Therapy-induced antitumor vaccination in neuroblastomas by the combined targeting of IL-2 and TNFalpha.
L19-IL2 and L19TNFalpha are fusion proteins composed of L19(scFv), specific for the angiogenesis-associated ED-B containing fibronectin isoform and IL-2 or TNFalpha. Because of the tumor targeting properties of L19, IL-2 and TNFalpha concentrate at therapeutic doses at the tumor vascular level. To evaluate the therapeutic effects of L19-IL2 and L19mTNFalpha in neuroblastoma (NB)-bearing mice, A/J mice bearing Neuro2A or NIE115 NB were systemically treated with L19-IL2 and L19mTNFalpha, alone or in combination protocols. Seventy percent of Neuro2A- and 30% of NIE115-bearing mice were cured by the combined treatment with L19-IL2 and L19mTNFalpha, and further rejected a homologous tumor challenge, indicating specific antitumor immune memory. The immunological bases of tumor cure and rejection were studied. A highly efficient priming of CD4(+) T helper cells and CD8(+) CTL effectors was generated, paralleled by massive infiltration in the tumor tissue of CD4(+) and CD8(+) T cells at day 16 after tumor cell implantation, when, after therapy, tumor volume was drastically reduced and tumor necrosis reached about 80%. The curative treatment resulted in a long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2 type of response. Concluding, L19-IL2 and L19mTNFalpha efficiently cooperate in determining a high percentage of NB cure that, in our experimental models, is strongly associated to the generation of adaptive immunity involving CD4(+) and CD8(+) T cells.
Balza
Enrica
E
Cell Biology Laboratory, Department of Translational Oncology, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Carnemolla
Barbara
B
Mortara
Lorenzo
L
Castellani
Patrizia
P
Soncini
Debora
D
Accolla
Roberto S
RS
Borsi
Laura
L
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000008:administration & dosage*; D051379:Mice; D009447:Neuroblastoma / Q000276:immunology / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
D019496:Cancer Vaccines; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha