Generation of an NFκB-Driven Alpharetroviral “All-in-One” Vector Construct as a Potent Tool for CAR NK Cell Therapy
Loreen Sophie Rudek, Katharina Zimmermann, Melanie Galla, Johann Meyer, Johannes Kuehle, Ανδριάνα Σταμοπούλου, Daniel Brand, I. Erol Sandalcioglu, Belal Neyazi, Moritz Thomas, Claudia Rössig, Bianca Altvater, Christine S. Falk, Hinrich Abken, Michael Morgan, Axel Schambach
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.