Abscopal Effect in Non-injected Tumors Achieved with Cytokine-Armed Oncolytic Adenovirus

Riikka Havunen; João M Santos; Suvi Sorsa; Tommi Rantapero; Dave Lumen; Mikko Siurala; Anu J Airaksinen; Victor Cervera-Carrascon; Siri Tähtinen; Anna Kanerva; Akseli Hemminki

doi:10.1016/j.omto.2018.10.005

Abscopal Effect in Non-injected Tumors Achieved with Cytokine-Armed Oncolytic Adenovirus

Mol Ther Oncolytics. 2018 Nov 6:11:109-121. doi: 10.1016/j.omto.2018.10.005. eCollection 2018 Dec 21.

Authors

Riikka Havunen^{1

2}, João M Santos^{1

2}, Suvi Sorsa^{1

2}, Tommi Rantapero³, Dave Lumen⁴, Mikko Siurala^{1

2}, Anu J Airaksinen⁴, Victor Cervera-Carrascon^{1

2}, Siri Tähtinen¹, Anna Kanerva^{1

5}, Akseli Hemminki^{1

2

6}

Affiliations

¹ Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
² TILT Biotherapeutics Ltd., Helsinki, Finland.
³ BioMediTech, University of Tampere, Tampere, Finland.
⁴ Laboratory of Radiochemistry, Department of Chemistry, University of Helsinki, Helsinki, Finland.
⁵ Department of Obstetrics and Gynecology, Helsinki University Hospital, Helsinki, Finland.
⁶ Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland.

Abstract

Cancer treatment with local administration of armed oncolytic viruses could potentially induce systemic antitumor effects, or the abscopal effect, as they self-amplify in tumors, induce danger signaling, and promote tumor-associated antigen presentation. In this study, oncolytic adenovirus coding for human tumor necrosis factor alpha (TNF-α) and interleukin-2 (IL-2) Ad5/3-E2F-d24-hTNF-α-IRES-hIL-2 (also known as [a.k.a.] TILT-123) provoked antitumor efficacy in tumors that were injected with Ad5/3-E2F-d24-hTNF-α-IRES-hIL-2 and those that were left non-injected in the same animal. Importantly, the virus was able to travel to distant tumors. To dissect the effects of oncolysis and cytokines, we studied replication-incompetent viruses in mice. Systemic antitumor effects were similar in both models, highlighting the importance of the arming device. The cytokines induced positive changes in immune cell infiltrates and induced the expression of several immune-reaction-related genes in tumors. In addition, Ad5/3-E2F-d24-hTNF-α-IRES-hIL-2 was able to increase homing of adoptively transferred tumor-infiltrating lymphocytes into both injected and non-injected tumors, possibly mediated through chemokine expression. In summary, local treatment with Ad5/3-E2F-d24-hTNF-α-IRES-hIL-2 resulted in systemic antitumor efficacy by inducing immune cell infiltration and trafficking into both treated and untreated tumors. Moreover, the oncolytic adenovirus platform had superior systemic effects over replication-deficient vector through spreading into distant tumors.

Keywords: abscopal effect; adenovirus; immunotherapy.