TY - JOUR
T1 - Radiation Attenuates Prostate Tumor Antiviral Responses to Vesicular Stomatitis Virus Containing IFNβ, Resulting in Pronounced Antitumor Systemic Immune Responses
AU - Udayakumar, Thirupandiyur S.
AU - Betancourt, Dillon M.
AU - Ahmad, Anis
AU - Tao, Wensi
AU - Totiger, Tulasigeri M.
AU - Patel, Mausam
AU - Marples, Brian
AU - Barber, Glen
AU - Pollack, Alan
N1 - Publisher Copyright:
©2020 American Association for Cancer Research.
Copyright:
This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-19-0836
DO - 10.1158/1541-7786.MCR-19-0836
M3 - Article
C2 - 32366674
AN - SCOPUS:85089161770
VL - 18
SP - 1232
EP - 1243
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 8
ER -