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常见癌症，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效益，但预计到 2022 年，预计将有 151,030 例结直肠癌新病例和 52,580 例结直肠癌死亡病例。除了筛查和早期发现之外，可以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体大有裨益，包括患有林奇综合征或家族性腺瘤性息肉病 (FAP) 的个体以及患有结直肠癌的个体。 炎症性肠病（IBD）。高危人群需要更安全有效的化学和/或免疫预防干预措施来持久预防结直肠癌。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。 最近开发非病毒性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，拦截致瘤过程并在癌前细胞发展为成熟癌症之前消除它们。基于免疫检查点抑制剂的多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反应。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引发有效的抗肿瘤免疫，这是非常合理的，因为肿瘤源性免​​疫抑制机制在肿瘤前体微环境中发挥的作用较小。如果能够建立长期免疫记忆，此类癌症疫苗可以作为预防癌症（包括结直肠癌）的更安全、更有效的方法。 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性癌症疫苗都集中在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，因此可以轻松简化以进行进一步的开发。有趣的是，免疫检查点封锁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，个体化（个性化）免疫预防性癌症疫苗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，人类和小鼠 iPSC 存在宿主的种系突变、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，用带有 CpG 佐剂的辐照 iPSC 进行疫苗接种可引发强烈的抗肿瘤免疫反应，这与体内小鼠同基因肿瘤移植模型中肿瘤生长显着消退相关。虽然这些数据表明基于 iPSC 的免疫预防性癌症疫苗具有针对每个宿主（尤其是患有遗传性癌症综合征的个体）进行个性化定制的潜在益处，但开发自体“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也是如此。在这方面，如果同种异体 iPSC 能够逃避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。据报道，同种异体 iPSC 的低同种异体衍生物可以逃避完全免疫功能的受体的免疫排斥反应。如果这些基于低同种异体 iPSC 的疫苗能够引发抗肿瘤免疫，那么它们可能会用作“现成的”基于低同种异体 iPSC 的疫苗来预防癌症。作为先前研究 (https://reporter.nih.gov/project-details/10412368) 的后续研究，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 的疫苗在炎症性肠病 (IBD) 相关结直肠 (CRC) 肿瘤发生的小鼠模型中的抗肿瘤功效。