title: 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.
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.
authors: Targeted Therapy Team, The Institute of Cancer Research, London, United Kingdom; Department of Academic Surgery, Sarcoma/Melanoma Unit, Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom.
authors: Tim D
authors: TD
authors: Pencavel
authors: Michelle J
authors: MJ
authors: Wilkinson
authors: David C
authors: DC
authors: Mansfield
authors: Aadil A
authors: AA
authors: Khan
authors: Rohit
authors: R
authors: Seth
authors: Eleni M
authors: EM
authors: Karapanagiotou
authors: Victoria
authors: V
authors: Roulstone
authors: Richard J
authors: RJ
authors: Aguilar
authors: Nanhai G
authors: NG
authors: Chen
authors: Aladar A
authors: AA
authors: Szalay
authors: Andrew J
authors: AJ
authors: Hayes
authors: Kevin J
authors: KJ
authors: Harrington
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D010478:Chemotherapy, Cancer, Regional Perfusion; D003131:Combined Modality Therapy; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D009368:Neoplasm Transplantation; D050504:Oncolytic Viruses / Q000502:physiology*; D011919:Rats, Inbred Strains; D012513:Sarcoma, Experimental / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage; D014616:Vaccinia virus / Q000502:physiology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D008558:Melphalan
keywords: isolated limb perfusion; melanoma; oncolytic virotherapy; sarcoma; surgery