SBIR Phase I: Engineered Induced Thymic Epithelial Cells for Novel T Cell Immunotherapies

这个小企业创新研究（SBIR）一期项目的更广泛影响是开发新的现成的T细胞免疫疗法。过继细胞疗法（ACT）已经彻底改变了癌症患者的医学，CAR-T疗法在治疗晚期和难治性白血病和淋巴瘤方面取得了显著成功。尽管在血液恶性肿瘤方面取得了成功，但占癌症约90%的实体肿瘤仍然难以治愈。为了根除大肿瘤块并达到完全缓解，成功的ACT需要持续的体内抗肿瘤作用。研究强调了ACT的有效性与体内扩增和记忆形成能力的T细胞转移之间的相关性。在主要的T细胞亚群中，naïve T细胞已被确定为ACT的最佳细胞来源，而不是进一步分化的细胞类型。在体内，naïve t衍生效应细胞表现出强大的增殖能力，强大的肿瘤杀伤能力和对终末分化和衰竭的抵抗力。在体外，这些细胞对血液恶性肿瘤和实体肿瘤具有显著更高的效率。该项目可能使大规模和可再生生产具有最佳和持久肿瘤杀伤特性的同质T细胞成为可能。该方法旨在解决T细胞耗竭的未满足挑战，提高可扩展性，减少重复采血，并提供广泛的患者访问。该项目旨在开发一种平台技术，用于生成ipsc衍生的naïve CD4+和CD8+ T细胞，具有保真度、可重复性和可扩展性。该平台采用专有方法生成ipsc衍生的胸腺上皮细胞，作为实现naïve T细胞生产的关键元件。其基本原理存在于胸腺的自然生物学中，未成熟的CD4+CD8+双阳性T细胞向naïve CD4+或CD8+ T细胞的转变需要通过一个称为阳性选择的过程与胸腺上皮细胞相互作用。人们对目前基于Notch激活的ipsc衍生T细胞方法的治疗效果提出了担忧，因为仅通过Notch激活发展的T细胞在表型和功能上与naïve T细胞不同。通过提供生物学相关的胸腺阳性选择信号，解决了基于Notch激活的胸腺外分化方法的主要技术限制。由此产生的产品使基于ipsc的T细胞免疫疗法的发展取得了重大进展，具有临床相关的细胞保真度。该平台的可重复性和可扩展性将在生物反应器中进行评估和优化，以证明商业化的可行性。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact of this Small Business Innovation Research (SBIR) Phase I project is to develop novel off-the-shelf T cell immunotherapies. Adoptive Cell Therapy (ACT) has revolutionized medicine for cancer patients, as evidenced by the remarkable success of CAR-T therapies in treating advanced and refractory leukemia and lymphoma. Despite the success in blood malignancies, solid tumors, representing approximately 90% of cancers, remain difficult to cure. To eradicate large tumor masses and reach complete remission, successful ACT requires persistent, in vivo anti-tumor effects. Studies have highlighted the correlation between greater ACT efficacy and transferring T cells with capacity of in vivo expansion and memory formation. Among major T cell subsets, naïve T cells have been identified as the optimal cell source for ACT compared to further differentiated cell types. In vivo, naïve T-derived effector cells demonstrate robust proliferation, potent tumor-killing and resistance to terminal differentiation and exhaustion. In vitro, these cells have significantly higher efficiency for blood malignancies and solid tumors. This project may enable large-scale and renewable production of homogenous T cells with optimal and persistent tumor-killing properties. This approach aims to address the unmet challenges of T cell exhaustion, improve scalability, reduce repeated blood collection, and offer broad patient access. The proposed project aims to develop a platform technology for generation of iPSC-derived naïve CD4+ and CD8+ T cells with fidelity, reproducibility and scalability. The platform employs a proprietary method to generate iPSC-derived thymic epithelial cells as a critical element to enable naïve T cell production. The rationale resides in the natural biology of the Thymus, where the transition of immature CD4+CD8+ double positive T cells to naïve CD4+ or CD8+ T cells requires interaction with thymic epithelial cells through a process called positive selection. Concerns have been raised regarding the therapeutic efficacy associated with current Notch-activation based iPSC-derived T cell methods because T cells developed through sole Notch activation are phenotypically and functionally different from naïve T cells. Major technical limitations in Notch activation-based extrathymic differentiation methods are addressed by providing biologically relevant thymic positive selection signals. The resulting product enables a significant advance in the development of iPSC-based T cell immunotherapies with clinically relevant cell fidelity. Reproducibility and scalability of the proposed platform will be assessed and optimized in a bioreactor to demonstrate viability for commercialization.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.