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Cancer Cell. 2015 Nov 9;28(5):638-652. doi: 10.1016/j.ccell.2015.09.022. Epub 2015 Oct 29.

T Cells Engineered against a Native Antigen Can Surmount Immunologic and Physical Barriers to Treat Pancreatic Ductal Adenocarcinoma.

Author information

1
Clinical Research Division, Seattle, WA, 98109.
2
Department of Immunology, University of Washington School of Medicine, Seattle, WA, 98195.
3
Department of Radiology, University of Washington School of Medicine, Seattle, WA, 98195.
4
Division of Medical Oncology, University of Washington School of Medicine, Seattle, WA, 98195.
5
Public Health Sciences Division of the Fred Hutchinson Cancer Research Center, Seattle, WA, 98109.
#
Contributed equally

Abstract

Pancreatic ductal adenocarcinomas (PDAs) erect physical barriers to chemotherapy and induce multiple mechanisms of immune suppression, creating a sanctuary for unimpeded growth. We tested the ability of T cells engineered to express an affinity-enhanced T cell receptor (TCR) against a native antigen to overcome these barriers in a genetically engineered model of autochthonous PDA. Engineered T cells preferentially accumulate in PDA and induce tumor cell death and stromal remodeling. However, tumor-infiltrating T cells become progressively dysfunctional, a limitation successfully overcome by serial T cell infusions that resulted in a near-doubling of survival without overt toxicities. Similarly engineered human T cells lyse PDA cells in vitro, further supporting clinical advancement of this TCR-based strategy for the treatment of PDA.

PMID:
26525103
PMCID:
PMC4724422
DOI:
10.1016/j.ccell.2015.09.022
[Indexed for MEDLINE]
Free PMC Article

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