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

Ingunn M. Stromnes, Thomas M. Schmitt, Ayaka Hulbert, J. Scott Brockenbrough, Hieu N. Nguyen, Carlos Cuevas, Ashley M. Dotson, Xiaoxia Tan, Jennifer L. Hotes, Philip D. Greenberg, Sunil R. Hingorani

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)638-652
Number of pages15
JournalCancer Cell
Volume28
Issue number5
DOIs
StatePublished - Nov 9 2015

Bibliographical note

Funding Information:
We thank Markus Carlson, Yen Ho, Fiona Pakiam, Joseph Ryan, Natalie Duerkopp, Megan Larmore, and the University of Washington Histology Core for technical support. We are grateful to Shelley Thorsen, Nathan Lee, and Deborah Banker for assistance with manuscript and figure preparation. We thank Howard Crawford for generously providing partially backcrossed p48 Cre/+ mice. This work was supported by the Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Cancer Center Support Grant CA015704 (S.R.H. and P.D.G.), Giles W. and Elise G. Mead Foundation (S.R.H.), The Safeway Foundation (S.R.H.), a gift from Maryanne Tagney and David Jones (S.R.H.), NIH National Cancer Institute (CA018029 and CA033084 to P.D.G. and CA161112 to S.R.H.), grants from the Korean Research Institute of Bioscience and Biotechnology (P.D.G.), Juno Therapeutics (P.D.G.), and the Irvington Institute Fellowship Program of the Cancer Research Institute and the Jack and Sylvia Paul Estate Fund to Support Collaborative Immunotherapy Research (I.M.S.). P.D.G. has ownership interest (including patents) in and is a scientific consultant/advisory board member for Juno Therapeutics. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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