title: The efficacy versus toxicity profile of combination virotherapy and TLR immunotherapy highlights the danger of administering TLR agonists to oncolytic virus-treated mice.
abstract: Injection of oncolytic vesicular stomatitis virus (VSV) into established B16ova melanomas results in tumor regression, in large part by inducing innate immune reactivity against the viral infection, mediated by MyD88- and type III interferon (IFN)-, but not TLR-4-, signaling. We show here that intratumoral (IT) treatment with lipopolysaccharide (LPS), a TLR-4 agonist, significantly enhanced the local therapy induced by VSV by combining activation of different innate immune pathways. Therapy was further enhanced by co-recruiting a potent antitumor, adaptive T-cell response by using a VSV engineered to express the ovalbumin tumor-associated antigen ova, in combination with LPS. However, the combination of IT LPS with systemically delivered VSV resulted in rapid morbidity and mortality in the majority of mice. Decreasing the intravenous (IV) dose of VSV to levels at which toxicity was ameliorated did not enhance therapy compared with IT LPS alone. Toxicity of the systemic VSV + IT LPS regimen was associated with rapidly elevated levels of serum tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, which neither systemic VSV, nor IT LPS, alone induced. These data show that therapy associated with direct IT injections of oncolytic viruses can be significantly enhanced by combination with agonists of innate immune activation pathways, which are not themselves activated by the virus alone. Importantly, they also highlight possible, unforeseen dangers of combination therapies in which an immunotherapy, even delivered locally at the tumor site, may systemically sensitize the patient to a cytokine shock-like response triggered by IV delivery of oncolytic virus.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Rommelfanger
authors.forename: Marta
authors.initials: M
authors.lastname: Compte
authors.forename: Marta C
authors.initials: MC
authors.lastname: Grau
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Diaz
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ilett
authors.forename: Luis
authors.initials: L
authors.lastname: Alvarez-Vallina
authors.forename: Jill M
authors.initials: JM
authors.lastname: Thompson
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kottke
authors.forename: Alan
authors.initials: A
authors.lastname: Melcher
authors.forename: Richard G
authors.initials: RG
authors.lastname: Vile
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000009:adverse effects / Q000379:methods; D015316:Genetic Therapy; D005822:Genetic Vectors; D007113:Immunity, Innate; D007167:Immunotherapy; D016898:Interferon-alpha / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D050130:Oncolytic Virotherapy / Q000009:adverse effects* / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology; D018116:Vesiculovirus / Q000235:genetics* / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D016898:Interferon-alpha; D015850:Interleukin-6; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha