Predictive biomarkers for the oncolytic virus, JX-594, through the HIF-dependent interferon beta pathway in metastatic renal cell carcinoma.

710 Background: Although combination approaches with an immunotherapy are established as the first-line setting in metastatic renal cell carcinoma (mRCC), immunotherapy are only efficacious for a subset of patients. Our group has been working on improving the benefit of immunotherapy using JX-594 (pexastimogene devacirepvec, Pexa-vec) in mRCC. The purpose of this study is to develop predictive biomarker for JX-594 in metastatic clear cell RCC (ccRCC). Methods: Using ccRCC cell lines representative of each four mutations (786-O (VHL mutation), Caki-2 (VHL and PBRM1 mutation), A-498 (VHL and SETD2 mutation), and 769-P (VHL and BAP1 mutation)), four cell line-derived xenograft (CDX) mouse models have been developed. 2-10x106 tumor cells were subcutaneously injected into the right flank of wild-type BALB/c nude mice. When tumors reached >50 mm3, mice were treated with either PBS or 1x107 plaque-forming units of JX-594 by intratumoral injection in day 0, 3, and 6. Interferon beta (IFN-β) expression were measured with qRT-PCR after the JX-594 treatment in 786-O CDX model. Results: All CDX models demonstrated significant decrease in tumor size by the JX-594 compared to control. Most rapid tumor growth was observed in BAP1-deficient xenografts while PBRM1-deficient xenografts demonstrated the slowest growth among four xenografts. The decrease of tumor volume by the JX-594 was most pronounced in BAP1-deficient tumors compared to VHL, PBRM1, and SETD2 mutation tumors. Even after adjusting the relative differences of tumor growth rate in each model, xenografts with BAP1 loss were still associated with significantly better response to JX-594. IFN-β expression significantly decreased in BAP1-deficient tumors compared to other tumors, while the expression level was recovered dramatically after JX-594. Conclusions: BAP1-deficient tumors demonstrated rapid tumor progression while they were most significantly reduced after JX-594. BAP1-deificient tumors had decreased levels of IFN-β expression while it was most dramatically recovered after JX-594, suggesting the mechanism of JX-594 through the HIF-dependent interferon beta induction. This is the first study to elucidate the potential of BAP1 as predictive biomarker for JX-594 and its underlying mechanisms.