AUTHOR=Rudek Loreen Sophie , Zimmermann Katharina , Galla Melanie , Meyer Johann , Kuehle Johannes , Stamopoulou Andriana , Brand Daniel , Sandalcioglu I. Erol , Neyazi Belal , Moritz Thomas , Rossig Claudia , Altvater Bianca , Falk Christine S. , Abken Hinrich , Morgan Michael Alexander , Schambach Axel TITLE=Generation of an NFκB-Driven Alpharetroviral “All-in-One” Vector Construct as a Potent Tool for CAR NK Cell Therapy JOURNAL=Frontiers in Immunology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.751138 DOI=10.3389/fimmu.2021.751138 ISSN=1664-3224 ABSTRACT=

Immune cell therapeutics are increasingly applied in oncology. Especially chimeric antigen receptor (CAR) T cells are successfully used to treat several B cell malignancies. Efforts to engineer CAR T cells for improved activity against solid tumors include co-delivery of pro-inflammatory cytokines in addition to CARs, via either constitutive cytokine expression or inducible cytokine expression triggered by CAR recognition of its target antigen—so-called “T cells redirected for universal cytokine-mediated killing” (TRUCKs) or fourth-generation CARs. Here, we tested the hypothesis that TRUCK principles could be expanded to improve anticancer functions of NK cells. A comparison of the functionality of inducible promoters responsive to NFAT or NFκB in NK cells showed that, in contrast to T cells, the inclusion of NFκB-responsive elements within the inducible promoter construct was essential for CAR-inducible expression of the transgene. We demonstrated that GD2CAR-specific activation induced a tight NFκB-promoter-driven cytokine release in NK-92 and primary NK cells together with an enhanced cytotoxic capacity against GD2+ target cells, also shown by increased secretion of cytolytic cytokines. The data demonstrate biologically relevant differences between T and NK cells that are important when clinically translating the TRUCK concept to NK cells for the treatment of solid malignancies.