Schedule-dependent therapeutic efficacy of L19mTNF-α and melphalan combined with gemcitabine

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. Targeted delivery of L19mTNF-α synergistically increases the antitumor activity of melphalan and gemcitabine, but optimal administration schedule requires a pretreatment with L19mTNF-α otherwise an antagonistic effect could occur. This study provides information for designing clinical studies using L19mTNF-α in combination with chemotherapeutic drugs.