Journal
MOLECULAR THERAPY-ONCOLYTICS
Volume 26, Issue -, Pages 265-274Publisher
CELL PRESS
DOI: 10.1016/j.omto.2022.07.006
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Funding
- Practical Research for Innovative Cancer Control, Japan Agency for Medical Research and Development [19K18416, 19KK0228, 17H06356, 20H03789]
- Translational Research Program, AMED [JP18ck0106416]
- Science and Technology Platform Program for Advanced Biological Medicine, AMED [JP20lm0203140]
- BINDS, AMED [JP21am0401013]
- [JP21am0101078]
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Lp2-CAR-T cells specifically target PDPN-expressing tumor cells and demonstrate selective cytotoxicity. Combination therapy with G47D further inhibits glioblastoma growth and improves survival.
Glioblastoma is a devastating malignant brain tumor with a poor prognosis despite standard therapy. Podoplanin (PDPN), a type I transmembrane mucin-like glycoprotein that is overexpressed in various cancers, is a potential therapeu-tic target for the treatment of glioblastoma. We previously re-ported the efficacy of chimeric antigen receptor (CAR)-T cells using an anti-pan-PDPN monoclonal antibody (mAb; NZ-1) -based third-generation CAR in a xenograft mouse model. How-ever, NZ-1 also reacted with PDPN-expressing normal cells, such as lymphatic endothelial cells, pulmonary alveolar type I cells, and podocytes. To overcome possible on-target-off-tumor effects, we produced a cancer-specific mAb (CasMab, LpMab-2)-based CAR. LpMab-2 (Lp2) reacted with PDPN-ex-pressing cancer cells but not with normal cells. In this study, Lp2-CAR-transduced T cells (Lp2-CAR-T) specifically targeted PDPN-expressing glioma cells while sparing the PDPN-ex-pressing normal cells. Lp2-CAR-T also killed patient-derived glioma stem cells, demonstrating its clinical potential against glioblastoma. Systemic injection of Lp2-CAR-T cells inhibited the growth of a subcutaneous glioma xenograft model in immunodeficient mice. Combination therapy with Lp2-CAR-T and oncolytic virus G47D, a third-generation recombinant herpes simplex virus (HSV)-1, further inhibited the tumor growth and improved survival. These findings indicate that the combination therapy of Lp2-CAR-T cells and G47D may be a promising approach to treat glioblastoma.
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