Journal
CANCERS
Volume 12, Issue 2, Pages -Publisher
MDPI
DOI: 10.3390/cancers12020375
Keywords
glioblastoma; all-in-one lentiviral vector; TRUCK; G(D2)CAR; NFAT; inducible cytokines; IL12; IL18
Categories
Funding
- From CARs to TRUCKs (Krebshilfe/German Cancer Aid-Priority Program in Translational Oncology)
- DFG [SFB738]
- Cluster of Excellence REBIRTH [EXC62/2]
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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.
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