Open AccessSchedule‐dependent therapeutic efficacy of L19m TNF ‐α and melphalan combined with gemcitabine
Author(s) -
Mortara Lorenzo,
Orecchia Paola,
Castellani Patrizia,
Borsi Laura,
Carnemolla Barbara,
Balza Enrica
Publication year - 2013
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.89
Subject(s) - gemcitabine , melphalan , tumor necrosis factor alpha , medicine , cancer research , pharmacology , fibrosarcoma , chemotherapy , immunology , multiple myeloma , pathology
L19‐tumor necrosis factor alpha (L19m TNF ‐α; L), a fusion protein consisting of mouse TNF α 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 L19m TNF ‐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 ( MDSC s) and an increase in CD 4 + and CD 8 + 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 L19m TNF ‐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 L19m TNF ‐α in combination with chemotherapeutic drugs.