Abstract
The prevention and treatment of metastatic sarcoma are areas of significant unmet need. Immune checkpoint inhibitor monotherapy has shown little activity in sarcoma and there is great interest in identifying novel treatment combinations that may augment responses. In vitro and in vivo, we investigated the potential for an oncolytic vaccinia virus (GLV-1h68) delivered using isolated limb perfusion (ILP) to promote antitumor immune responses and augment response to PD-1 blockade in sarcoma.Experimental Design: In an established animal model of extremity sarcoma, we evaluated the potential of locoregional delivery of a vaccinia virus (GLV-1h68) alongside biochemotherapy (melphalan/TNFα) in ILP. Complementary in vitro assays for markers of immunogenic cell death were performed in sarcoma cell lines. PD-1 monotherapy had minimal efficacy in vivo, mimicking the clinical scenario. Pretreatment with GLV-1h68 delivered by ILP (viral ILP) significantly improved responses. Furthermore, when performed prior to surgery and radiotherapy, viral ILP and PD-1 blockade prevented both local and distant relapse, curing a previously treatment-refractory model. Enhanced therapy was associated with marked modulation of the tumor microenvironment, with an increase in the number and penetrance of intratumoral CD8+ T cells and expansion and activation of dendritic cells. GLV-1h68 was capable of inducing markers of immunogenic cell death in human sarcoma cell lines. Viral ILP augments the response to PD-1 blockade, transforming this locoregional therapy into a potentially effective systemic treatment for sarcoma and warrants translational evaluation.
Highlights
Soft-tissue sarcomas are a group of rare, heterogeneous tumors derived from mesenchymal tissues, with an annual incidence of approximately 5/100,000 persons [1]
Viral isolated limb perfusion (ILP) augments the response to PD-1 blockade, transforming this locoregional therapy into a potentially effective systemic treatment for sarcoma and warrants translational evaluation
We demonstrate that the response to PD-1 inhibition can be dramatically enhanced following prior treatment with a vaccinia virus delivered alongside biochemotherapy in isolated limb perfusion (ILP) in a model of extremity soft-tissue sarcoma
Summary
Soft-tissue sarcomas are a group of rare, heterogeneous tumors derived from mesenchymal tissues, with an annual incidence of approximately 5/100,000 persons [1]. The most commonly affected sites are the extremities, accounting for approximately 40% of all cases [2]. Limb-conserving surgery and adjuvant radiotherapy is highly effective in securing long-term control of the primary tumor [3]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). K.J. Harrington and A.J. Hayes are the co-senior authors of this article
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