Colorectal cancer (CRC) is the third most common cancer diagnosed in men and women, and the second leading cause of cancer death in the US. The US Preventive Services Task Force recommends screening for colorectal cancer starting at age 50 years and continuing until 75 years of age for asymptomatic adults with average risk of CRC and without a family history of known genetic disorders associated with an increased risk of CRC such as Lynch syndrome or familial adenomatous polyposis (FAP). While the evidence supports that CRC-screening confers a substantial benefit overall, there will be an estimated 145,600 new CRC cases and 51,020 deaths from CRC expected in 2019. In addition to screening and early detection, prevention strategies that can further reduce the CRC risk will be of great benefit, in particular in high risk populations. A number of previous studies have shown that use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of cancers, including CRC. However, their extended use can be associated with serious side effects, such as gastrointestinal bleeding. Safer and more efficacious approaches are needed for durable long-term CRC prevention. Cancer vaccines targeting tumor-associated antigens (TAA) overexpressed in pre-cancerous and cancerous lesions may elicit antitumor immunity that intercepts tumorigenic process and eliminates precancerous cells before they progress to form a full-blown cancer. Recent advances in immunotherapies for various cancers have clearly shown that the immune system can mount effective antitumor immune responses if tumor-associated immunosuppression is abrogated, for example, by immune checkpoint blockade. It is conceivable that effective antitumor immunity may be more efficiently elicited by active immunization against TAA in the cancer prevention setting, as tumor-derived immunosuppressive mechanisms may play a lesser role in premalignant lesions. If long-term immunological memory can be established, such cancer vaccines can serve as a safer and more effective approach to cancer prevention. One of the most important steps toward developing effective cancer preventive vaccines is the selection of the antigens. Disis and colleagues have previously shown that high binding affinity across multiple HLA class II alleles predicts immunogenic human epitopes. They developed a scoring system designed to identify epitopes with optimal binding affinity and promiscuity across multiple class II alleles. Using the scoring algorithms, they demonstrated that peptides selected from the identified immunogenic hotspots of the target protein could induce robust antigen-specific type 1 T cell response in cancer patients and healthy volunteers. Immunization with these peptides mediated an antitumor effect in preclinical models of tumorigenesis. They further optimized the epitope selection process by eliminating Th2-epitopes from candidate peptides and demonstrated that highly robust protective immunity could be elicited by a multi-peptide vaccine with potent antitumor activity. Current approaches to the development of preventive vaccines for non-viral cancers are centered on strategies to target known oncogenic proteins. However, novel and more broadly applicable promising target antigens for preventive cancer vaccines may be identified from careful analyses of genes that are overexpressed in premalignant and malignant tissues but not in normal tissues. Disis et al. have recently reported highly immunogenic Th1-promoting epitopes from three TAAs, CDC25B, COX2 and EGFR, all of which are overexpressed in CRC and associated with poor disease outcomes. They showed these selected TAA-peptide based vaccine, referred to as Colovac, induced type 1 immunity and decreased tumor burden in preclinical models of intestinal tumorigenesis. Separately, her group has also demonstrated that NSAIDs significantly reduced polyp formation while increasing the number of CD8+ T-cell infiltrates in polyps in ApcMin/+ mice. This study is based on the work performed under the Task Order HHSN261201500036I/ HHSN26100004 (https://projectreporter.nih.gov/project_info_details.cfm?aid=9360921), which focused on determining immunologic synergy and antitumor activity of the combination regimen of Colovac and naproxen in preclinical models of intestinal tumorigenesis. The current study aims to further advance the Colovac vaccine towards clinical applications.