Evaluation of γ-retroviral vectors that mediate the inducible expression of IL-12 for clinical application.

Journal of Immunotherapy
Ling ZhangRichard A Morgan

Abstract

The clinical application of interleukin-12 (IL-12) has been hindered by the toxicity associated with its systemic administration. To potentially overcome this problem, we developed a promoter designed to direct IL-12 expression within the tumor environment using an inducible composite promoter containing binding motifs for the nuclear factor of activated T cells (NFAT) linked to a minimal IL-2 promoter. In this study, the NFAT promoter was coupled to a single-chain human IL-12 gene and inserted into 2 γ-retroviral self-inactivating vectors (SERS.NFAT.hIL12 and SERS.NFAT.hIL12.PA2) and 1 γ-retroviral vector (MSGV1.NFAT.hIL.12 PA2). Peripheral blood lymphocytes (PBLs) were double transduced with an antigen-specific T-cell receptor and the 3 NFAT.hIL12 vectors. Evaluation of inducible IL-12 expression, transduction efficiency, and vector production considerations led to the choice of the MSGV1.NFAT.hIL12.PA2 vector for clinical application. MSGV1.NFAT.hIL12.PA2 PG13 retroviral vector producer cell clones were screened by transduction of tumor antigen-specific PBLs. On the basis of expression studies in PBL, clone D3 was chosen to produce clinical-grade viral vector supernatant and was demonstrated to efficiently transduce young tu...Continue Reading

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Citations

Dec 6, 2012·Archives of Pharmacal Research·Young-Chang ChoBok Yun Kang
May 20, 2015·Expert Opinion on Biological Therapy·Markus Chmielewski, Hinrich Abken
Nov 4, 2015·The Journal of Experimental Medicine·Douglas C PalmerNicholas P Restifo
Dec 18, 2013·Immunological Reviews·Christian S Hinrichs, Steven A Rosenberg
May 28, 2016·Molecular Therapy Oncolytics·Daniel Abate-Daga, Marco L Davila
Aug 1, 2016·Current Hematologic Malignancy Reports·Marco Ruella, Carl H June
Jul 24, 2012·Current Opinion in Immunology·Cameron J TurtleStanley R Riddell
Dec 18, 2013·Immunological Reviews·Marco Ruella, Michael Kalos
Sep 13, 2015·Oncotarget·Sergiu ChiraIoana Berindan-Neagoe
Mar 5, 2019·Frontiers in Immunology·Christopher DeRenzo, Stephen Gottschalk
Nov 10, 2017·International Journal of Cancer. Journal International Du Cancer·Maria-Luisa SchubertMichael Schmitt
Apr 28, 2017·Annual Review of Immunology·Kole T Roybal, Wendell A Lim
Dec 15, 2019·International Journal of Molecular Sciences·Sophia StockLeopold Sellner
Feb 20, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ling ZhangSteven A Rosenberg

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