Abstract
Fibroblast activation protein (FAP) is a membrane-bound enzyme with gelatinase and peptidase activity that is up-regulated in cancer-associated fibroblasts in over 90% of human carcinomas. Previous studies have shown that ablation of FAP-expressing cells from transgenic mice attenuates tumor growth and synergizes with other immune therapies such as immune checkpoint blockade. Groups have additionally shown that T cells expressing chimeric antigen receptors targeting FAP slow tumor progression; however, in some mouse strains these CARs cause lethal toxicity. There is therefore a need to develop safer therapies targeting FAP. In this study we designed a novel consensus-based FAP DNA vaccine to help break tolerance. We hypothesized that this FAP vaccine could break tolerance and synergize with other immunotherapies to induce anti-tumor immunity without causing overt toxicity. Upon delivery of our FAP DNA vaccine intramuscularly followed by electroporation (EP), we detected IFN-γ and TNF-α CD8 T cell responses (p<0.05), and TNF-α CD4 responses (p<0.05) against native mouse FAP peptides, indicating that our vaccine is capable of breaking tolerance. Furthermore, we detected cytotoxic CD107a/IFNγ/T-bet triple-positive CD8 T cells that are reactive to native FAP peptides (p<0.05). In a prostate cancer model, vaccination with FAP alone or the prostate cancer antigen PSMA alone did not significantly alter tumor growth. However, vaccination with a combination of FAP and PSMA significantly attenuated tumor growth (p<0.0005), with final tumor volumes that were approximately 9 times smaller than tumors in naïve mice. Thus, our results support the use of FAP vaccines to target the tumor microenvironment in combination with immune therapies targeting the tumor cells themselves. We are investigating additional combination therapies with our FAP vaccine to modulate tumor infiltrating lymphocytes and to broaden responses to additional tumor antigens.
Citation Format: Elizabeth Duperret, Dylan Ammons, Megan C. Wise, Jian Yan, Laurent M. Humeau, David B. Weiner. A novel DNA vaccine targeting fibroblast activation protein (FAP) breaks tolerance and synergizes with anticancer immune therapy in mice [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A010.
