Overcoming Immunological Resistance Enhances the Efficacy of A Novel Anti-tMUC1-CAR T Cell Treatment against Pancreatic Ductal Adenocarcinoma.
CAR T cell
Immunotherapy
MUC1
engineered T cell
pancreatic cancer
pancreatic ductal adenocarcinoma
resistance
targeted therapy
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
11 09 2019
11 09 2019
Historique:
received:
21
08
2019
revised:
07
09
2019
accepted:
09
09
2019
entrez:
14
9
2019
pubmed:
14
9
2019
medline:
12
5
2020
Statut:
epublish
Résumé
Chimeric antigen receptor (CAR) T cells have shown remarkable success in treating hematologic cancers. However, this efficacy has yet to translate to treatment in solid tumors. Pancreatic ductal adenocarcinoma (PDA) is a fatal malignancy with poor prognosis and limited treatment options. We have developed a second generation CAR T cell using the variable fragments of a novel monoclonal antibody, TAB004, which specifically binds the tumor-associated-MUC1 (tMUC1). tMUC1 is overexpressed on ~85% of all human PDA. We present data showing that TAB004-derived CAR T cells specifically bind to tMUC1 on PDA cells and show robust killing activity; however, they do not bind or kill normal epithelial cells. We further demonstrated that the tMUC1-CAR T cells control the growth of orthotopic pancreatic tumors in vivo. We witnessed that some PDA cells (HPAFII and CFPAC) were refractory to CAR T cell treatment. qPCR analysis of several genes revealed overexpression of indoleamine 2, 3-dioxygenases-1 (IDO1), cyclooxygenase 1 and 2 (COX1/2), and galectin-9 (Gal-9) in resistant PDA cells. We showed that combination of CAR T cells and biological inhibitors of IDO1, COX1/2, and Gal-9 resulted in significant enhancement of CAR T cell cytotoxicity against PDA cells. Overcoming PDA resistance is a significant advancement in the field.
Identifiants
pubmed: 31514488
pii: cells8091070
doi: 10.3390/cells8091070
pmc: PMC6770201
pii:
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
MUC1 protein, human
0
Mucin-1
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : R01 CA135650
Pays : United States
Organisme : NCI NIH HHS
ID : R15 CA173668
Pays : United States
Déclaration de conflit d'intérêts
Pinku Mukherjee is a board member of OncoTab, Inc. The other authors declare that they have no conflict of interest.
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