FURTHER DEVELOPMENT OF IPSC-BASED VACCINE FOR COLON CANCER PREVENTION

进一步开发基于 IPSC 的结肠癌预防疫苗

• 批准号: 10893658
• 负责人: PREMA ROBINSON
• 金额: $ 129.3万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-26 至 2026-07-25
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10893658
• 关键词: Active Immunization; Adjuvant; Affect; Allogenic; Antigens; Autologous; Cancer Etiology; Cancer Vaccines; Cancerous; Cell surface; Cessation of life; Colorectal Cancer; Common Neoplasm; Data; Development; Early Diagnosis; Familial Adenomatous Polyposis Syndrome; Germ-Line Mutation; Goals; Hereditary Nonpolyposis Colorectal Neoplasms; Heritability; Human; Immune Evasion; Immune checkpoint inhibitor; Immune response; Immune system; Immunocompetent; Immunologic Memory; Immunoprevention; Immunosuppression; Immunotherapy; Individual; Inflammatory Bowel Diseases; Intercept; Intervention; Knowledge; Lesion; Malignant Neoplasms; Molecular Profiling; Mus; Mutation; Neoplasm Transplantation; Oncogenic; Play; Premalignant Cell; Prevention; Prevention strategy; Preventive vaccine; Process; Proteins; Regimen; Reporter; Reporting; Research Personnel; Role; Syndrome; Tumor Antigens; Tumor Immunity; Tumor-Derived; Vaccination; Vaccine Antigen; Vaccines; Woman; anti-tumor immune response; cancer diagnosis; cancer prevention; cohort; colon cancer prevention; colon tumorigenesis; colorectal cancer prevention; colorectal cancer risk; colorectal cancer screening; cost; experience; follow-up; gene network; high risk population; immune checkpoint blockade; immunogenic; imprint; in vivo Model; individual patient; induced pluripotent stem cell; induced pluripotent stem cell technology; manufacturing process; men; mouse model; overexpression; premalignant; preservation; screening; tumor; tumor growth; tumorigenic; vaccination strategy; vaccine trial

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.

结直肠癌 (CRC) 是男性和女性中第三大最常见的癌症，也是美国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具有显着益处，但预计将有 151,030 例新病例。预计 2022 年将出现 CRC 病例，并有 52,580 人死于 CRC。除了筛查和早期发现之外，可进一步降低 CRC 风险的主动策略将对 CRC 增加的个体大有裨益需要更安全有效的化疗和/或免疫预防干预措施，以对高危人群进行持久的 CRC 预防。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。 最近开发非病毒癌症免疫预防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或肿瘤相关抗原（TAA），这些癌症疫苗旨在引发抗肿瘤免疫，从而阻止肿瘤发生过程。并在癌前细胞发展为成熟癌症之前将其消除。针对各种癌症的基于免疫检查点抑制剂的免疫疗法的最新进展清楚地表明，免疫系统可以有效地发挥作用。如果通过免疫检查点阻断消除肿瘤相关的免疫抑制，则可能会出现抗肿瘤免疫反应，因此在预防环境中针对肿瘤特异性抗原的主动免疫可以更有效地引发有效的抗肿瘤免疫，因为肿瘤衍生的免疫抑制机制发挥的作用较小。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，包括结直肠癌。 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，迄今为止研究的大多数免疫预防癌症疫苗都集中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群体中具有广泛的免疫原性。因此可以很容易地简化以进行进一步的开发，表明免疫检查点阻断所释放的抗肿瘤免疫反应已被证明可以针对个体患者特有的大量肿瘤特异性抗原。由于在预防环境中开发此类疫苗预计会面临技术和后勤方面的挑战，因此被认为是不切实际的。 自 2006 年发现诱导多能干细胞 (iPSC) 以来，人们在 iPSC 技术及其在各个生物医学领域的潜在用途方面获得了很多知识和经验，先前的研究表明，人类和鼠类 iPSC 带有宿主的种系突变（即印记）。基因网络失调和癌症相关突变，并在细胞表面表达肿瘤相关和肿瘤特异性抗原。这些研究人员进一步证明，用经过 CpG 照射的 iPSC 进行疫苗接种。佐剂在体内小鼠同基因肿瘤移植模型中引发了强烈的抗肿瘤免疫反应，与显着的肿瘤生长消退相关，而这些数据表明基于 iPSC 的针对每个宿主的个性化免疫预防癌症疫苗的潜在益处，特别是对于那些受遗传影响的人。癌症综合症，开发自体“个性化”iPSC 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，同种异体 iPSC 可能提供替代的疫苗接种策略。如果它们能够逃避同种异体抗原的免疫识别，同时保留细胞表面上的特定肿瘤抗原库，据报道，如果这些基于低同种异体 iPSC 的疫苗能够逃避完全免疫功能的受体的免疫排斥。引发抗肿瘤免疫力，它们可以用作“现成的”基于低同种异体 iPSC 的疫苗，用于癌症预防。与之前的研究 (https://reporter.nih.gov/project-details/10412368) 相比，当前的研究旨在评估基于低同种异体 iPSC 的疫苗与基于自体 iPSC 的疫苗在小鼠炎症模型中的抗肿瘤功效肠病（IBD）相关结直肠（CRC）肿瘤发生。