PD-1 Blockade Following Isolated Limb Perfusion with Vaccinia Virus Prevents Local and Distant Relapse of Soft-tissue Sarcoma.
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Date
2019-06-01ICR Author
Author
Smith, HG
Mansfield, D
Roulstone, V
Kyula-Currie, JN
McLaughlin, M
Patel, RR
Bergerhoff, KF
Paget, JT
Dillon, MT
Khan, A
Melcher, A
Thway, K
Harrington, KJ
Hayes, AJ
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
T-Lymphocyte Subsets
Lymphocytes, Tumor-Infiltrating
Cell Line, Tumor
Animals
Humans
Mice
Vaccinia virus
Sarcoma
Disease Models, Animal
Treatment Outcome
Immunohistochemistry
Xenograft Model Antitumor Assays
Immunophenotyping
Oncolytic Virotherapy
Oncolytic Viruses
Programmed Cell Death 1 Receptor
Genetic Therapy
Antineoplastic Agents, Immunological
Research team
Sarcoma and Melanoma Surgery
Targeted Therapy
Translational Immunotherapy
Language
eng
Date accepted
2019-03-08
License start date
2019-06
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2019, 25 (11), pp. 3443 - 3454
Publisher
AMER ASSOC CANCER RESEARCH