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

• Published in: Molecular therapy 2016-08, Vol.24 (8), p.1435-1443
• Main Authors: Siurala, Mikko, Havunen, Riikka, Saha, Dipongkor, Lumen, Dave, Airaksinen, Anu J., Tähtinen, Siri, Cervera-Carrascon, Víctor, Bramante, Simona, Parviainen, Suvi, Vähä-Koskela, Markus, Kanerva, Anna, Hemminki, Akseli
• Format: Article
• Language: English
• Subjects: Adenoviridae; Adenoviridae - genetics; Adenovirus; 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; Original; Programmed Cell Death 1 Receptor - metabolism; Single Photon Emission Computed Tomography Computed Tomography; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2016.137

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 111In-labeled cells. Our results suggest the utility of cytokine-coding adenoviruses for improving the efficacy of adoptive T-cell therapies.