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Simple Summary Cancer immunotherapy involves the application of strategies aimed at enhancing the body’s immune system to recognize and clear tumor cells. One such immunotherapeutic approach utilizes cytotoxic immune cells (T cells) harvested from the patient, which are expanded and activated, followed by re-infusion to the same patient. This process is termed adoptive cell therapy (ACT). Although effective in a limited setting, efforts are being made to improve these therapies through the development of rationally designed combination treatments. We have developed an approach, whereby tumors are pretreated with a virus, which has oncolytic effects on the tumor cells, in addition to modulating changes in the tumor microenvironment, thereby improving the recruitment of the adoptively transferred cytotoxic T cells and resulting in synergistic therapeutic responses in the tumor. This results in a substantial prolongation of survival, as demonstrated in an immune-competent mouse model of melanoma. Abstract Cancer immunotherapies have made major advancements in recent years and are becoming the prevalent treatment options for numerous tumor entities. However, substantial response rates have only been observed in specific subsets of patients since pre-existing factors determine the susceptibility of a tumor to these therapies. The development of approaches that can actively induce an anti-tumor immune response, such as adoptive cell transfer and oncolytic virotherapy, have shown clinical success in the treatment of leukemia and melanoma, respectively. Based on the immune-stimulatory capacity of oncolytic VSV-NDV virotherapy, we envisioned a combination approach to synergize with adoptive T cell transfer, in order to enhance tumor cell killing. Using the immune-competent B16 melanoma model, we demonstrate that combination treatment has beneficial effects on the suppressive microenvironment through upregulation of MHC-I and maintaining low expression levels of PD-L1 on tumor cells. The approach led to additive cytotoxic effects and improved the recruitment of T cells to virus-infected tumor cells in vitro and in vivo. We observed substantial delays in tumor growth and evidence of abscopal effects, as well as prolongation of overall survival time when administered at clinically relevant dosing conditions. Our results indicate that treatment with oncolytic VSV-NDV, combined with adoptive T cell therapy, induces multi-mechanistic and synergistic tumor responses, which supports the further development of this promising translational approach.

Das maligne Melanom stellt eine bösartige Tumorerkrankung dar, die nach Ausbildung von Metastasen eine ungünstige Prognose für die Patienten aufweist. Zwar existieren eine Reihe von verschiedensten Medikamenten, die bei der Behandlung des Melanoms zum Einsatz kommen, dennoch besteht, aufgrund von auftretenden Resistenzen und Nebenwirkungen das Bedürfnis, vor allem die vielversprechende Immuntherapie zu optimieren und zu verbessern. Dazu gehört die Erforschung und Entwicklung von onkolytischen Viren. In dieser Arbeit wurden die neu entwickelten VSV-NDV-sPD1-Varianten im Hinblick auf ihre Replikationsfähigkeit, Zytotoxizität und Effektivität in vitro und in vivo charakterisiert. Außerdem diente diese Arbeit dazu, die Kombinationstherapie aus dem Immuncheckpoint-Inhibitor Anti-CTLA-4 und dem rekombinanten onkolytischen Virus VSV-NDV zu analysieren und die Rolle des RIG-I-Rezeptors, der virale RNA erkennen kann, in diesem Zusammenhang zu untersuchen. Die Ergebnisse dieser Arbeit machen deutlich, dass VSV-NDV eine vielversprechende Virusplattform als zukünftiges Immuntherapeutikum darstellt. Weitere Modifikationen ermöglichen einen gezielten Eingriff in Signalwege zwischen Tumorzellen und Immunzellen, um eine gezielte Antitumor-Immunantwort zu induzieren, zu verbessern und zu verstärken.