Enhancing the Potency and Specificity of Engineered T Cells for Cancer Treatment

Cancer Discov. 2018 Aug;8(8):972-987. doi: 10.1158/2159-8290.CD-17-1298. Epub 2018 Jun 7.


The adoptive transfer of chimeric antigen receptor (CAR)-modified T cells has produced tumor responses even in patients with refractory diseases. However, the paucity of antigens that are tumor selective has resulted, on occasion, in "on-target, off-tumor" toxicities. To address this issue, we developed an approach to render T cells responsive to an expression pattern present exclusively at the tumor by using a trio of novel chimeric receptors. Using pancreatic cancer as a model, we demonstrate how T cells engineered with receptors that recognize prostate stem cell antigen, TGFβ, and IL4, and whose endodomains recapitulate physiologic T-cell signaling by providing signals for activation, costimulation, and cytokine support, produce potent antitumor effects selectively at the tumor site. In addition, this strategy has the benefit of rendering our cells resistant to otherwise immunosuppressive cytokines (TGFβ and IL4) and can be readily extended to other inhibitory molecules present at the tumor site (e.g., PD-L1, IL10, and IL13).Significance: This proof-of-concept study demonstrates how sophisticated engineering approaches can be utilized to both enhance the antitumor efficacy and increase the safety profile of transgenic T cells by incorporating a combination of receptors that ensure that cells are active exclusively at the tumor site. Cancer Discov; 8(8); 972-87. ©2018 AACR.See related commentary by Achkova and Pule, p. 918This article is highlighted in the In This Issue feature, p. 899.

Publication types

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

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology*
  • Cell Line, Tumor
  • Cell Survival
  • GPI-Linked Proteins / immunology
  • Genetic Engineering / methods*
  • Humans
  • Immunotherapy, Adoptive
  • Interleukin-4 / immunology*
  • Lymphocyte Activation
  • Mice
  • Neoplasm Proteins / immunology*
  • Organ Specificity
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / therapy*
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / transplantation
  • Transforming Growth Factor beta / immunology*
  • Xenograft Model Antitumor Assays


  • Antigens, Neoplasm
  • GPI-Linked Proteins
  • IL4 protein, human
  • Neoplasm Proteins
  • PSCA protein, human
  • Receptors, Antigen, T-Cell
  • Transforming Growth Factor beta
  • Interleukin-4