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Cancer Immunol Res. 2016 Aug;4(8):658-68. doi: 10.1158/2326-6066.CIR-16-0043. Epub 2016 Jun 21.

A Tet-On Inducible System for Controlling CD19-Chimeric Antigen Receptor Expression upon Drug Administration.

Author information

1
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
2
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan. tseit@med.nagoya-u.ac.jp.
3
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Division of Clinical Hematology, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.

Abstract

T cells genetically modified with a CD19 chimeric antigen receptor (CD19CAR) are remarkably effective against B-cell malignancies in clinical trials. However, major concerns remain regarding toxicities, such as hypogammaglobulinemia, due to B-cell aplasia or severe cytokine release syndrome after overactivation of CAR T cells. To resolve these adverse events, we aimed to develop an inducible CAR system by using a tetracycline regulation system that would be activated only in the presence of doxycycline (Dox). In this study, the second-generation CD19CAR was fused into the third-generation Tet-On vector (Tet-CD19CAR) and was retrovirally transduced into primary CD8(+) T cells. Tet-CD19CAR T cells were successfully generated and had minimal background CD19CAR expression without Dox. Tet-CD19CAR T cells in the presence of Dox were equivalently cytotoxic against CD19(+) cell lines and had equivalent cytokine production and proliferation upon CD19 stimulation, compared with conventional CD19CAR T cells. The Dox(+) Tet-CD19CAR T cells also had significant antitumor activity in a xenograft model. However, without Dox, Tet-CD19CAR T cells lost CAR expression and CAR T-cell functions in vitro and in vivo, clearly segregating the "On" and "Off" status of Tet-CD19CAR cells by Dox administration. In addition to suicide-gene technology, controlling the expression and the functions of CAR with an inducible vector is a potential solution for CAR T-cell therapy-related toxicities, and may improve the safety profile of CAR T-cell therapy. This strategy might also open the way to treat other malignancies in combination with other CAR or TCR gene-modified T cells. Cancer Immunol Res; 4(8); 658-68. ©2016 AACRSee related Spotlight by June, p. 643.

PMID:
27329987
DOI:
10.1158/2326-6066.CIR-16-0043
[Indexed for MEDLINE]
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