Blockade of TGF-β Signaling Greatly Enhances the Efficacy of TCR Gene Therapy of Cancer

Research output: Contribution to journalArticle

Authors

  • Gavin Bendle
  • Carsten Linnemann
  • Laura Bies
  • Ji-Ying Song
  • Ton N M Schumacher

Colleges, School and Institutes

Abstract

TCR gene therapy is a promising approach for the treatment of various human malignancies. However, the tumoricidal activity of TCR-modified T cells may be limited by local immunosuppressive mechanisms within the tumor environment. In particular, many malignancies induce T cell suppression in their microenvironment by TGF-β secretion. In this study, we evaluate whether blockade of TGF-β signaling in TCR-modified T cells enhances TCR gene therapy efficacy in an autochthonous mouse tumor model. Treatment of mice with advanced prostate cancer with T cells genetically engineered to express a tumor-reactive TCR and a dominant-negative TGF-β receptor II induces complete and sustained tumor regression, enhances survival, and leads to restored differentiation of prostate epithelium. These data demonstrate the potential to tailor the activity of TCR-modified T cells by additional genetic modification and provide a strong rationale for the clinical testing of TGF-β signaling blockade to enhance TCR gene therapy against advanced cancers.

Details

Original languageEnglish
Pages (from-to)3232-3239
JournalJournal of Immunology
Volume191
Issue number6
Early online date12 Aug 2013
Publication statusPublished - 15 Sep 2013