Active immunotherapy combined with blockade of a coinhibitory pathway achieves regression of large tumor masses in cancer-prone mice

Marcio O. Lasaro, Marina Sazanovich, Wynetta Giles-Davis, Paulus Mrass, Ralph M. Bunte, Duane A. Sewell, S. Farzana Hussain, Yang Xin Fu, Wolfgang Weninger, Yvonne Paterson, Hildegund C J Ertl

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Vaccines that aim to expand tumor-specific CD8 T cells have yielded disappointing results in cancer patients although they showed efficacy in transplantable tumor mouse models. Using a system that more faithfully mimics a progressing cancer and its immunoinhibitory microenvironment, we here show that in transgenic mice, which gradually develop adenocarcinomas due to expression of HPV-16 E7 within their thyroid, a highly immunogenic vaccine expressing E7 only induces low E7-specific CD8 T-cell responses, which fail to affect the size of the tumors. In contrast, the same type of vaccine expressing E7 fused to herpes simplex virus (HSV)-1 glycoprotein D (gD), an antagonist of the coinhibitory B-and T-lymphocyte attenuator (BTLA)/CD160-herpes virus entry mediator (HVEM) pathways, stimulates potent E7-specific CD8 T-cell responses, which can be augmented by repeated vaccination, resulting in initial regression of even large tumor masses in all mice with sustained regression in more than half of them. These results indicate that active immunization concomitantly with blockade of the immunoinhibitory HVEM-BTLA/CD160 pathways through HSV-1 gD may result in sustained tumor regression.

Original languageEnglish (US)
Pages (from-to)1727-1736
Number of pages10
JournalMolecular Therapy
Volume19
Issue number9
DOIs
StatePublished - Sep 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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