Current immunotherapy, such as therapeutic vaccination, has not yet shown effective treatment against cancer. The tumor environment often forms immune barriers that prevent sufficient levels of antigens or antigen presenting cells from entering draining lymph nodes thereby resulting in ineffective T cell priming. Furthermore, the local tumor environment often fails to activate incoming CD8+ T cells. The expression of mutant murine TNF superfamily member 14 (TNFSF14), LIGHT, on tumor cells leads to a rapid rejection of highly aggressive tumors in vivo through the formation of the lymphoid-like structure inside the tumors, which serves to recruit T cells. We hypothesize that targeting tumor tissues with ad-LIGHT can break tumor barriers and convert the suppressive microenvironment inside tumor tissue into a proinflammatory one, facilitate T cell recruitment and priming such that CTL can develop sufficiently to eradicate micro-metastases. In phase I of this project, this novel immunotherapeutic strategy for treating metastatic cancers will be developed in the following two specific aims: 1) To generate adenovirus expressing mutant human LIGHT, we would like to generate human mutant and gene modified LIGHT for future clinical trials. We will test its expression in human tumors and its toxicity in rodent. 2) To determine whether mutant human LIGHT can enhance immunity inside human tumors, we will also test whether hLIGHT can enhance anti-tumor activity in mouse tumor and further with transferred human immune cells in a mouse xenograft model. The ultimate goal of this research and development program is to develop a novel drug that targets metastatic tumor. Phase II of the project will include safety tests for ad-LIGHT in rodents and primates, to carry out phase I and pilot phase II clinical trials in patients with potential micro-metastasis to evaluate safety, efficacy and risk of ad-LIGHT, and to establish clinical monitoring system using gene array, tissue array and protein array. The study will produce gene modified human LIGHT and then generate clinical relevant delivery system, adenovirus-LIGHT. Therefore, this application aspires to develop clinically relevant approaches in the treatment of established cancers and continues to explore the molecular mechanisms for not only tumor-induced immune tolerance but also LIGHT-mediated tumor rejection. This study will also provide important data for future clinical trials by targeting tumor microenvironment. The Phase II study of this project will pave the way for expanded phase I/II clinical trials of the novel drug for the treatment of cancer with implications in other diseases. ? ? ?
