Anti-IL-10R antibody improves the therapeutic efficacy of targeted liposomal oligonucleotides.
High-risk Neuroblastoma (NB) has still a poor prognosis. Liposomes targeted to NB cells and encapsulating antisense CpG-containing oligonucleotides (TL-asCpG) had increased anti-tumour efficacy in NB xenografts compared to free asCpG. Interleukin 10 (IL-10) suppresses antigen presenting cell activation contributing to tumour-mediated immune suppression. In principle, combination of TL-asCpG and antibodies against IL-10 receptor (aIL-10R) could prolong immune system activation, leading to better therapeutic results. Mice treated with TL-asCpG 4 h after human NB cell inoculation survived significantly longer than controls. An increased life span was achieved also in mice receiving TL-asCpG 24 and 72 h after NB cell challenge. The addition of aIL-10R to TL-asCpG in the 4-h protocol significantly increased the percentage of long term survivors compared to TL-asCpG only. Surviving mice treated with the combined strategy were completely cured. In contrast, long term surviving mice treated only with TL-asCpG presented lymph node infiltration with NB cells. TL-asCpG plus aIL-10R treatment was significantly superior to TL-asCpG alone also for the 24-h protocol. Ex vivo experiments demonstrated that the combined therapy evoked a stronger and more prolonged immune system activation compared to monotherapy. These results support the feasibility of a clinical trial with TL-asCpG and aIL-10R in advanced NB patients.
Laboratory of Oncology, G. Gaslini Children's Hospital, 16147 Genoa, Italy. chiarabrignole@ospedale-gaslini.ge.it
Chiara
C
Brignole
Danilo
D
Marimpietri
Fabio
F
Pastorino
Daniela
D
Di Paolo
Gabriella
G
Pagnan
Monica
M
Loi
Federica
F
Piccardi
Michele
M
Cilli
Andrea
A
Tradori-Cappai
Gianluigi
G
Arrigoni
Vito
V
Pistoia
Mirco
M
Ponzoni
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018899:CpG Islands / Q000276:immunology; D005260:Female; D005732:Gangliosides / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D016753:Interleukin-10 / Q000037:antagonists & inhibitors* / Q000276:immunology; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D020598:Proto-Oncogene Proteins c-myb / Q000276:immunology; D053701:Receptors, Interleukin-10 / Q000037:antagonists & inhibitors* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D005732:Gangliosides; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D020598:Proto-Oncogene Proteins c-myb; D053701:Receptors, Interleukin-10; D016753:Interleukin-10; C019403:ganglioside, GD2