FURTHER DEVELOPMENT OF IPSC-BASED VACCINE FOR COLON CANCER PREVENTION

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. While the evidence supports that CRC-screening confers a substantial benefit overall, there will be an estimated 151,030 new CRC cases and 52,580 deaths from CRC expected in 2022. In addition to screening and early detection, proactive prevention strategies that can further reduce the CRC risk will be of great benefit to individuals with an increased CRC risk, including those with Lynch syndrome or familial adenomatous polyposis (FAP) and individuals with inflammatory bowel diseases (IBD).

Safer and efficacious chemo- and/or immunopreventive interventions are needed for durable long-term CRC prevention in the high-risk populations. While cancer vaccines hold promise for immunoprevention, their feasibility and utility have yet to be fully explored.

Recent approaches to the development of immunopreventive vaccines for non-viral cancers have centered on targeting known oncogenic proteins or tumor-associated antigens (TAA) overexpressed in pre-cancerous and cancerous lesions. These cancer vaccines are intended to elicit antitumor immunity that intercepts tumorigenic process and eliminates precancerous cells before they progress to form a full-blown cancer.

Recent advances in immune-checkpoint inhibitor-based immunotherapies for various cancers have clearly shown that the immune system can mount effective antitumor immune responses if tumor-associated immunosuppression is abrogated by immune checkpoint blockade. It is highly plausible that effective antitumor immunity can be more efficiently elicited by active immunization against tumor-specific antigens in the prevention setting, as tumor-derived immunosuppressive mechanisms play a lesser role in tumor precursor microenvironment.

If long-term immunological memory can be established, such cancer vaccines can serve as a safer and more effective approach to cancer prevention including for colorectal cancer.

One of the most important steps toward developing effective cancer preventive vaccines is the selection of vaccine antigens. The majority of immunopreventive cancer vaccines studied to date have focused on targeting common tumor-specific antigens that are expected to be widely immunogenic in a given target cohort and thus can be easily streamlined for further development.

Interestingly, antitumor immune responses unleashed by immune checkpoint blockade have been shown to target a large repertoire of tumor specific antigens that are unique to individual patients. Individualized (personalized) immunopreventive cancer vaccines have been considered impractical because of the technical and logistical challenges expected with the development of such vaccines in the prevention setting.

Since the discovery of induced pluripotent stem cells (iPSCs) in 2006, much knowledge and experience have been gained with iPSC technology and its potential utility in various biomedical fields. Previous studies have shown that human and murine iPSCs harbor the host’s germline mutations, the imprinted gene network dysregulation, and cancer-related mutations, and express tumor-associated and tumor-specific antigens on the cell surface.

These investigators further demonstrated that vaccination with irradiated iPSCs with CpG adjuvant elicited robust antitumor immune responses that were associated with significant tumor growth regression in murine syngenetic tumor transplant models in vivo. While these data suggested the potential benefit of iPSCs based-immunopreventive cancer vaccines that are personalized for each host, especially for those affected with heritable cancer syndromes, logistical challenges of developing autologous “personalized” iPSCs vaccines are enormous, not only from the point of manufacturing processes but also associated costs.

In this regard, allogeneic iPSCs may offer alternative strategies for vaccination if they can evade the immune recognition of allogeneic antigens while preserving the specific tumor-antigen repertoire on the cell surface. It has been reported that hypoallogenic derivatives of allogeneic iPSCs could evade immune rejection in fully immunocompetent recipients.

If these hypoallogeneic iPSC-based vaccines can elicit antitumor immunity, they may be used as “off-the-shelf” hypoallogeneic iPSCs-based vaccines for cancer prevention. As a follow-up to the previous study (https://reporter.nih.gov/project-details/10412368), the current study is aimed to evaluate the antitumor efficacy of hypoallogeneic iPSC-based vs. autologous iPSC-based vaccines in a murine model of inflammatory bowel disease (IBD)-associated colorectal (CRC) tumorigenesis.