Radiation Attenuates Prostate Tumor Antiviral Responses to Vesicular Stomatitis Virus Containing IFNβ, Resulting in Pronounced Antitumor Systemic Immune Responses.

Wensi Tao,Thirupandiyur S Udayakumar,Alan Pollack,Tulasigeri M Totiger,Anis Ahmad,Brian Marples,Mausam Patel,Glen Barber,Dillon M Betancourt

doi:10.1158/1541-7786.mcr-19-0836

Abstract

Vesicular stomatitis virus (VSV) expressing IFNβ induces apoptosis in multiple tumor models while maintaining an excellent safety profile. VSV-IFNβ is oncoselective due to permissive replication in cells with an altered IFN pathway. The human VSV-IFNβ (hIFNβ) vector is currently used in clinical trials as a standalone therapy; however, we hypothesized that oncolytic virotherapy might be more effective when used in combination with radiotherapy (RT). We investigated the synergistic effects of RT and VSV-hIFNβ in the subcutaneous PC3 and orthotopic LNCaP prostate xenograft models and a syngeneic RM9 prostate tumor model. VSV-IFNβ combined with RT amplified tumor killing for PC3 and LNCaP xenografts, and RM9 tumors. This was attributed to the induction of proapoptotic genes leading to increased VSV-IFNβ infection and replication, VSV expression, and oncolysis. In the RM9 tumors, combination therapy resulted in a robust antitumor immune response. Treated RM9 tumor-bearing mice demonstrated an increase in CD8+ and CD4+ T-cell numbers, 100% resistance to tumor rechallenge, and reduced resistance to reimplantation challenge with CD8+ knockdown. RT enhanced the activity of VSV-mediated oncolysis via attenuation of the innate antiviral response, resulting in increased VSV replication and the generation of an adaptive immune response earmarked by an increase in CD8+ lymphocyte numbers and antitumor activity. Local tumor irradiation combined with VSV-IFNβ affects tumor cell death through direct and systemic activity in conjunction with pronounced antitumor immunity. IMPLICATIONS: Radiotherapy enhances VSV-mediated oncolysis and anti-tumor immunity, indicating that the ombination has promise for very high risk prostate cancer.

Highlights

Prostate cancer remains the second leading cause of cancer-related death in men [1]
Vesicular stomatitis virus (VSV)-human VSV-IFNb (hIFNb) combined with RT inhibits cell proliferation in human prostate cancer cells
Similar results were seen for LNCaP cells when VSV-hIFNb infection was combined with RT (Fig. 1C and D), albeit the greater sensitivity of LNCaP cells to VSV infection resulted in a more rapid reduction in growth as indicated by the reduced timeframe and at lower viral multiplicities of infection (MOI) (0.000125–0.01; Fig. 1D)

Summary

Introduction

Prostate cancer remains the second leading cause of cancer-related death in men [1]. Combined modality treatment using radiotherapy (RT) with systemic androgen deprivation therapy (ADT), when compared with either agent alone, improves survival for men with high-risk disease that is not metastatic and has become the standard of care [2]. 30% to 40% of high-risk patients who receive RT þ ADT experience biochemical or disease failure within 5 years of completion of therapy. This high failure rate, coupled with the morbidity associated with the use of ADT, has driven the search for more refined and targeted strategies to improve the therapeutic index of radiation-based treatments.

Methods

Results

Conclusion