Therapy-induced antitumor vaccination by targeting tumor necrosis factor alpha to tumor vessels in combination with melphalan.
Treatment of tumor-bearing mice with mouse (m)TNF-alpha, targeted to tumor vasculature by the anti-ED-B fibronectin domain antibody L19(scFv) and combined with melphalan, induces a therapeutic immune response. Upon treatment, a highly efficient priming of CD4+ T cells and consequent activation and maturation of CD8+ CTL effectors is generated, as demonstrated by in vivo depletion and adoptive cell transfer experiments. Immunohistochemical analysis of the tumor tissue demonstrated massive infiltration of CD4+ and CD8+ T cells 6 days after treatment and much earlier in the anamnestic response to tumor challenge in cured mice. In fact, the curative treatment with L19mTNF-alpha and melphalan resulted in long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2-type response and significant in vitro tumor-specific cytolytic activity. Finally, the combined treatment reduced the percentage and absolute number of CD4+CD25+ regulatory T cells in the tumor-draining lymph nodes of mice responding to therapy, and this was associated with the establishment of protective immunity. These findings pave the way for alternative therapeutic strategies based on the targeted delivery of biological and pharmacological cytotoxic compounds that not only kill most of the tumor cells but, more importantly, trigger an effective and long-lasting antitumor adaptive immune response.
Mortara
Lorenzo
L
Department of Clinical and Biological Sciences, School of Medicine, University of Insubria, Varese, Italy.
Balza
Enrica
E
Sassi
Francesca
F
Castellani
Patrizia
P
Carnemolla
Barbara
B
De Lerma Barbaro
Andrea
A
Fossati
Sara
S
Tosi
Giovanna
G
Accolla
Roberto S
RS
Borsi
Laura
L
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000276:immunology / Q000628:therapy; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003110:Colonic Neoplasms / Q000473:pathology; D003131:Combined Modality Therapy; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D005354:Fibrosarcoma / Q000098:blood supply / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D018796:Immunoconjugates / Q000008:administration & dosage / Q000627:therapeutic use*; D007128:Immunoglobulin Fragments / Q000008:administration & dosage / Q000276:immunology; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008558:Melphalan / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D014611:Vaccination
D018906:Antineoplastic Agents, Alkylating; D018796:Immunoconjugates; D007128:Immunoglobulin Fragments; D014409:Tumor Necrosis Factor-alpha; D008558:Melphalan