Zelluläre Immuneffekte einer Gliomvirotherapie, basierend auf YB-1-abhängigen, onkolytischen Adenoviren
Immunologie
Virologie
Zusammenfassung der Projektergebnisse
GBM is a devastating disease and approved treatment options after recurrence do not exist. Thus, the development of new treatment strategies against GBM are urgently needed. Besides targeted therapies and immunotherapy (vaccination and active cellular immunotherapy), oncolytic viruses are currently being explored as a therapeutic “weapon” against glioma. In particular, with regard of their combinability with different existing immunogenic therapies, OVs hold much promise to improve the outcome of GBM patients. The effectiveness of oncolytic viruses including our YB-1 dependent OAV XVir-N-31 and its offspring XVir-N-31-anti- PD-L1 depend (i) on their capacity to replicate within and kill cancer cells efficiently and (ii) to induce immunogenic cell death, which is characterized by the release of DAMPs such as HSP70 and HMGB1. We show that the replication and lytic efficacy of XVir-N-31 can be further significantly potentiated using approved cell cycle CDK4/6 inhibitors that induce a G1 arrest in cancer cells, or by BRD4 inhibitors like JQ1 that is largely acknowledged to inhibit RNA polymerase II, by this limiting the expression of oncogenic transcription factors like MYC and E2F. Since both classes of inhibitors also trigger anti-tumor immunity, our results provide a strong rationale for a new combination regimens comprising CDK4/6 and BRD/BET inhibitors and XVir-N-31 as an anti-cancer treatment. Although OVs are attractive candidates for the induction of ICD it is well known that viruses have developed different mechanism to avoid immune recognition by limiting the induction of ICD. XVir-N-31 demonstrates significant lower cell killing capacity, but a much stronger induction of ICD than Ad-WT. In vivo this leads to an abscopal effect of ICD in contralaterally growing, uninfected tumors that have never been a target of viral replication. Again, also in these tumors no ICD was detected if using Ad-WT for treatment. Importantly, by an additional immune checkpoint inhibition (ICI) using either systemic application of Nivolumab in comibination with XVir-N-31, or by the intratumoral injection of XVir-N-31-anti-PD-L, these abscopal effect of ICD induction was further elevated. In addition, at least in immunohumanized mice harboring HLA-A/B-matched GBM we demonstrate that our OVT strategy, and especially if combined with the blockade of the PD-1/PD-L1 axis, provides the potential to recruit not only T cells, but also NK cells as members of the innate immune system and potent fighters against cancer cells, into the tumor area. Nevertheless, in regard to tumor growth, best abscopal effects were observed if our XVir-N-31 based OVT was combined with an immune checkpoint inhibition. In summary, the obtained results in this DFG-funded project clearly prove the enormous immunological potential of our OVT approach. Additionally, it provides important insights into the optimization and design of OAVs, their choice (which OAV and its combination with which inhibitor) fits best to which tumor entity. Last but not least, the results from this study give insight into how to plan and develop a therapeutically successful XVir-N- 31-based oncolytic immunotherapy (OVIT).
Projektbezogene Publikationen (Auswahl)
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Concepts in Oncolytic Adenovirus Therapy. International Journal of Molecular Sciences, 22(19), 10522.
Mantwill, Klaus; Klein, Florian Gerhard; Wang, Dongbiao; Hindupur, Sruthi Vasantamadhava; Ehrenfeld, Maximilian; Holm, Per Sonne & Nawroth, Roman
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Virotherapy in Germany—Recent Activities in Virus Engineering, Preclinical Development, and Clinical Studies. Viruses, 13(8), 1420.
Nettelbeck, Dirk M.; Leber, Mathias F.; Altomonte, Jennifer; Angelova, Assia; Beil, Julia; Berchtold, Susanne; Delic, Maike; Eberle, Jürgen; Ehrhardt, Anja; Engeland, Christine E.; Fechner, Henry; Geletneky, Karsten; Goepfert, Katrin; Holm, Per Sonne; Kochanek, Stefan; Kreppel, Florian; Krutzke, Lea; Kühnel, Florian; Lang, Karl Sebastian ... & Ungerechts, Guy
