KAKEN_id
Morita, Craig T.
Author's alias: 林, 晃佑
上高原, 浩
湊, 長博
戸井, 雅和
Keywords: adoptive cancer immunotherapy
bisphosphonate
farnesyl diphosphate synthase
Vγ2Vδ2 T cells
zoledronic acid
Issue Date: 3-Mar-2018
Publisher: Wiley-Blackwell
Journal title: Cancer Science
Volume: 109
Issue: 3
Start page: 587
End page: 599
Abstract: 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.
Rights: © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
URI: http://hdl.handle.net/2433/230430
DOI(Published Version): 10.1111/cas.13491
PubMed ID: 29288540
Appears in Collections:Journal Articles

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