[HTML][HTML] Adenoviral delivery of tumor necrosis factor-α and interleukin-2 enables successful adoptive cell therapy of immunosuppressive melanoma

M Siurala, R Havunen, D Saha, D Lumen… - Molecular Therapy, 2016 - cell.com
M Siurala, R Havunen, D Saha, D Lumen, AJ Airaksinen, S Tähtinen, V Cervera-Carrascon
Molecular Therapy, 2016cell.com
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 …
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.
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