Oncolytic poliovirus therapy and immunization with poliovirus-infected cell lysate induces potent antitumor immunity against neuroblastoma in vivo.
In a previous study, we demonstrated that neuroblastoma subcutaneously implanted in immuno-competent mice is eliminated by intratumoral administration of neuroattenuated poliovirus (PV). Our results also suggested that the in vivo destruction of neuroblastoma cells by virotherapy lead to a robust antitumor immune response. In this work, splenocytes harvested from neuroblastoma-bearing animals treated with neuroattenuated PV exhibited significantly higher lytic activity against tumor target cells than did those from splenocytes derived from control mice. In vitro T-cell depletion experiments indicated that CD8(+) T cells were essential for the cytotoxic antitumor activity of splenocytes. Moreover, adoptive transfer of splenocytes obtained from mice cured of neuroblastoma by PV virotherapy markedly delayed the tumor growth of previously established neuroblastomas in recipient naïve mice. These results confirmed that treatment with a neuroattenuated oncolytic PV strain induces antitumor immunity against neuroblastoma that is mainly mediated by cytotoxic CD8(+) T cells. Immunocompetent mice, on the other hand, were immunized with PV-infected neuroblastoma cell lysate prior intravenous challenge with neuroblastoma cells. As a control, mice were vaccinated with either non-infected neuroblastoma cell lysate alone or mixed with PV, or with PBS prior tumor cell injection. Results showed that survival is significantly prolonged only in mice immunized with PV-infected tumor lysate. This finding clearly suggested that in vitro poliovirus infection of neuroblastoma cells turns these cells into a potent tumor immunogen. Further studies in oncolytic treatment of neuroblastoma using attenuated PV alone or in combination with immunotherapy with PV oncolysate should improve the probability for successful translation in the clinic.
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11790, USA.
Hidemi
H
Toyoda
Eckard
E
Wimmer
Jeronimo
J
Cello
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D007114:Immunization; D007167:Immunotherapy / Q000379:methods; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000276:immunology / Q000628:therapy* / Q000821:virology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D017955:Poliovirus / Q000276:immunology*; D011991:Receptors, Virus / Q000096:biosynthesis / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology* / Q000821:virology
D011991:Receptors, Virus; C066100:poliovirus receptor