FURTHER DEVELOPMENT OF IPSC-BASED VACCINE FOR COLON CANCER PREVENTION

结直肠癌(CRC)是美国男性和女性诊断的第三大常见癌症，也是导致癌症死亡的第二大原因。虽然有证据表明，结直肠癌筛查总体上带来了实质性的好处，但预计2022年将有151,030例新的结直肠癌病例和52,580例结直肠癌死亡病例。除了筛查和早期发现外，能够进一步降低结直肠癌风险的积极预防策略将对结直肠癌风险增加的个人大有裨益，包括林奇综合征或家族性腺瘤性息肉病(FAP)和炎症性肠病(IBD)患者。要在高危人群中长期持久地预防结直肠癌，需要采取更安全有效的化学和/或免疫预防干预措施。虽然癌症疫苗有望用于免疫预防，但其可行性和实用性尚未得到充分探索。 最近针对非病毒性癌症的免疫预防疫苗的开发方法主要集中在针对癌前病变和癌前病变中过度表达的已知癌基因蛋白或肿瘤相关抗原(TAA)。这些癌症疫苗旨在激发抗肿瘤免疫，阻止肿瘤形成过程，并在癌前细胞发展为全面癌症之前消除它们。基于免疫检查点抑制剂的各种癌症免疫治疗的最新进展清楚地表明，如果免疫检查点阻断取消了肿瘤相关的免疫抑制，免疫系统就可以产生有效的抗肿瘤免疫反应。由于肿瘤免疫抑制机制在肿瘤前体微环境中的作用较小，因此在预防环境中通过针对肿瘤特异性抗原的主动免疫可以更有效地诱导有效的抗肿瘤免疫。如果能够建立长期的免疫记忆，这种癌症疫苗可以作为一种更安全、更有效的癌症预防方法，包括对结直肠癌的预防。 开发有效的癌症预防疫苗最重要的步骤之一是选择疫苗抗原。到目前为止，大多数研究的免疫预防癌症疫苗都专注于针对常见的肿瘤特异性抗原，这些抗原预计在给定的目标队列中具有广泛的免疫原性，因此可以很容易地简化，以便进一步开发。有趣的是，免疫检查点阻断释放的抗肿瘤免疫反应被证明是针对个体患者特有的大量肿瘤特异性抗原的。个体化(个人化)免疫预防癌症疫苗一直被认为是不切实际的，因为在预防环境中开发这种疫苗预计会带来技术和后勤挑战。 自2006年诱导多能干细胞(IPSCs)被发现以来，IPSC技术及其在各个生物医学领域的潜在应用已经积累了大量的知识和经验。以往的研究表明，人和小鼠的IPSCs存在宿主的胚系突变、印记基因网络失调和肿瘤相关突变，并在细胞表面表达肿瘤相关抗原和肿瘤特异性抗原。这些研究人员进一步证明，用CpG佐剂照射的IPSCs接种可引发强大的抗肿瘤免疫反应，这与体内小鼠同基因肿瘤移植模型中的肿瘤生长显著减退有关。虽然这些数据表明，为每个宿主个性化的基于IPSCs的免疫预防癌症疫苗的潜在好处，特别是对那些受可遗传癌症综合征影响的人，但开发自体“个性化”IPSCs疫苗的后勤挑战是巨大的，不仅从制造工艺的角度来看，而且从相关成本的角度来看。在这方面，如果异体IPSCs能够避开同种异体抗原的免疫识别，同时保留细胞表面的特定肿瘤抗原库，那么它们可能会提供替代的疫苗接种策略。有报道称，异体IPSCs的同种异体衍生物可以在完全具有免疫功能的受体中逃避免疫排斥反应。如果这些基于IPSC的低同种异体疫苗能够激发抗肿瘤免疫，它们可能会被用作用于癌症预防的现成的基于低同种异体IPSCs的疫苗。作为先前研究(https://reporter.nih.gov/project-details/10412368)，的后续研究，本研究旨在评估基于低异基因免疫球蛋白干细胞的疫苗与基于自体免疫球蛋白干细胞的疫苗在炎症性肠病相关结直肠癌小鼠模型中的抗肿瘤效果。

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.