Functional Analysis of an Inducible Promoter Driven by Activation Signals from a Chimeric Antigen Receptor
Autor: | Junichi Mineno, Hiroaki Mizukami, Ryosuke Uchibori, Masashi Urabe, Yoshihide Sehara, Takeshi Teruya, Hiroyuki Ido, Keiya Ozawa, Ken Ohmine |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Cancer Research Adoptive cell transfer Reporter gene biology Chemistry Effector Transgene Redirected Cytolysis lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens lcsh:RC254-282 CD19 Chimeric antigen receptor Cell biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology 030220 oncology & carcinogenesis biology.protein Molecular Medicine Cytotoxic T cell Pharmacology (medical) human activities |
Zdroj: | Molecular Therapy: Oncolytics, Vol 12, Iss, Pp 16-25 (2019) |
ISSN: | 2372-7705 |
Popis: | Adoptive transfer of T cells expressing a chimeric antigen receptor (CAR) is a promising cell-based anticancer therapy. Although clinical studies of this approach show therapeutic efficacy, additional genetic modification is necessary to enhance the efficacy and safety of CAR-T cells. For example, production of an antitumor cytokine from CAR-T cells can potentially enhance their tumor-killing activity, but there are concerns that constitutive expression of anticancer molecules will cause systemic side effects. Therefore, it is important that exogenous gene expression is confined to the tumor locality. Here, we aimed to develop an inducible promoter driven by activation signals from a CAR. Transgene expression in T cells transduced with the CD19-targeted CAR and an inducible promoter, including inducible reporter genes (CAR-T/iReporter), was only induced strongly by co-culture with CD19-positive target cells. CAR-T/iReporter cells also showed redirected cytolysis toward CD19-positive, but not CD19-negative, tumor cells. Overall, our study indicated that the inducible promoter was selectively driven by activation signals from the CAR, and transduction with the inducible promoter did not affect original effector activities including interleukin-2 and interferon-γ production and the antitumor activity of CAR-redirected cytotoxic T lymphocytes. Moreover, this inducible promoter permits visualization and quantification of the activation status in CAR-T cells. Keywords: inducible gene expression, chimeric antigen receptor, adoptive T cell therapy, B cell lymphoma, CD19, tumor targeting, in vivo imaging |
Databáze: | OpenAIRE |
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