Blockade of TGF-β signaling greatly enhances the efficacy of TCR gene therapy of cancer - PubMed (original) (raw)

. 2013 Sep 15;191(6):3232-9.

doi: 10.4049/jimmunol.1301270. Epub 2013 Aug 12.

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Blockade of TGF-β signaling greatly enhances the efficacy of TCR gene therapy of cancer

Gavin M Bendle et al. J Immunol. 2013.

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.

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