Anti-4-1BB scFv immunogene therapy and low dose cyclophosphamide exhibit a synergistic antitumor effect in established murine lung tumors.
T-cell costimulatory molecules such as 4-1BB may provide a distinct and important signal for promoting positive immune regulation. 4-1BB is thought to have potential use as a cancer immunotherapeutic drug. In our previous study, a nonreplicative adenovirus (Ad.4-1BB scFv) carrying single-chain Fv fragments (scFv) specific for the 4-1BB gene (anti-4-1BB scFv) possessed remarkable in vivo anti-hepatoma efficacy. However, monotherapy achieved by triggering 4-1BB signaling was not sufficient to induce eradicative antitumor activities in low immunogenic tumors. It is of great interest to explore any possible synergistic antitumor effect of 4-1BB signaling combined with low dose cyclophosphamide (CTX), which is well documented to inhibit the suppressive capability of regulatory T-cells in mice and humans. In the present study, recombinant nonreplicative adenoviruses carrying an anti-4-1BB scFv gene were generated, characterized and explored for their stimulation of antilung tumor (TC-1) immunity in immunocompetent C57BL/6 mice. Compared to adenovirus and cyclophosphamide alone, adenovirus-mediated anti-4-1BB scFv in combination with low dose CTX treatment could obviously augment the antitumor activity, in which some established TC-1 tumors were eradicated and the survival of mice was significantly extended. This synergistic antitumor effect could be largely attributed to the depletion of T regulatory cells induced by low dose CTX. These findings may provide a new and promising strategy for immunogene therapy against cancer.
Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Fang
F
Liu
Chao
C
Fang
Xun
X
Ye
Qin
Q
Lu
De-Hong
DH
Yu
Wei-Wei
WW
Zhang
Hong
H
Qi
Jing
J
Xie
Andre
A
Lieber
Hong-Zhuan
HZ
Chen
D053330:4-1BB Ligand / Q000235:genetics*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004357:Drug Synergism; D005434:Flow Cytometry; D015316:Genetic Therapy; D007124:Immunoenzyme Techniques; D007135:Immunoglobulin Variable Region / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D053330:4-1BB Ligand; D000951:Antigens, Neoplasm; D018906:Antineoplastic Agents, Alkylating; D007135:Immunoglobulin Variable Region; D003520:Cyclophosphamide