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

预防临床前药物开发计划：临床前疗效和中间生物标志物；

• 批准号: 10412368
• 负责人: POWEL BROWN
• 金额: $ 63.57万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-12 至 2022-11-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10412368
• 关键词: Active Immunization; Adjuvant; Affect; Allogenic; Antigens; Autologous; Biological Markers; Cancer Vaccine Related Development; Cancer Vaccines; Cancerous; Cell surface; Cells; Colorectal Cancer; Colorectal Neoplasms; Common Neoplasm; Data; Development; Evaluation Studies; Future; Genes; Germ-Line Mutation; Goals; Heritability; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunocompetent; Immunologic Memory; Immunosuppression; Immunotherapy; Intercept; Knowledge; Lesion; Logistics; Malignant Neoplasms; Modeling; Mus; Mutation; Neoplasm Transplantation; Oncogenic; Play; Preclinical Drug Development; Premalignant Cell; Prevention; Preventive vaccine; Process; Program Development; Proteins; Reporting; Role; Syndrome; Tumor Antigens; Tumor Immunity; Tumor-Derived; Vaccinated; Vaccination; Vaccine Antigen; Vaccines; anti-tumor immune response; base; cancer invasiveness; cancer prevention; cohort; colon tumorigenesis; colorectal cancer prevention; cost; efficacy evaluation; experience; immune checkpoint blockade; immunogenic; immunogenicity; imprint; in vivo; in vivo Model; individual patient; induced pluripotent stem cell; induced pluripotent stem cell technology; manufacturing process; neoantigens; overexpression; preclinical efficacy; premalignant; preservation; prevent; stem cells; tumor; tumor growth; tumorigenic; vaccine trial

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.

最近开发用于非病毒癌症的癌症疫苗的方法集中于靶向在癌前病变和癌性病变中过表达的已知致癌蛋白（新抗原）或肿瘤相关抗原（TAA）。在预防背景下，这些癌症疫苗旨在引发抗肿瘤免疫，预防或拦截肿瘤发生过程，并在癌前细胞发展为侵袭性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。在预防环境中，通过针对肿瘤抗原（新抗原和TAA）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。如果可以建立长期免疫记忆，这种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技术及其在各种生物医学领域的潜在效用已经获得了许多知识和经验。Wu，Levy等人（Cell 2015，161：240; Cell Stem Cell 2018，22：501; Cell Stem Cell 2021，28：10）先前已经表明，人和鼠iPSC具有宿主的生殖系突变、印记基因网络失调和癌症相关突变，并在细胞表面上表达肿瘤特异性抗原。Wu等人进一步证明，用具有CpG佐剂的经辐照的iPSC接种引发了稳健的抗肿瘤免疫应答，所述抗肿瘤免疫应答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。或者，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，则它们可以用作抗原递送载体。Deuse等人最近报道了同种异体iPSC的低免疫原性衍生物可以在完全免疫活性的受体中逃避免疫排斥。虽然目前尚不清楚这些低免疫原性同种异体（hypoallogeneic）iPSC是否仍然可以在同种异体宿主中引发抗肿瘤免疫应答，但值得评估“现成的”基于hypoallogeneic iPSC的疫苗用于癌症预防的功效和潜在效用。 本研究的目的是在结直肠肿瘤发生的鼠同基因肿瘤移植模型中检查基于低同种异体iPSC的疫苗与基于自体iPSC的疫苗的免疫原性和抗肿瘤功效，以确定用于未来体内功效评价研究的最佳iPSC疫苗平台。