Antitumor effects of recombinant antivascular protein ABRaA-VEGF121 combined with IL-12 gene therapy.
Development and neoplastic progression strongly rely on tumor microenvironment cells. Various kinds of cells that form such tumor milieu play substantial roles in angiogenesis and immunosuppression. Attempts to inhibit tumor vascularization alter tumor milieu and enhance immune response against the tumor. Anticancer therapeutic strategy bringing together antiangiogenic and immunostimulating agents has emerged as a promising approach. We here investigated whether therapy directed against preexisting vessels, combined with an immunomodulatory factor would be equally effective in arresting tumor growth. To this goal, we investigated the effectiveness of ABRaA-vascular endothelial growth factor isoform 121 (VEGF121), an antivascular drug constructed by us. It is a fusion protein composed of VEGF121, and abrin A chain (translation-inhibiting toxin). We used it in combination with interleukin (IL-12) gene therapy and tried to inhibit B16-F10 melanoma tumor growth. ABRaA-VEGF121 is a chimeric recombinant protein capable of destroying tumor vasculature and triggering necrosis in the vicinity of damaged vessels. IL-12 cytokine, in turn, activates both specific and non-specific immune responses. Our results demonstrate that combination of ABRaA-VEGF121 antivascular agent with immunostimulatory cytokine IL-12 indeed inhibits tumor growth more effectively than either agent alone, leading to complete cure of ca. 20 % mice. Post-therapeutic analysis of tumors excised from mice treated with combination therapy showed decreased numbers of blood microvessels in the tumor microenvironment, lowered numbers of regulatory T lymphocytes, as well as showed higher levels of CD4(+) and CD8(+) as compared to control mice. It seems that bringing together antivascular strategy and the action of immunostimulating agents indeed inhibits growth of tumors.
Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-101, Gliwice, Poland.
Agnieszka
A
Ciomber
Andrzej
A
Smagur
Iwona
I
Mitrus
Tomasz
T
Cichoń
Ryszard
R
Smolarczyk
Aleksander
A
Sochanik
Stanisław
S
Szala
Magdalena
M
Jarosz
D000036:Abrin / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D048708:Cell Growth Processes / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000036:Abrin; D018664:Interleukin-12