Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses

JCI Insight. 2018 Apr 5;3(7):e99573. doi: 10.1172/jci.insight.99573.

Abstract

Pancreatic ductal adenocarcinoma (PDA) is characterized by its highly immunosuppressive tumor microenvironment (TME) that limits T cell infiltration and induces T cell hypofunction. Mesothelin-redirected chimeric antigen receptor T cell (meso-CAR T cell) therapy has shown some efficacy in clinical trials but antitumor efficacy remains modest. We hypothesized that combined meso-CAR T cells with an oncolytic adenovirus expressing TNF-α and IL-2 (Ad5/3-E2F-D24-TNFa-IRES-IL2, or OAd-TNFa-IL2) would improve efficacy. OAd-TNFa-IL2 enhanced the antitumor efficacy of meso-CAR T cells in human-PDA-xenograft immunodeficient mice and efficacy was associated with robustly increased tumor-infiltrating lymphocytes (TILs), enhanced and prolonged T cell function. Mice treated with parental OAd combined with meso-CAR T developed tumor metastasis to the lungs even if primary tumors were controlled. However, no mice treated with combined OAd-TNFa-IL2 and meso-CAR T died of tumor metastasis. We also evaluated this approach in a syngeneic mouse tumor model by combining adenovirus expressing murine TNF-α and IL-2 (Ad-mTNFa-mIL2) and mouse CAR T cells. This approach induced significant tumor regression in mice engrafted with highly aggressive and immunosuppressive PDA tumors. Ad-mTNFa-mIL2 increased both CAR T cell and host T cell infiltration to the tumor and altered host tumor immune status with M1 polarization of macrophages and increased dendritic cell maturation. These findings indicate that combining cytokine-armed oncolytic adenovirus to enhance the efficacy of CAR T cell therapy is a promising approach to overcome the immunosuppressive TME for the treatment of PDA.

Keywords: Cancer; Cancer gene therapy; T cells; Therapeutics.

Publication types

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

MeSH terms

  • Adenoviridae / immunology
  • Animals
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / therapy*
  • Cell Line, Tumor
  • Combined Modality Therapy / methods
  • GPI-Linked Proteins / immunology*
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • Oncolytic Virotherapy / methods*
  • Oncolytic Viruses / immunology
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / therapy*
  • Receptors, Chimeric Antigen / immunology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / transplantation
  • Tumor Microenvironment / immunology
  • Xenograft Model Antitumor Assays

Substances

  • GPI-Linked Proteins
  • Receptors, Chimeric Antigen
  • mesothelin