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

: Siurala M, Havunen R, Saha D, Lumen D, Airaksinen AJ, Tähtinen S, Cervera-Carrascon V, Bramante S, Parviainen S, Vähä-Koskela M, Kanerva A, Hemminki A

Publisher: CELL PRESS

: 2016

: Molecular Therapy

: MOLECULAR THERAPY

: MOL THER

: 24

: 8

: 1435

: 1443

: 9

: 1525-0016

DOI: https://doi.org/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 post-conditioning 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 adeno-viruses 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-alpha (mTNF alpha) when compared with T-cell transfer alone or viruses alone. Further improvement in efficacy was achieved with a triple combination of mIL-2, mTNFa, and OT-I T-cells. Mechanistic studies suggest that mIL-2 has an important role in activating T-cells at the tumor, while mTNF alpha 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.