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

这个小企业创新研究（SBIR）第一阶段项目的更广泛影响是开发新的现成T细胞免疫疗法。免疫细胞疗法（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着的成功。尽管在血液恶性肿瘤方面取得了成功，但占癌症约90%的实体瘤仍然难以治愈。为了根除大的肿瘤肿块并达到完全缓解，成功的ACT需要持久的体内抗肿瘤作用。研究强调了更大的ACT功效与转移具有体内扩增和记忆形成能力的T细胞之间的相关性。在主要的T细胞亚群中，与进一步分化的细胞类型相比，幼稚T细胞已被确定为ACT的最佳细胞来源。在体内，幼稚T细胞衍生的效应细胞表现出稳健的增殖、有效的肿瘤杀伤和对终末分化和耗竭的抗性。在体外，这些细胞对血液恶性肿瘤和实体瘤具有显著更高的效率。该项目可以大规模和可再生地生产具有最佳和持久肿瘤杀伤特性的同质T细胞。这种方法旨在解决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，用于产生具有保真度，可重复性和可扩展性的iPSC衍生的幼稚CD 4+和CD 8 + T细胞。该平台采用专有方法生成iPSC衍生的胸腺上皮细胞，作为实现幼稚T细胞生产的关键要素。其原理在于胸腺的天然生物学，其中未成熟的CD 4 + CD 8+双阳性T细胞向幼稚的CD 4+或CD 8 + T细胞的转变需要通过称为阳性选择的过程与胸腺上皮细胞相互作用。已经提出了关于与当前基于Notch活化的iPSC衍生的T细胞方法相关的治疗功效的担忧，因为通过单独的Notch活化开发的T细胞在表型和功能上不同于幼稚T细胞。基于Notch激活的胸腺外分化方法的主要技术限制通过提供生物学相关的胸腺阳性选择信号来解决。由此产生的产品能够在开发具有临床相关细胞保真度的基于iPSC的T细胞免疫疗法方面取得重大进展。建议平台的可再生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NSF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.