Research Project
7800734
DESCRIPTION (provided by applicant): Metastases are the leading cause of death of most cancer patients. Leveraging the immune system to eliminate micrometastasis has long been attempted with only modest success. One limitation is that the local tumor environment often forms immune barriers that prevent sufficient antigen presentation and thus ineffective T-cell priming and activation leading to a failed antitumor immune response. A novel approach to breaching this tumor barrier has been identified which employs the introduction of a member of the tumor necrosis factor superfamily member, TNFSF member 14 or LIGHT. Expression of LIGHT within tumors leads to the formation of lymphoid-like structures within tumors and recruitment of T-cells. Subsequently, there is a rapid rejection of highly aggressive tumors and eradication of metastases in preclinical models. Our working hypothesis is that by targeting tumor tissues with AdLIGHT (LIGHT delivered via an adenoviral vector directly into tumors), this can break tumor barriers and generate cytotoxic T-lymphocytes (CTLs) that can eradicate micrometastases. The goal of this Phase I SBIR application is to translate research findings using the murine form of LIGHT and construct the human analogue of LIGHT in an adenovector system and verify its antimetastatic activity in preclinical cancer models. If shown to be feasible, a future Phase II SBIR grant will be submitted with the intent of completing studies necessary for an IND application to the FDA with the intent to initiate a Phase I clinical trial. The specific aims of this Phase I application are: 1) Construct the human analogue of modified mouse LIGHT in an adenoviral vector system and verify its antitumor and antimetastatic activity in preclinical cancer model systems and 2) Optimize the expression and production of LIGHT, which could increase the efficacy in future clinical trials. Preliminary data with LIGHT indicate that local therapy can eradicate metastases and will be an innovative and unexpected strategy to control local tumors and combat metastatic disease. To achieve the goals of this application in a timely manner, this grant application is a collaboration of three laboratory groups each with unique expertise: Dr. Fu with expertise in immunology and lymphogenesis, Dr. Weichselbaum with preclinical cancer models and cancer biology, and Dr. Wei with adenovector delivery, lead molecule selection and drug development experience. PUBLIC HEALTH RELEVANCE: Cancer metastases are the major cause of death still for most cancer patients;medical therapies that target this are still direly needed. This grant application proposes a novel strategy to combat metastases by leveraging the tumor stroma and utilizing it to stimulate the immune system to eradicate both tumors and metastases.
