Blockade of TGF-β signaling greatly enhances the efficacy of TCR gene therapy of cancer.
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.
Division of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands. g.bendle@bham.ac.uk
Gavin M
GM
Bendle
Carsten
C
Linnemann
Laura
L
Bies
Ji-Ying
JY
Song
Ton N M
TN
Schumacher
D000818:Animals; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta