%0 Journal Article
%A Silvestre, Renata Nacasaki
%A Eitler, Jiri
%A de Azevedo, Julia Teixeira Cottas
%A Tirapelle, Mariane Cariati
%A Fantacini, Daianne Maciely Carvalho
%A de Souza, Lucas Eduardo Botelho
%A Swiech, Kamilla
%A Covas, Dimas Tadeu
%A Calado, Rodrigo T
%A Montero, Paola Ortiz
%A Malmegrim, Kelen Cristina Ribeiro
%A Figueiredo, Marxa L
%A Tonn, Torsten
%A Picanço-Castro, Virginia
%T Engineering NK-CAR.19 cells with the IL-15/IL-15Rα complex improved proliferation and anti-tumor effect in vivo.
%J Frontiers in immunology
%V 14
%@ 1664-3224
%C Lausanne
%I Frontiers Media
%M DKFZ-2023-02038
%P 1226518
%D 2023
%X Natural killer 92 (NK-92) cells are an attractive therapeutic approach as alternative chimeric antigen receptor (CAR) carriers, different from T cells, once they can be used in the allogeneic setting. The modest in vivo outcomes observed with NK-92 cells continue to present hurdles in successfully translating NK-92 cell therapies into clinical applications. Adoptive transfer of CAR-NK-92 cells holds out the promise of therapeutic benefit at a lower rate of adverse events due to the absence of GvHD and cytokine release syndrome. However, it has not achieved breakthrough clinical results yet, and further improvement of CAR-NK-92 cells is necessary.In this study, we conducted a comparative analysis between CD19-targeted CAR (CAR.19) co-expressing IL-15 (CAR.19-IL15) with IL-15/IL-15Rα (CAR.19-IL15/IL15Rα) to promote NK cell proliferation, activation, and cytotoxic activity against B-cell leukemia. CAR constructs were cloned into lentiviral vector and transduced into NK-92 cell line. Potency of CAR-NK cells were assessed against CD19-expressing cell lines NALM-6 or Raji in vitro and in vivo in a murine model. Tumor burden was measured by bioluminescence.We demonstrated that a fourth- generation CD19-targeted CAR (CAR.19) co-expressing IL-15 linked to its receptor IL-15/IL-15Rα (CAR.19-IL-15/IL-15Rα) significantly enhanced NK-92 cell proliferation, proinflammatory cytokine secretion, and cytotoxic activity against B-cell cancer cell lines in vitro and in a xenograft mouse model.Together with the results of the systematic analysis of the transcriptome of activated NK-92 CAR variants, this supports the notion that IL-15/IL-15Rα comprising fourth-generation CARs may overcome the limitations of NK-92 cell-based targeted tumor therapies in vivo by providing the necessary growth and activation signals.
%K B-cell malignances (Other)
%K CAR-NK cells (Other)
%K IL-15 (Other)
%K IL-15 receptor (Other)
%K NK-92 (Other)
%K adoptive cell therapy (Other)
%K allogeneic therapy (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37818365
%2 pmc:PMC10561086
%R 10.3389/fimmu.2023.1226518
%U https://inrepo02.dkfz.de/record/284631