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

Mol Ther. 2017 Nov 1;25(11):2440-2451. doi: 10.1016/j.ymthe.2017.09.010. Epub 2017 Sep 14.


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.

Keywords: CAR T cell therapy; adenovirotherapy; head and neck cancer; oncolytic virus; orthotopic animal model.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Adenoviridae / immunology*
  • Animals
  • Antibodies, Neoplasm / genetics
  • Antibodies, Neoplasm / immunology
  • Antibodies, Neutralizing / genetics
  • Antibodies, Neutralizing / immunology
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / immunology
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / therapy*
  • Combined Modality Therapy / methods*
  • Female
  • Gene Expression
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / immunology
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / therapy*
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology
  • Lymphocyte Transfusion
  • Mice
  • Oncolytic Virotherapy / methods*
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / immunology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Survival Analysis
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / transplantation
  • Tumor Burden
  • Xenograft Model Antitumor Assays


  • Antibodies, Neoplasm
  • Antibodies, Neutralizing
  • B7-H1 Antigen
  • CD274 protein, human
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • Interleukin-12
  • ERBB2 protein, human
  • Receptor, ErbB-2