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

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

Author information

1
Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
2
TILT Biotherapeutics Ltd, Helsinki, Finland.
3
Laboratory of Radiochemistry, Department of Chemistry, University of Helsinki, Helsinki, Finland.
4
Department of Obstetrics and Gynecology, Helsinki University Central Hospital (HUCH), Helsinki, Finland.
5
Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.

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.

PMID:
27357626
PMCID:
PMC5023385
DOI:
10.1038/mt.2016.137
[Indexed for MEDLINE]
Free PMC Article

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