Footnote:
Hinweis: Link zur Erstveröffentlichung URL: https://doi.org/10.3390/ijms20030660
Description:
Novel therapeutic approaches against ovarian cancer (OC) are urgently needed because of
its high rate of recurrence even after extensive surgery and multi-agent chemotherapy. We aimed
to develop a novel anti-CD24 chimeric antigen receptor (CAR) as an immunotherapeutic approach
against OC cells and cancer stem cells (CSC). CSC represents a subpopulation of the tumor
characterized by enhanced chemoresistance as well as the increased capability of self-renewal and
metastasis. We designed a codon-optimized third-generation CAR containing the highly active
single chain variable fragment (scFv) “SWA11” against CD24. We equipped the human NK-cell
line NK-92 with the anti-CD24 CAR and an anti-CD19 control CAR using lentiviral transduction.
Engineered NK-92 cells showed high cytotoxic activity against CD24-positive OC cell lines (SKOV3,
OVCAR3). This effect was restricted to CD24-expressing cells as shown after lentiviral transduction
of CD24-negative cell lines (A2780, HEK-293T) with CD24 transmembrane proteins. Additionally,
NK-92 cells equipped with our novel anti-CD24 CAR were highly effective against patient-derived
primary ovarian cancer cells. The activation of NK cells was shown by specific IFN
secretion
upon antigen stimulation. To further reduce possible off-target effects in vivo, we applied a
dual-CAR approach using an anti-CD24-CD28-41BB fusion protein linked via a 2A sequence to an
anti-mesothelin-CD3-CAR. The dual-CAR was simultaneously active against CD24 and mesothelin
expressing cells. Our novel anti-CD24-CAR showed a highly cytotoxic effect against OC cell lines and
primary OC cells and will be evaluated in future in vivo trials as a promising immunotherapeutic
approach against OC.