PD-1 Blockade Following Isolated Limb Perfusion with Vaccinia Virus Prevents Local and Distant Relapse of Soft-tissue Sarcoma.

Abstract

PURPOSE:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Henry G Smith, David Mansfield, Victoria Roulstone, Joan N Kyula-Currie, Martin McLaughlin, Radhika R Patel, Katharina F Bergerhoff, James T Paget, Magnus T Dillon, Aadil Khan, Alan Melcher, Khin Thway, Kevin J Harrington, Andrew J Hayes
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 11 Pg. 3443-3454 (06 01 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 30885937 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Immunological
• Programmed Cell Death 1 Receptor

Topics

• Animals
• Antineoplastic Agents, Immunological (pharmacology)
• Cell Line, Tumor
• Disease Models, Animal
• Genetic Therapy
• Humans
• Immunohistochemistry
• Immunophenotyping
• Lymphocytes, Tumor-Infiltrating (immunology, metabolism, pathology)
• Mice
• Oncolytic Virotherapy
• Oncolytic Viruses (genetics)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• Sarcoma (etiology, metabolism, pathology, therapy)
• T-Lymphocyte Subsets (drug effects, immunology, metabolism)
• Treatment Outcome
• Vaccinia virus (genetics)
• Xenograft Model Antitumor Assays