Adenovirotherapy Delivering Cytokine and Checkpoint Inhibitor Augments CAR T Cells against Metastatic Head and Neck Cancer

Amanda Rosewell Shaw, Caroline E. Porter, Norihiro Watanabe, Kiyonori Tanoue, Andrew Sikora, Stephen Gottschalk, Malcolm Brenner, Masataka Suzuki

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

In solid tumors, chimeric antigen receptor (CAR)-modified T cells must overcome the challenges of the immunosuppressive tumor microenvironment. We hypothesized that pre-treating tumors with our binary oncolytic adenovirus (CAd), which produces local oncolysis and expresses immunostimulatory molecules, would enhance the antitumor activity of HER2-specific CAR T cells, which alone are insufficient to cure solid tumors. We tested multiple cytokines in conjunction with PD-L1-blocking antibody and found that Ad-derived IL-12p70 prevents the loss of HER2.CAR-expressing T cells at the tumor site. Accordingly, we created a construct encoding the PD-L1-blocking antibody and IL-12p70 (CAd12_PDL1). In head and neck squamous cell carcinoma (HNSCC) xenograft models, combining local treatment with CAd12_PDL1 and systemic HER2.CAR T cell infusion improved survival to >100 days compared with approximately 25 days with either approach alone. This combination also controlled both primary and metastasized tumors in an orthotopic model of HNSCC. Overall, our data show that CAd12_PDL1 augments the anti-tumor effects of HER2.CAR T cells, thus controlling the growth of both primary and metastasized tumors. Rosewell Shaw et al. combine their binary oncolytic adenoviral vector with chimeric antigen receptor-modified T cells to overcome the inherent limitations of each agent. Locally injected adenovirus expressing both PDL1 checkpoint antibody and IL-12 augments the systemic anti-tumor activity of HER2.CAR-T cells, improving survival from human head and neck cancer xenografts.

Original languageEnglish (US)
Pages (from-to)2440-2451
Number of pages12
JournalMolecular Therapy
Volume25
Issue number11
DOIs
StatePublished - Nov 1 2017

Keywords

  • CAR T cell therapy
  • adenovirotherapy
  • head and neck cancer
  • oncolytic virus
  • orthotopic animal model

ASJC Scopus subject areas

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

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