Oncolytic Adenoviruses Armed with Tumor Necrosis Factor Alpha and Interleukin-2 Enable Successful Adoptive Cell Therapy

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http://hdl.handle.net/10138/197460

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Havunen , R , Siurala , M , Sorsa , S , Gronberg-Vaha-Koskela , S , Behr , M , Tähtinen , S , Santos , J M , Karell , P , Rusanen , J , Nettelbeck , D M , Ehrhardt , A , Kanerva , A & Hemminki , A 2017 , ' Oncolytic Adenoviruses Armed with Tumor Necrosis Factor Alpha and Interleukin-2 Enable Successful Adoptive Cell Therapy ' , Molecular Therapy - Oncolytics , vol. 4 , pp. 77-86 . https://doi.org/10.1016/j.omto.2016.12.004

Title: Oncolytic Adenoviruses Armed with Tumor Necrosis Factor Alpha and Interleukin-2 Enable Successful Adoptive Cell Therapy
Author: Havunen, Riikka; Siurala, Mikko; Sorsa, Suvi; Gronberg-Vaha-Koskela, Susanna; Behr, Michael; Tähtinen, Siri; Santos, Joao Manuel; Karell, Pauliina; Rusanen, Juuso; Nettelbeck, Dirk M.; Ehrhardt, Anja; Kanerva, Anna; Hemminki, Akseli
Contributor: University of Helsinki, Clinicum
University of Helsinki, Clinicum
University of Helsinki, Clinicum
University of Helsinki, Clinicum
University of Helsinki, Clinicum
University of Helsinki, Clinicum
Date: 2017-03-17
Language: eng
Number of pages: 10
Belongs to series: Molecular Therapy - Oncolytics
ISSN: 2372-7705
URI: http://hdl.handle.net/10138/197460
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-alpha), 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-alpha 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.
Subject: METASTATIC MELANOMA PATIENTS
SOLID TUMORS
TNF-ALPHA
T-CELLS
IN-VIVO
CANCER
IMMUNOTHERAPY
EFFICACY
TRANSDUCTION
VIROTHERAPY
3122 Cancers
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