GMCSF‐armed vaccinia virus induces an antitumor immune response

• Published in: International journal of cancer 2015-03, Vol.136 (5), p.1065-1072
• Main Authors: Parviainen, Suvi, Ahonen, Marko, Diaconu, Iulia, Kipar, Anja, Siurala, Mikko, Vähä‐Koskela, Markus, Kanerva, Anna, Cerullo, Vincenzo, Hemminki, Akseli
• Format: Article
• Language: English
• Subjects: Animals; Cancer; Cell Movement; Cell Proliferation; Cells, Cultured; Cercopithecus aethiops; Coculture Techniques; Cricetinae; DNA, Viral - genetics; GMCSF; Granulocyte-Macrophage Colony-Stimulating Factor - administration & dosage; Humans; Immunoenzyme Techniques; immunotherapy; Macrophages; Medical research; Mesocricetus; oncolytic vaccinia virus; Oncolytic Virotherapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - therapy; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Rodents; Smallpox; T-Lymphocytes; Tumors; Vaccines; Vaccinia virus; Vaccinia virus - genetics; Vaccinia virus - immunology; Vero Cells; Virus Replication - immunology; Viruses; Xenograft Model Antitumor Assays
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.29068

Oncolytic Western Reserve strain vaccinia virus selective for epidermal growth factor receptor pathway mutations and tumor‐associated hypermetabolism was armed with human granulocyte‐macrophage colony‐stimulating factor (GMCSF) and a tdTomato fluorophore. As the assessment of immunological responses to human transgenes is challenging in the most commonly used animal models, we used immunocompetent Syrian golden hamsters, known to be sensitive to human GMCSF and semipermissive to vaccinia virus. Efficacy was initially tested in vitro on various human and hamster cell lines and oncolytic potency of transgene‐carrying viruses was similar to unarmed virus. The hGMCSF‐encoding virus was able to completely eradicate subcutaneous pancreatic tumors in hamsters, and to fully protect the animals from subsequent rechallenge with the same tumor. Induction of specific antitumor immunity was also shown by ex vivo co‐culture experiments with hamster splenocytes. In addition, histological examination revealed increased infiltration of neutrophils and macrophages in GMCSF‐virus‐treated tumors. These findings help clarify the mechanism of action of GMCSF‐armed vaccinia viruses undergoing clinical trials. What's new? Oncolytic vaccinia viruses have shown promising results in cancer treatment. Tumor oncolysis is also an immunogenic phenomenon, thus it has been proposed to enhance activation of the immune system by arming the viruses with immunostimulatory molecules like granulocyte‐macrophage colony‐stimulating factor (GMCSF). However, this approach has not been studied much in model systems due to species incompatibility issues, even in the case of viruses in late‐stage clinical investigation like JX‐594. This study provides insight into the mechanism of action of a human GMCSF‐expressing Western Reserve strain double‐deleted vaccinia virus as well as clues on how JX‐594 exert their effects in humans.