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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens / immunology*
  • Carcinoma, Pancreatic Ductal / immunology*
  • Carcinoma, Pancreatic Ductal / pathology
  • Carcinoma, Pancreatic Ductal / therapy
  • Cell Line, Tumor
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / immunology
  • GPI-Linked Proteins / metabolism
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Immunotherapy, Adoptive / methods
  • Jurkat Cells
  • Kaplan-Meier Estimate
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / therapy
  • Protein Engineering / methods
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / transplantation
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Antigens
  • GPI-Linked Proteins
  • Receptors, Antigen, T-Cell
  • mesothelin