TY  - JOUR
AU  - Silvestre, Renata Nacasaki
AU  - Eitler, Jiri
AU  - de Azevedo, Julia Teixeira Cottas
AU  - Tirapelle, Mariane Cariati
AU  - Fantacini, Daianne Maciely Carvalho
AU  - de Souza, Lucas Eduardo Botelho
AU  - Swiech, Kamilla
AU  - Covas, Dimas Tadeu
AU  - Calado, Rodrigo T
AU  - Montero, Paola Ortiz
AU  - Malmegrim, Kelen Cristina Ribeiro
AU  - Figueiredo, Marxa L
AU  - Tonn, Torsten
AU  - Picanço-Castro, Virginia
TI  - Engineering NK-CAR.19 cells with the IL-15/IL-15Rα complex improved proliferation and anti-tumor effect in vivo.
JO  - Frontiers in immunology
VL  - 14
SN  - 1664-3224
CY  - Lausanne
PB  - Frontiers Media
M1  - DKFZ-2023-02038
SP  - 1226518
PY  - 2023
AB  - 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.
KW  - B-cell malignances (Other)
KW  - CAR-NK cells (Other)
KW  - IL-15 (Other)
KW  - IL-15 receptor (Other)
KW  - NK-92 (Other)
KW  - adoptive cell therapy (Other)
KW  - allogeneic therapy (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37818365
C2  - pmc:PMC10561086
DO  - DOI:10.3389/fimmu.2023.1226518
UR  - https://inrepo02.dkfz.de/record/284631
ER  -