Harnessing the immunostimulatory properties of oncolytic reovirus for anticancer immunotherapy

Groeneveldt, P.C. (2023)

Doctoral Thesis

In this thesis, we unraveled the immunostimulatory potential of oncolytic reovirus and investigated how these immunostimulatory characteristics could be exploited for effective anticancer immunotherapy. We demonstrated that administration of oncolytic reovirus does not lead to strong oncolytic effects in tumors, but instead unleashes a very potent immune response, including the priming of reovirus-specific CD8 T cells. We showed that these reovirus-specific CD8 T cells can be effectively employed for anticancer immunotherapy, by either bypassing their specificity (with CD3-bsAbs) or by exploiting their specificity (via installing a preinduced pool using SLP vaccination). Besides the induction of reovirus-specific CD8 T cells, reovirus administration also leads to very fast B-cell responses. We demonstrated that the presence of neutralizing antibodies (NAbs) restricts the use of reovirus as an oncolytic agent, but that the reovirus-induced influx of CD8 T cells is retained and the use of reovirus in combination with T-cell-based immunotherapy can still result in potent antitumor responses. Lastly, we showed that blockade of Transforming Growth Factor-β (TGF-β) does not impair reovirus infection and reovirus-induced ISG expression or the reovirus-induced attraction and activation of T cells, but that intrinsic differences between preclinical tumor models can determine if TGF-β blockade is a beneficial addition to combined reovirus and T-cell-based immunotherapy.

• Oncolytic Reovirus
• Cancer Immunotherapy
• Solid Tumors
• Virus-specific CD8 T cells
• Neutralizing Antibodies
• Preexisting Immunity
• Transforming Growth Factor-β

• All authors: Groeneveldt, P.C.
• Supervisor: Burg, S.H. van der; Hall, T. van
• Co-supervisor: Montfoort, A.G. van
• Committee: Wiertz, E.J.H.J.; Gruijl, T.D. de; Heemskerk, M.H.M.; Toes, R.E.M.; Yazdanbakhsh, M.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2023-11-23
• ISBN (print): 9789464833942
• Sponsorship: The research described in this thesis was performed at the Department of Medical Oncology of the Leiden University Medical Center, Leiden and was financially supported by a PhD fellowship from Leiden University Medical Center, the Dutch Cancer Society Bas Mulder Award (11056) and the Support Casper campaign by the Dutch foundation ‘Stichting Overleven met Alvleesklierkanker’ (project numbers SOAK 17.04, 19.03 and 22.02).