Back to Search
Start Over
PLAP -CAR T cells mediate high specific cytotoxicity against colon cancer cells.
- Source :
-
Frontiers in bioscience (Landmark edition) [Front Biosci (Landmark Ed)] 2020 Jun 01; Vol. 25 (9), pp. 1765-1786. Date of Electronic Publication: 2020 Jun 01. - Publication Year :
- 2020
-
Abstract
- Placental alkaline phosphatase, PLAP encoded by ALPP gene in humans is mainly expressed in placenta and testis, and not expressed in any other normal tissues. PLAP is overexpressed in colorectal cancers which makes it an attractive target for CAR (chimeric antigen receptor)-T cell therapy. PLAP mRNA expression was detected in 21.5% (25 out of 116) of colorectal cancer cell lines and this expression was confirmed by FACS at the protein level. In addition, IHC staining on primary colorectal cancer tumors demonstrated PLAP expression in >20% of colorectal cancer tumors. We generated mouse and humanized PLAP ScFv-CAR-T cells and demonstrated high specificity against PLAP-positive colon cancer cells using RTCA (real-time cytotoxicity assay) and IFN-gamma secretion. In addition, humanized-CAR-T cells significantly decreased Lovo xenograft tumor growth in vivo . The combination of hPLAP-CAR-T cells with PD-1, PD-L1 or LAG-3 checkpoint inhibitors significantly increased the activity of hPLAP-CAR-T cells. This study demonstrates ability of novel PLAP-CAR-T cells to kill colorectal cancers and that the extent of killing can be increased by combination with checkpoint inhibitors.
- Subjects :
- Alkaline Phosphatase antagonists & inhibitors
Alkaline Phosphatase metabolism
Animals
Caco-2 Cells
Cell Line, Tumor
Cell Survival drug effects
Cell Survival immunology
Colonic Neoplasms metabolism
Colonic Neoplasms therapy
GPI-Linked Proteins antagonists & inhibitors
GPI-Linked Proteins immunology
GPI-Linked Proteins metabolism
HCT116 Cells
HEK293 Cells
HT29 Cells
Humans
Immune Checkpoint Inhibitors pharmacology
Immunotherapy, Adoptive methods
Interferon-gamma immunology
Interferon-gamma metabolism
Isoenzymes antagonists & inhibitors
Isoenzymes metabolism
Male
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Receptors, Chimeric Antigen metabolism
Single-Chain Antibodies metabolism
T-Lymphocytes metabolism
Xenograft Model Antitumor Assays methods
Alkaline Phosphatase immunology
Colonic Neoplasms immunology
Isoenzymes immunology
Receptors, Chimeric Antigen immunology
Single-Chain Antibodies immunology
T-Lymphocytes immunology
Subjects
Details
- Language :
- English
- ISSN :
- 2768-6698
- Volume :
- 25
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Frontiers in bioscience (Landmark edition)
- Publication Type :
- Academic Journal
- Accession number :
- 32472757
- Full Text :
- https://doi.org/10.2741/4877