Replicating viral vector platform exploits alarmin signals for potent CD8+ T cell-mediated tumour immunotherapy

Sandra M. Kallert, Stephanie Darbre, Weldy V. Bonilla, Mario Kreutzfeldt, Nicolas Page, Philipp Müller, Matthias Kreuzaler, Min Lu, Stéphanie Favre, Florian Kreppel, Max Löhning, Sanjiv A. Luther, Alfred Zippelius, Doron Merkler and Daniel D. Pinschewer ()
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Sandra M. Kallert: University of Basel
Stephanie Darbre: Departement de Pathologie et Immunologie, Centre Médical Universitaire, University of Geneva
Weldy V. Bonilla: University of Basel
Mario Kreutzfeldt: Departement de Pathologie et Immunologie, Centre Médical Universitaire, University of Geneva
Nicolas Page: Departement de Pathologie et Immunologie, Centre Médical Universitaire, University of Geneva
Philipp Müller: University Hospital and University of Basel
Matthias Kreuzaler: University Hospital and University of Basel
Min Lu: University of Basel
Stéphanie Favre: Center for Immunity and Infection Lausanne, University of Lausanne
Florian Kreppel: Witten/Herdecke University (UW/H), Faculty of Health/School of Medicine
Max Löhning: Experimental Immunology and Osteoarthritis Research, Charité–Universitätsmedizin Berlin
Sanjiv A. Luther: Center for Immunity and Infection Lausanne, University of Lausanne
Alfred Zippelius: University Hospital and University of Basel
Doron Merkler: Departement de Pathologie et Immunologie, Centre Médical Universitaire, University of Geneva
Daniel D. Pinschewer: University of Basel

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTLeff) responses. Conversely, the induction of protective tumour-specific CTLeff and their recruitment into the tumour remain challenging tasks. Here we show that lymphocytic choriomeningitis virus (LCMV) can be engineered to serve as a replication competent, stably-attenuated immunotherapy vector (artLCMV). artLCMV delivers tumour-associated antigens to dendritic cells for efficient CTL priming. Unlike replication-deficient vectors, artLCMV targets also lymphoid tissue stroma cells expressing the alarmin interleukin-33. By triggering interleukin-33 signals, artLCMV elicits CTLeff responses of higher magnitude and functionality than those induced by replication-deficient vectors. Superior anti-tumour efficacy of artLCMV immunotherapy depends on interleukin-33 signalling, and a massive CTLeff influx triggers an inflammatory conversion of the tumour microenvironment. Our observations suggest that replicating viral delivery systems can release alarmins for improved anti-tumour efficacy. These mechanistic insights may outweigh safety concerns around replicating viral vectors in cancer immunotherapy.

Date: 2017
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DOI: 10.1038/ncomms15327

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