Zimmermann, Katharina, Kuehle, Johannes, Dragon, Anna Christina ORCID: 0000-0002-5228-7627, Galla, Melanie, Kloth, Christina, Rudek, Loreen Sophie, Sandalcioglu, I. Erol, Neyazi, Belal, Moritz, Thomas, Meyer, Johann, Rossig, Claudia, Altvater, Bianca, Eiz-Vesper, Britta, Morgan, Michael Alexander, Abken, Hinrich and Schambach, Axel (2020). Design and Characterization of an All-in-One Lentiviral Vector System Combining Constitutive Anti-G(D2) CAR Expression and Inducible Cytokines. Cancers, 12 (2). BASEL: MDPI. ISSN 2072-6694

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Abstract

Genetically modified T cells expressing chimeric antigen receptors (CARs) so far have mostly failed in the treatment of solid tumors owing to a number of limitations, including an immunosuppressive tumor microenvironment and insufficient CAR T cell activation and persistence. Next-generation approaches using CAR T cells that secrete transgenic immunomodulatory cytokines upon CAR signaling, known as TRUCKs (T cells redirected for universal cytokine-mediated killing), are currently being explored. As TRUCKs were engineered by the transduction of T cells with two separate vectors, we developed a lentiviral modular all-in-one vector system that combines constitutive CAR expression and inducible nuclear factor of activated T cells (NFAT)-driven transgene expression for more efficient production of TRUCKs. Activation of the G(D2)-specific CAR via GD2(+) target cells induced NFAT promoter-driven cytokine release in primary human T cells, and indicated a tight linkage of CAR-specific activation and transgene expression that was further improved by a modified NFATsyn promoter. As proof-of-concept, we showed that T cells containing the all-in-one vector system secrete the immunomodulatory cytokines interleukin (IL)12 or IL18 upon co-cultivation with primary human GD2(+) tumor cells, resulting in enhanced effector cell properties and increased monocyte recruitment. This highlights the potential of our system to simplify application of TRUCK-modified T cells in solid tumor therapy.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Zimmermann, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuehle, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dragon, Anna ChristinaUNSPECIFIEDorcid.org/0000-0002-5228-7627UNSPECIFIED
Galla, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kloth, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rudek, Loreen SophieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sandalcioglu, I. ErolUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neyazi, BelalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moritz, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meyer, JohannUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rossig, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altvater, BiancaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eiz-Vesper, BrittaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morgan, Michael AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abken, HinrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schambach, AxelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-346077
DOI: 10.3390/cancers12020375
Journal or Publication Title: Cancers
Volume: 12
Number: 2
Date: 2020
Publisher: MDPI
Place of Publication: BASEL
ISSN: 2072-6694
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CHIMERIC ANTIGEN RECEPTORS; T-CELL THERAPY; ANTITUMOR-ACTIVITY; IMMUNOTHERAPY; REMISSIONS; CANCER; INTERLEUKIN-12; NFATMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34607

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