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）是男性和女性中诊断的第三大常见癌症，也是美国癌症死亡的第二大原因。虽然证据支持CRC筛查总体上带来了巨大的益处，但预计2022年将有151，030例新的CRC病例和52，580例CRC死亡。除了筛查和早期发现，可以进一步降低CRC风险的积极预防策略将对CRC风险增加的个体非常有益，包括Lynch综合征或家族性腺瘤性息肉病（FAP）和炎症性肠病（IBD）的个体。需要更安全有效的化疗和/或免疫预防干预措施，以在高危人群中持久长期预防CRC。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。 最近开发用于非病毒癌症的免疫预防疫苗的方法集中在靶向癌前病变和癌性病变中过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力，拦截肿瘤发生过程并在癌前细胞进展形成全面癌症之前消除癌前细胞。用于各种癌症的基于免疫检查点通道的免疫疗法的最新进展已经清楚地表明，如果通过免疫检查点阻断消除肿瘤相关的免疫抑制，则免疫系统可以产生有效的抗肿瘤免疫应答。这是非常合理的，有效的抗肿瘤免疫可以更有效地引发主动免疫肿瘤特异性抗原的预防设置，因为肿瘤源性免疫抑制机制在肿瘤前体微环境中发挥较小的作用。如果可以建立长期免疫记忆，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的最重要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靶向常见的肿瘤特异性抗原，这些抗原预计在给定的靶群中具有广泛的免疫原性，因此可以很容易地简化以用于进一步开发。有趣的是，由免疫检查点阻断释放的抗肿瘤免疫应答已显示靶向个体患者特有的大量肿瘤特异性抗原。个体化（个性化）免疫预防癌症疫苗被认为是不切实际的，因为在预防环境中开发这种疫苗预期会带来技术和后勤挑战。 自2006年发现诱导多能干细胞（iPSC）以来，人们对iPSC技术及其在各个生物医学领域的潜在用途获得了大量知识和经验。先前的研究表明，人和鼠的iPSC具有宿主的种系突变、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，用具有CpG佐剂的经照射的iPSC接种引起了强有力的抗肿瘤免疫应答，其与体内鼠同源肿瘤移植模型中的显著肿瘤生长消退相关。虽然这些数据表明，基于iPSC的免疫预防性癌症疫苗对于每个宿主都是个性化的，特别是对于那些受遗传性癌症综合征影响的宿主，但开发自体“个性化”iPSC疫苗的后勤挑战是巨大的，不仅从制造过程的角度来看，而且从相关成本来看。在这方面，如果同种异体iPSC可以逃避同种异体抗原的免疫识别，同时保留细胞表面上的特异性肿瘤抗原库，那么它们可以提供用于疫苗接种的替代策略。据报道，同种异体iPSC的低同种异体衍生物可以在完全免疫活性的受体中逃避免疫排斥。如果这些基于低同种异体iPSC的疫苗可以引发抗肿瘤免疫，则它们可以用作“现成的”基于低同种异体iPSC的疫苗用于癌症预防。作为先前研究（https：//paster.nih.gov/project-details/10412368）的后续研究，本研究旨在评价基于低同种异体iPSC的疫苗与基于自体iPSC的疫苗在炎性肠病（IBD）相关结直肠（CRC）肿瘤发生的鼠模型中的抗肿瘤功效。