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.