Adenoviral Delivery of Tumor Necrosis Factor-α and Interleukin-2 Enables Successful Adoptive Cell Therapy of Immunosuppressive Melanoma

Mol Ther. 2016 Aug;24(8):1435-43. doi: 10.1038/mt.2016.137. Epub 2016 Jun 30.

Abstract

Adoptive T-cell transfer is a promising treatment approach for metastatic cancer, but efficacy in solid tumors has only been achieved with toxic pre- and postconditioning regimens. Thus, adoptive T-cell therapies would benefit from complementary modalities that enable their full potential without excessive toxicity. We aimed to improve the efficacy and safety of adoptive T-cell transfer by using adenoviral vectors for direct delivery of immunomodulatory murine cytokines into B16.OVA melanoma tumors with concomitant T-cell receptor transgenic OT-I T-cell transfer. Armed adenoviruses expressed high local and low systemic levels of cytokine when injected into B16.OVA tumors, suggesting safety of virus-mediated cytokine delivery. Antitumor efficacy was significantly enhanced with adenoviruses coding for murine interleukin-2 (mIL-2) and tumor necrosis factor-α (mTNFα) when compared with T-cell transfer alone or viruses alone. Further improvement in efficacy was achieved with a triple combination of mIL-2, mTNFα, and OT-I T-cells. Mechanistic studies suggest that mIL-2 has an important role in activating T-cells at the tumor, while mTNFα induces chemokine expression. Furthermore, adenovirus treatments enhanced tumor-infiltration of OT-I T-cells as demonstrated by SPECT/CT imaging of (111)In-labeled cells. Our results suggest the utility of cytokine-coding adenoviruses for improving the efficacy of adoptive T-cell therapies.

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • B7-H1 Antigen / metabolism
  • Cell- and Tissue-Based Therapy
  • Disease Models, Animal
  • Gene Expression
  • Genetic Therapy
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics*
  • Immunocompromised Host
  • Immunotherapy, Adoptive*
  • Injections, Intralesional
  • Interleukin-2 / genetics*
  • Interleukin-2 / metabolism
  • Lymphocyte Subsets / immunology
  • Lymphocyte Subsets / metabolism
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Melanoma, Experimental / diagnosis
  • Melanoma, Experimental / genetics*
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / therapy
  • Mice
  • Programmed Cell Death 1 Receptor / metabolism
  • Single Photon Emission Computed Tomography Computed Tomography
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • B7-H1 Antigen
  • Interleukin-2
  • Programmed Cell Death 1 Receptor
  • Tumor Necrosis Factor-alpha