Koji Tamada, MD, PhD
Johns Hopkins University
LIGHT co-stimulatory system for cancer gene therapy.
Effectiveness of cancer vaccine to elicit immunity against tumor cells has been fundamentally proved in experimental animals or in some clinical conditions. Currently, one of the most important subjects of cancer vaccine is how to maximize its potency. In this regard, recent studies have suggested that LIGHT, a molecule belonging to tumor necrosis factor superfamily, induces potent anti-tumor immunity by a unique mechanism that facilitates both migration and activation of lymphocytes at the site of tumor.
In this study, we will delineate the molecular-based mechanism of this phenomenon and to develop further efficient cancer vaccine using LIGHT. To this end, we will first take advantage of mutant protein of LIGHT or neutralizing monoclonal antibodies against HVEM or LTbetaR, two functional receptors of LIGHT. These experiments will elucidate the relative importance of HVEM versus LTbetaR or membrane versus soluble LIGHT in association with T cell trafficking and activation as well as anti-tumor efficacy.
In the following experiments, we will attempt to develop innovative and more potent strategies of LIGHT cancer vaccine. By molecular engineering techniques, we will express stimulatory anti-HVEM antibody on the surface of tumor cells as cancer vaccine or generate pentameric constructs of this antibody to facilitate the signal delivery. In addition, attenuated measles virus vector that is specifically targeted to tumor cells will be utilized for tumor-selective LIGHT expression in vivo.
Successful completion of this project will strongly support the potency of LIGHT as a target for advanced cancer immunotherapy, and thus lay the foundation of translational studies on LIGHT-based cancer gene therapy aiming at clinical applications.