title: Schedule-dependent therapeutic efficacy of L19mTNF-α and melphalan combined with gemcitabine.
abstract: L19-tumor necrosis factor alpha (L19mTNF-α; L), a fusion protein consisting of mouse TNFα and the human antibody fragment L19 directed to the extra domain-B (ED-B) of fibronectin, is able to selectively target tumor vasculature and to exert a long-lasting therapeutic activity in combination with melphalan (M) in syngeneic mouse tumor models. We have studied the antitumor activity of single L19mTNF-α treatment in combination with melphalan and gemcitabine (G) using different administration protocols in two histologically different murine tumor models: WEHI-164 fibrosarcoma and K7M2 osteosarcoma. All responding mice showed significant reduction in myeloid-derived suppressor cells (MDSCs) and an increase in CD4(+) and CD8(+) T cells in the tumor infiltrates, as well as significant reduction in regulatory T cells (Treg) at the level of draining lymph nodes. What is important is that all cured mice rejected tumor challenge up to 1 year after therapy. Targeted delivery of L19mTNF-α synergistically increases the antitumor activity of melphalan and gemcitabine, but optimal administration schedules are required. This study provides information for designing clinical studies using L19mTNF-α in combination with chemotherapeutic drugs.
authors.affiliation: Department of Biotechnology and Life Sciences, University of Insubria Varese, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Mortara
authors.forename: Paola
authors.initials: P
authors.lastname: Orecchia
authors.forename: Patrizia
authors.initials: P
authors.lastname: Castellani
authors.forename: Laura
authors.initials: L
authors.lastname: Borsi
authors.forename: Barbara
authors.initials: B
authors.lastname: Carnemolla
authors.forename: Enrica
authors.initials: E
authors.lastname: Balza
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004357:Drug Synergism; D007156:Immunologic Memory; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating; D008558:Melphalan / Q000008:administration & dosage; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: C558733:L19mTNFalpha protein; D011993:Recombinant Fusion Proteins; D003841:Deoxycytidine; D008558:Melphalan; D000093542:Gemcitabine
keywords: Gemcitabine; L19mTNF-α; immune response; melphalan; mouse tumor models