Anti-4-1BB scFv immunogene therapy and low dose cyclophosphamide exhibit a synergistic antitumor effect in established murine lung tumors

Abstract

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 anti-tumor 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 anti-lung

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 anti-tumor 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.