학술논문
Pre-clinical validation of a pan-cancer CAR-T cell immunotherapy targeting nfP2X7
Document Type
Original Paper
Author
Bandara, Veronika; Foeng, Jade; Gundsambuu, Batjargal; Norton, Todd S.; Napoli, Silvana; McPeake, Dylan J.; Tyllis, Timona S.; Rohani-Rad, Elaheh; Abbott, Caitlin; Mills, Stuart J.; Tan, Lih Y.; Thompson, Emma J.; Willet, Vasiliki M.; Nikitaras, Victoria J.; Zheng, Jieren; Comerford, Iain; Johnson, Adam; Coombs, Justin; Oehler, Martin K.; Ricciardelli, Carmela; Cowin, Allison J.; Bonder, Claudine S.; Jensen, Michael; Sadlon, Timothy J.; McColl, Shaun R.; Barry, Simon C.
Source
Nature Communications. 14(1)
Subject
Language
English
ISSN
2041-1723
Abstract
Chimeric antigen receptor (CAR)-T cell immunotherapy is a novel treatment that genetically modifies the patients’ own T cells to target and kill malignant cells. However, identification of tumour-specific antigens expressed on multiple solid cancer types, remains a major challenge. P2X purinoceptor 7 (P2X7) is a cell surface expressed ATP gated cation channel, and a dysfunctional version of P2X7, named nfP2X7, has been identified on cancer cells from multiple tissues, while being undetectable on healthy cells. We present a prototype -human CAR-T construct targeting nfP2X7 showing potential antigen-specific cytotoxicity against twelve solid cancer types (breast, prostate, lung, colorectal, brain and skin). In xenograft mouse models of breast and prostate cancer, CAR-T cells targeting nfP2X7 exhibit robust anti-tumour efficacy. These data indicate that nfP2X7 is a suitable immunotherapy target because of its broad expression on human tumours. CAR-T cells targeting nfP2X7 have potential as a wide-spectrum cancer immunotherapy for solid tumours in humans.
The scarcity of targetable proteins broadly expressed on cancer cells, but not on healthy cells, is an obstacle for chimeric antigen receptor (CAR)-T cell therapy. Here the authors establish that a functionally impaired version of P2X purinoceptor 7, non-functional P2X7 (nfP2X7), fulfils these criteria, and demonstrate that CAR-T cells targeting nfP2X7 efficiently and selectively kill breast and prostate cancer cells in mouse models.
The scarcity of targetable proteins broadly expressed on cancer cells, but not on healthy cells, is an obstacle for chimeric antigen receptor (CAR)-T cell therapy. Here the authors establish that a functionally impaired version of P2X purinoceptor 7, non-functional P2X7 (nfP2X7), fulfils these criteria, and demonstrate that CAR-T cells targeting nfP2X7 efficiently and selectively kill breast and prostate cancer cells in mouse models.