title: PolySia-Specific Retargeting of Oncolytic Viruses Triggers Tumor-Specific Immune Responses and Facilitates Therapy of Disseminated Lung Cancer.
abstract: Polysialic acid (polySia) is expressed on several malignant tumors of neuroendocrine origin, including small cell lung cancer. In this study, we investigated the therapeutic efficacy of tumor-directed T-cell responses, elicited by polySia-retargeted oncolytic adenovirus infection, in an orthotopic murine model of disseminated polySia-positive lung cancer. In several cell lines, we demonstrated highly polySia-selective retargeting of adenoviral infection using a bispecific adapter comprising the ectodomain of the coxsackievirus/adenovirus receptor and a polySia-recognizing single-chain antibody domain. PolySia-dependent systemic infection in vivo facilitated effective uptake of viruses in subcutaneous polySia-expressing human tumors, whereas hepatic viral load and hepatotoxicity were significantly reduced. The impact and nature of antitumoral immune responses triggered by systemic delivery of polySia-retargeted oncolytic adenoviruses were investigated in an orthotopic model of disseminated lung cancer. Interestingly, improved transduction by polySia-retargeted oncolytic adenoviruses led to CD45-positive cell infiltrates in close association with large lytic areas. Consistently, enhanced tumor regression and prolonged survival was only observed in immunocompetent mice, but not in T-cell-deficient mice. To investigate whether improved systemic infection by polySia retargeting would elicit a tumor-specific T-cell response, we screened the used lung cancer cells for mutated oncogenes by complete exon sequencing. In agreement with our other results, only retargeted oncolysis was able to induce a significant response specific for the tumor-associated neoepitope Gsta2-Y9H. In conclusion, we demonstrated that effective retargeting of oncolytic adenovirus against polySia-expressing tumors elicits an effective tumor-directed T-cell response after systemic virus delivery and facilitates therapy of disseminated lung cancer.
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
authors.forename: Arnold
authors.initials: A
authors.lastname: Kloos
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
authors.forename: Norman
authors.initials: N
authors.lastname: Woller
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
authors.forename: Engin
authors.initials: E
authors.lastname: Gürlevik
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
authors.forename: Cristina-Ileana
authors.initials: CI
authors.lastname: Ureche
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Niemann
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Armbrecht
authors.affiliation: Institute for Cellular Chemistry, Medical School Hannover, Hannover, Germany.
authors.forename: Nikolas T
authors.initials: NT
authors.lastname: Martin
authors.affiliation: RG Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.affiliation: Institute for Cellular Chemistry, Medical School Hannover, Hannover, Germany.
authors.forename: Rita
authors.initials: R
authors.lastname: Gerardy-Schahn
authors.affiliation: Clinic for Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany. kuehnel.florian@mh-hannover.de.
authors.forename: Florian
authors.initials: F
authors.lastname: Kühnel
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D012794:Sialic Acids / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D012794:Sialic Acids; C021319:polysialic acid