Therapeutic vaccines could have a transformative impact on cancer therapy, but are currently hindered by inefficient expansion of the correct types of immune cells needed to migrate to tumors and destroy these tissues, while also establishing immune memory that prevents tumor relapse.
The goal of this project is to locally engineer the microenvironment of lymph nodes – the tissues that control immunity – using controlled release vaccine depots. These depots are formulated with activating immune signals, cues to promote immune memory, and DNA encoding molecules commonly upregulated on cancer cells.
Local delivery of these signals to lymph nodes could promote potent tumor immunity and long-lasting anti-tumor T cells. This work will shed new light on how the kinetics and concentrations of tumor vaccine components impact lymph node structure and function and support the development of a new class of cancer vaccines that could clear existing tumors and prevent new tumor growth.
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.