Systemic Injection of Oncolytic Vaccinia Virus Suppresses Primary Tumor Growth and Lung Metastasis in Metastatic Renal Cell Carcinoma by Remodeling Tumor Microenvironment.

Jee Soo Park,Se Mi Park,Won Sik Jang,Namhee Lee,Myung Eun Lee,Won Sik Ham,Jongchan Kim,Keunhee Oh

doi:10.3390/biomedicines10010173

Abstract

Immune checkpoint inhibitors and tyrosine kinase inhibitors are the first-line treatment for metastatic renal cell carcinoma (mRCC), but their benefits are limited to specific patient subsets. Here, we aimed to evaluate the therapeutic efficacy of JX-594 (pexastimogene devacirepvec, Pexa-vec) monotherapy by systemic injection in comparison with sunitinib monotherapy in metastatic orthotopic RCC murine models. Two highly metastatic orthotopic RCC models were developed to compare the treatment efficacy in the International Metastatic RCC Database Consortium favorable-risk and intermediate- or poor-risk groups. JX-594 was systemically injected through the peritoneum, whereas sunitinib was orally administered. Post-treatment, tumor microenvironment (TME) remodeling was determined using immunofluorescence analysis. Systemic JX-594 monotherapy injection demonstrated therapeutic benefit in both early- and advanced-stage mRCC models. Sunitinib monotherapy significantly reduced the primary tumor burden and number of lung metastases in the early-stage, but not in the advanced-stage mRCC model. Systemic JX-594 delivery remodeled the primary TME and lung metastatic sites by increasing tumor-infiltrating CD4/8+ T cells and dendritic cells. Systemic JX-594 monotherapy demonstrated significantly better therapeutic outcomes compared with sunitinib monotherapy in both early- and advanced-stage mRCCs by converting cold tumors into hot tumors. Sunitinib monotherapy effectively suppressed primary tumor growth and lung metastasis in early-stage mRCC.

Highlights

One-third of all patients diagnosed with renal cell carcinoma (RCC)already have systemic diseases at the time of the first diagnosis [1]
We aimed to evaluate the therapeutic efficacy of JX-594 monotherapy via systemic injection in comparison with sunitinib monotherapy in metastatic orthotopic RCC
Similar to the human RCC cell lines, infection of Renca cells with mouse variant of JX-594 (mJX-594) resulted in cytotoxicity (Figure 2A)

Summary

Introduction

One-third of all patients diagnosed with renal cell carcinoma (RCC)already have systemic diseases at the time of the first diagnosis [1]. Significant improvements in the therapeutic strategies for metastatic RCC (mRCC) have been achieved, the five-year survival rate is less than 10%, with incidence and mortality rates rising at a rate of 2–3% per decade [2]. MRCC remains a significant health issue as it is an incurable disease [3]. Sunitinib (Sutent; Pfizer, New York, NY, USA), a multikinase inhibitor with antiangiogenic properties, has developed into a standard first-line treatment option for advanced mRCC [4]. Cancer immunotherapy, with immune checkpoint inhibitors (ICIs), has recently emerged as a potent and effective therapeutic strategy for advanced cancers, replacing sunitinib [5,6]. 214 demonstrated the superiority of nivolumab and ipilimumab over sunitinib in patients with intermediate- and poor-risk disease [7]. Immuno-oncology (IO) agents have changed the treatment paradigm for mRCC as IO combination therapies have become the first-line therapy for mRCC [8]

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Discussion

Conclusion