Abstract 1501: Tumor cells engineered to codisplay on their surface 4-1BBL and LIGHT costimulatory proteins as a novel vaccine approach for cancer immunotherapy

Abstract

Abstract Therapeutic vaccines based on whole tumor cells genetically modified to express various immunomodulatory molecules represent an important modality for the treatment of cancer. However, generation of genetically modified tumor cells as vaccine is not only cost, labor, and time intensive, but also has safety repercussions. As an alternative, we have recently developed the ProtEx™ technology that involves modification of the cell membrane with biotin and engineering of biotinylated cells with proteins of interest chimeric with core streptavidin. We herein tested if tumor cells can be engineered efficiently to simultaneously display on their surface two SA-chimeric costimulatory ligands, SA-4-1BBL and SA-LIGHT, and if vaccination with such engineered cells has better therapeutic efficacy than cells displaying single molecule in the TC-1 cervical cancer mouse model. The choice of 4-1BBL is due to pleiotropic immune activity of 4-1BBL to stimulate innate, adaptive immune responses as well as overcome various immune evasion mechanisms. The choice of LIGHT is due to its stimulatory effects on tumor stroma, which pose a physical barrier to the entry of effector immune cells to tumor site. Biotinylated TC-1 tumor cells codisplayed both chimeric costimulatory ligands on their surface with equal efficiency after incubation with equal molar of SA-4-1BBL and SA-LIGHT proteins. Vaccination with irradiated TC-1 tumor cells codisplaying both chimeric costimulatory ligands resulted in the generation of antigen specific T cell proliferative and killing responses, resulting in 100% efficacy in prophylactic and > 57% efficacy in therapeutic settings. In marked contrast, vaccination with TC-1 tumor cells displaying on their surface either of these molecules singly only delayed the tumor growth in the prophylactic setting. Vaccine efficacy was associated with effective generation of primary and memory T cell and Ab responses, enhanced CD8+ T cell infiltration into the tumor, IFN-γ production, and tumor-specific killing. In conclusion, engineering tumor cells in a rapid and effective manner to simultaneously display on their surface a collection of immunostimulatory molecules with distinct immune functions presents a novel approach with considerable potential for cancer immunotherapy. Funded in parts by NIH 2R44 AI071618-02, R43 AI074176, R41 CA121665, KLCP, the W.M. Keck Foundation, and the Commonwealth of Kentucky Research Challenge Trust Fund. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1501.