title: Adenoviral Delivery of Tumor Necrosis Factor-α and Interleukin-2 Enables Successful Adoptive Cell Therapy of Immunosuppressive Melanoma.
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.
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|TILT Biotherapeutics Ltd, Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Siurala
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Havunen
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Dipongkor
authors.initials: D
authors.lastname: Saha
authors.affiliation: Laboratory of Radiochemistry, Department of Chemistry, University of Helsinki, Helsinki, Finland.
authors.forename: Dave
authors.initials: D
authors.lastname: Lumen
authors.affiliation: Laboratory of Radiochemistry, Department of Chemistry, University of Helsinki, Helsinki, Finland.
authors.forename: Anu J
authors.initials: AJ
authors.lastname: Airaksinen
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Siri
authors.initials: S
authors.lastname: Tähtinen
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|TILT Biotherapeutics Ltd, Helsinki, Finland.
authors.forename: Víctor
authors.initials: V
authors.lastname: Cervera-Carrascon
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Simona
authors.initials: S
authors.lastname: Bramante
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|TILT Biotherapeutics Ltd, Helsinki, Finland.
authors.forename: Suvi
authors.initials: S
authors.lastname: Parviainen
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Markus
authors.initials: M
authors.lastname: Vähä-Koskela
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|Department of Obstetrics and Gynecology, Helsinki University Central Hospital (HUCH), Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kanerva
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|TILT Biotherapeutics Ltd, Helsinki, Finland.|Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism; D064987:Cell- and Tissue-Based Therapy; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D016867:Immunocompromised Host; D016219:Immunotherapy, Adoptive; D015552:Injections, Intralesional; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D000072098:Single Photon Emission Computed Tomography Computed Tomography; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; D007376:Interleukin-2; D061026:Programmed Cell Death 1 Receptor; D014409:Tumor Necrosis Factor-alpha