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Isolated limb perfusion with melphalan, tumour necrosis factor-alpha and oncolytic vaccinia virus improves tumour targeting and prolongs survival in a rat model of advanced extremity sarcoma.

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Date
2015-02
ICR Author
Harrington, Kevin
Mansfield, David
Hayes, Andrew
Khan, Aadil
Author
Pencavel, TD
Wilkinson, MJ
Mansfield, DC
Khan, AA
Seth, R
Karapanagiotou, EM
Roulstone, V
Aguilar, RJ
Chen, NG
Szalay, AA
Hayes, AJ
Harrington, KJ
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Type
Journal Article
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Abstract
Isolated limb perfusion (ILP) is a treatment for advanced extremity sarcoma and in-transit melanoma. Advancing this procedure by investigating the addition of novel agents, such as cancer-selective oncolytic viruses, may improve both the therapeutic efficacy of ILP and the tumour-targeted delivery of oncolytic virotherapy. Standard in vitro assays were used to characterise single agent and combinatorial activities of melphalan, tumour necrosis factor-alpha (TNF-α) and Lister strain vaccinia virus (GLV-1h68) against BN175 rat sarcoma cells. An orthotopic model of advanced extremity sarcoma was used to evaluate survival of animals after ILP with combinations of TNF-α, melphalan and GLV-1h68. We investigated the efficiency of viral tumour delivery by ILP compared to intravenous therapy, the locoregional and systemic biodistribution of virus after ILP, and the effect of mode of administration on antibody response. The combination of melphalan and GLV-1h68 was synergistic in vitro. The addition of virus to standard ILP regimens was well tolerated and demonstrated superior tumour targeting compared to intravenous administration. Triple therapy (melphalan/TNF-α/GLV-1h68) resulted in increased tumour growth delay and enhanced survival compared to other treatment regimens. Live virus was recovered in large amounts from perfused regions, but in smaller amounts from systemic organs. The addition of oncolytic vaccinia virus to existing TNF-α/melphalan-based ILP strategies results in survival advantage in an immunocompetent rat model of advanced extremity sarcoma. Virus administered by ILP has superior tumour targeting compared to intravenous delivery. Further evaluation and clinical translation of this approach is warranted.
URI
https://repository.icr.ac.uk/handle/internal/1745
DOI
https://doi.org/10.1002/ijc.29059
Collections
  • Cancer Biology
  • Radiotherapy and Imaging
Subject
Cell Line, Tumor
Hindlimb
Animals
Rats, Inbred Strains
Humans
Vaccinia virus
Sarcoma, Experimental
Melphalan
Tumor Necrosis Factor-alpha
Antineoplastic Combined Chemotherapy Protocols
Combined Modality Therapy
Neoplasm Transplantation
Apoptosis
Male
Chemotherapy, Cancer, Regional Perfusion
Oncolytic Viruses
Research team
Sarcoma and Melanoma Surgery
Targeted Therapy
Language
eng
Date accepted
2014-05-08
License start date
2015-02
Citation
International journal of cancer, 2015, 136 (4), pp. 965 - 976

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