Cancer gene therapy of adenovirus-mediated anti-4-1BB scFv  in immunocompetent mice.
The use of immunostimulatory molecule genes aiming at enhancing anti-tumor immunity has emerged as a new approach to treat cancers. 4-1BB signaling, an important costimulatory pathway delivering a signal for T cell activation, survival and growth, has become one of the most promising targets for cancer immunotherapy. In this work, a recombinant nonreplicative adenovirus (Ad.4-1BB scFv) carrying a single-chain Fv fragments (scFv) specific for 4-1BB gene (anti-4-1BB scFv) was generated, haracterized and explored for its stimulation of anti-tumor immunity in immunocompetent C57BL/6 mice. Ad.4-1BB scFv could efficiently infect murine hepatoma Hepa 1-6 cells and induce anti-4-1BB scFv expression on the cell surface. Moreover, Ad.4-1BB scFv did not cause obvious cytotoxicity effect on human and murine tumor cell lines (A549, PLC/PRF/5, Hepa 1-6 and TC-1) even at a high MOI, which suggested Ad.4-1BB scFv had no direct effect on tumor cells. Intratumoral injection of Ad.4-1BB scFv to established Hepa 1-6 tumors significantly suppressed the tumor growth in C57BL/6 mice. The anti-tumor effect might be mainly attributed to the anti-4-1BB scFv-mediated immune activity, as evidenced by enhanced interferon-gamma-producing splenic cells and increased lymphocytes infiltration in the tumor microenvironment. These results indicated that nonreplicative adenovirus carrying the anti-4-1BB scFv gene possessed powerful in vivo anti-tumor efficacy and might be a valuable tool for cancer immunotherapy.
Liu
Fang
F
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Lu
Qin
Q
Ye
Xun
X
Fang
Chao
C
Zhao
Yi
Y
Liang
Min
M
Hu
Fang
F
Lieber
Andre
A
Chen
Hong-Zhuan
HZ
D053330:4-1BB Ligand / Q000037:antagonists & inhibitors*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015316:Genetic Therapy; D007121:Immunocompetence / Q000502:physiology*; D007128:Immunoglobulin Fragments / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology*
D053330:4-1BB Ligand; D007128:Immunoglobulin Fragments; C055966:immunoglobulin Fv