Abstract SY17-02: Multiantigen vaccines for colon cancer prevention
Authors: Sei Shizuko 
Published: July 2021

Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US when men and women are combined. While overall CRC incidence has declined over the years, there has been an increase in CRC diagnosis in young and middle-aged adults. The US Preventive Services Task Force has recently issued draft recommendations for CRC screening to begin at 45 years of age instead of the previously recommended age of 50 for asymptomatic healthy individuals, who are at average risk of CRC, i.e. without a family history of hereditary CRC syndromes such as Lynch syndrome and familial adenomatous polyposis, or with no prior diagnosis of CRC, adenomatous polyps, inflammatory bowel disease. While the evidence supports that CRC-screening and early detection confers a substantial benefit, additional CRC prevention strategies can greatly help reduce the cancer burden in the US and around the world. A number of previous studies have shown that the 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, including gastrointestinal bleeding. Safer and more efficacious preventive approaches are needed for durable long-term CRC prevention. The majority of newly diagnosed CRC are non-familial (sporadic) and non-hypermutated/microsatellite-stable (MSS). Compared to CRC with high microsatellite instability, MSS CRC and adenomas have significantly lower somatic mutation frequencies, thus lower neoantigen load. Furthermore, MSS CRC have generally lower levels of tumor-infiltrating lymphocytes (TILs), higher density of myeloid derived suppressor cells (MDSC), and downregulation of HLA molecules. These are characteristic of immunologically “cold” tumors, making it highly challenging to immunologically control tumor growth. If cancer vaccines can successfully prime the immune system, in particular before the development of invasive cancer, vaccine-induced adaptive antitumor immunity may render “cold” tumors “hot” and achieve a favorable tumor control. One of the key questions, however, is what tumor antigens can be targeted by vaccines if tumors have lower levels of neoantigens that are known to elicit robust antitumor immune responses. Another approach for cancer vaccine-mediated immune priming is to target tumor associated antigens (TAAs). Unlike tumor-specific neoantigens, TAAs are self-antigens that are overexpressed in tumors, but may also be expressed in normal cells at various levels. Therefore, it is highly critical to identify T cell epitopes that break tolerance and help elicit effective antitumor immunity. Clinically beneficial antitumor immunity is characterized by high-density infiltrates of effector CD8+ cytotoxic T lymphocytes and effector memory T cells and the low abundance of immunosuppressive elements (e.g. regulatory T cells, MDSC, and M2-polarized tumor-associated macrophages) in the tumor microenvironment. Disis and colleagues from University of Washington have previously established a systematic and stepwise approach to identify Th1-selective epitopes for efficacious cancer vaccines while eliminating Th2-epitopes. They have shown cancer vaccines targeting TAAs thus developed could elicit robust Th1 immune response associated with antitumor effects. The NCI PREVENT Cancer Preclinical Drug Development Program (PREVENT) is a peer-reviewed agent development program focused on preclinical development of innovative interventions, including cancer vaccines and drugs, for precision cancer prevention-interception towards clinical applications (https://prevention.cancer.gov/major-programs/prevent-cancer-preclinical). PREVENT and Disis team collaborated on the development of a multi-antigen multi-peptide colon cancer vaccine, named Colovac, for immunoprevention of CRC. It consists of highly immunogenic Th1-promoting epitopes from three TAAs that are selected through CRC genomic database and literature search. TAAs selected are overexpressed in CRC, known to play a role in CRC oncogenesis, and associated with poor disease outcomes. This presentation will cover the background of Colovac development, preclinical antitumor efficacy data on Colovac used alone or in combination with naproxen, characterization of immune correlates of protection, and current ongoing development efforts toward clinical trials.
Citation Format: Shizuko Sei. Multiantigen vaccines for colon cancer prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY17-02.