Day 3

Abstract:

Gabriel van der Pluijm
Leiden University Medical Center, Dept of Urology, Leiden, The Netherlands.

Introduction & Objectives
The clinical effectiveness of current immunotherapeutic approaches for the treatment of urological cancers, in particular for prostate cancer, has been disappointing. Aggressive urological cancers often induce immunosuppressive and immune evasion mechanisms that restrict anti-tumor responses and immunotherapies.
Oncolytic viruses offer a promising, safe therapeutic option in the treatment of cancer(1,2). Although oncolytic viruses were originally designed to function as tumor-lysing therapeutics, they have now been shown to initiate systemic anti-tumor immune responses (innate and adaptive immunity).
In this study we have evaluated and compared the oncolytic and immunomodulatory properties of optimized reovirus variants in multiple patient-derived prostate and urothelial cancer models.  The aim of this study is to develop tools to predict oncolytic virus efficacy and design strategies to personalise oncolytic virus therapy in in cancer patients(2).

Materials & Methods
Optimized mammalian reovirus variants were generated, which represent promising oncolytic agents. Besides wild-type T3D reovirus, spontaneous reovirus mutants were generated with mutations in the spike protein Sigma-1. In this way, the so-called Jin-3 reovirus mutants are able to infect cells independently of the classical viral entry receptor (JAM-A) on the tumor cell surface(2).
The direct oncolytic effects of bioselected reovirus variants were determined in various ‘near-patient’ human prostate and bladder cancer models(2-5); 1) monolayer and 3D tumor cell cultures, 2) new patient-derived xenograft (PDX) and cell-derived xenograft (CDX) models in vivo and 3) in ex vivo cultured tumor tissue slices. The changes in the immunomodulatory and anti-viral pathways were studied by challenging the human cancer cells with candidate reovirus variants.

Results
Jin-3 reovirus variants dose-dependently induced cancer cell death in human prostate and bladder cancer cells in vitro.  In line with these observations, Jin-3 reoviruses caused a rapid and almost complete regression in our PDX models in vivo. The use of our ex vivo cultured patient-derived tissue slice model confirmed the efficacy of Jin-3 reoviruses to infect and replicate in human cancer cells.
Our data show that Jin-3 viruses elicits stronger immunomodulatory and anti-viral responses in human tumor cells when compared with the wild-type T3D reovirus.

Conclusions
-Jin-3 reoviruses display enhanced natural tropism for prostate and bladder cancer cells and have superior oncolytic and immunomodulatory properties.
-Patient-derived prostate and bladder cancer models represent tools for the stratification of patients for future clinical trials with oncolytic viruses. 
-Optimized reoviruses may provide a “kick start” for cancer immunotherapy.
-Jin-3 reovirus is a promising candidate for clinical translation.

References
1: van den Wollenberg DJ et al. Isolation of reovirus T3D mutants capable of infecting human tumor cells independent of junction adhesion molecule-A. PLoS One. 2012;7(10):e48064.
2: Kemp V, Lamfers MLM, van der Pluijm G, van den Hoogen BG, Hoeben RC. Developing oncolytic viruses for clinical use: A consortium approach. Cytokine Growth Factor Rev. 2020 Jun 10:S1359-6101(20)30145-3.
3: van de Merbel AF et al. An ex vivo Tissue Culture Model for the Assessment of Individualized Drug Responses in Prostate and Bladder Cancer. Front Oncol. 2018 Oct 2;8:400.
4: van de Merbel AF, van der Horst G, van der Pluijm G. Patient-derived tumour models for personalized therapeutics in urological cancers. Nat Rev Urol. 2020 Nov 10.
5: van der Horst G et al. Cationic amphiphilic drugs as potential anticancer therapy for bladder cancer. Mol Oncol. 2020 Dec;14(12):3121-3134.