PREVENT PRECLINICAL DRUG DEVELOPMENT PROGRAM: PRECLINICAL EFFICACY AND INTERMEDIATE BIOMARKERS; TASK ORDER: PREVENTION OF COLORECTAL CANCER WITH IPSC-

最近针对非病毒性癌症开发癌症疫苗的方法集中在针对癌前病变和癌性病变中过度表达的已知致癌蛋白（新抗原）或肿瘤相关抗原（TAA）。在预防方面，这些癌症疫苗旨在引发抗肿瘤免疫，以防止或阻断致瘤过程，并在癌前细胞发展为侵袭性癌症之前将其消除。基于免疫检查点抑制剂的各种癌症免疫疗法的最新进展清楚地表明，如果通过免疫检查点阻断来消除肿瘤相关的免疫抑制，免疫系统可以产生有效的抗肿瘤免疫应答。由于肿瘤源性免疫抑制机制在肿瘤前体微环境中发挥的作用较小，因此在预防环境中，针对肿瘤抗原（新抗原和TAA）的主动免疫可以更有效地激发有效的抗肿瘤免疫，这是非常可信的。如果能够建立长期的免疫记忆，这种癌症疫苗将成为预防包括结直肠癌在内的癌症的更安全、更有效的方法。

Recent approaches to the development of cancer vaccines for non-viral cancers have centered on targeting known oncogenic proteins (neoantigens) or tumor-associated antigens (TAA) overexpressed in pre-cancerous and cancerous lesions. In the prevention setting, these cancer vaccines are intended to elicit antitumor immunity that prevents or intercepts tumorigenic process and eliminates precancerous cells before they progress to invasive 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 antigens (neoantigens and TAA) 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 preventing cancer including 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 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. Wu, Levy and others (Cell 2015, 161:240; Cell Stem Cell 2018, 22:501; Cell Stem Cell 2021, 28:10) have previously shown that human and murine iPSCs harbor the host’s germline mutations, the imprinted gene network dysregulation, and cancer-related mutations, and express tumor specific antigens on the cell surface. Wu et al. 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. Alternatively, allogeneic iPSCs may be useful as antigen-delivery carriers if they can evade the immune recognition of allogeneic antigens while preserving the specific tumor-antigen repertoire on the cell surface. Deuse et al. has recently reported that hypoimmunogenic derivatives of allogeneic iPSCs could evade immune rejection in fully immunocompetent recipients. Although it is unclear whether these hypoimmunogenic allogeneic (hypoallogeneic) iPSCs can still elicit antitumor immune responses in allogeneic hosts, it is worth evaluating the efficacy and potential utility of “off-the-shelf” hypoallogeneic iPSCs-based vaccines for cancer prevention. The current study aims to examine the immunogenicity and antitumor efficacy of hypoallogeneic iPSC-based vs. autologous iPSC-based vaccines in a murine syngeneic tumor graft model of colorectal tumorigenesis in order to determine the optimal iPSC vaccine platform(s) for future in vivo efficacy evaluation studies.