title: Oncolytic Adenoviruses Armed with Tumor Necrosis Factor Alpha and Interleukin-2 Enable Successful Adoptive Cell Therapy.
abstract: Adoptive cell therapy holds much promise in the treatment of cancer but results in solid tumors have been modest. The notable exception is tumor-infiltrating lymphocyte (TIL) therapy of melanoma, but this approach only works with high-dose preconditioning chemotherapy and systemic interleukin (IL)-2 postconditioning, both of which are associated with toxicities. To improve and broaden the applicability of adoptive cell transfer, we constructed oncolytic adenoviruses coding for human IL-2 (hIL2), tumor necrosis factor alpha (TNF-α), or both. The viruses showed potent antitumor efficacy against human tumors in immunocompromised severe combined immunodeficiency (SCID) mice. In immunocompetent Syrian hamsters, we combined the viruses with TIL transfer and were able to cure 100% of the animals. Cured animals were protected against tumor re-challenge, indicating a memory response. Arming with IL-2 and TNF-α increased the frequency of both CD4+and CD8+TILs in vivo and augmented splenocyte proliferation ex vivo, suggesting that the cytokines were important for T cell persistence and proliferation. Cytokine expression was limited to tumors and treatment-related signs of systemic toxicity were absent, suggesting safety. To conclude, cytokine-armed oncolytic adenoviruses enhanced adoptive cell therapy by favorable alteration of the tumor microenvironment. A clinical trial is in progress to study the utility of Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (TILT-123) in human patients with cancer.
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Havunen
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland; TILT Biotherapeutics, Ltd., 00290 Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Siurala
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland; TILT Biotherapeutics, Ltd., 00290 Helsinki, Finland.
authors.forename: Suvi
authors.initials: S
authors.lastname: Sorsa
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Susanna
authors.initials: S
authors.lastname: Grönberg-Vähä-Koskela
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Michael
authors.initials: M
authors.lastname: Behr
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Siri
authors.initials: S
authors.lastname: Tähtinen
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland; TILT Biotherapeutics, Ltd., 00290 Helsinki, Finland.
authors.forename: João Manuel
authors.initials: JM
authors.lastname: Santos
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Pauliina
authors.initials: P
authors.lastname: Karell
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Juuso
authors.initials: J
authors.lastname: Rusanen
authors.affiliation: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Nettelbeck
authors.affiliation: Faculty of Health, Institute for Virology and Microbiology, University Witten/Herdecke, 58448 Witten, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Ehrhardt
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland; Department of Obstetrics and Gynecology, Helsinki University Central Hospital, 00610 Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kanerva
authors.affiliation: Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland; TILT Biotherapeutics, Ltd., 00290 Helsinki, Finland; Comprehensive Cancer Center, Helsinki University Hospital, 00290 Helsinki, Finland.
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
keywords: TNF; adenovirus; cytokines; interleukin 2; tumor-infiltrating lymphocytes