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

最近开发非病毒性癌症癌症疫苗的方法主要集中在靶向已知的癌基因蛋白(新抗原)或在癌前病变和癌组织中过度表达的肿瘤相关抗原(TAA)。在预防方面，这些癌症疫苗旨在诱导抗肿瘤免疫，以防止或拦截肿瘤形成过程，并在癌前细胞进展为侵袭性癌症之前消除它们。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，通过主动免疫肿瘤抗原(新抗原和TAA)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、更有效的方法来预防癌症，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。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抗原。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。Wu，Levy等人(Cell 2015,161：240；Cell Stem Cell 2018，22：501；Cell Stem Cell 2021，28：10)先前已经证明，人和小鼠的IPSCs含有宿主的生殖系突变、印记基因网络失调和癌症相关突变，并在细胞表面表达肿瘤特异性抗原。Wu等人。进一步证明，用CpG佐剂照射的iPSCs接种可诱导出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。或者，如果异体IPSCs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，那么它们可能是有用的抗原递送载体。Deuse等人。最近有报道称，异体免疫干细胞的低免疫原性衍生物可以在完全具有免疫能力的受体中逃避免疫排斥反应。虽然目前尚不清楚这些低免疫原性同种异体(低同种异体)IPSCs是否仍能在同种异体宿主中引发抗肿瘤免疫反应，但值得评估基于现成的低同种异体IPSCs疫苗用于癌症预防的有效性和潜在用途。 本研究旨在比较同种异体IPSC疫苗和自体IPSC疫苗在小鼠同种异体结直肠癌移植瘤模型中的免疫原性和抗肿瘤效果，为今后的体内疗效评价研究确定最佳的IPSC疫苗平台(S)。

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.