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

SBIR 第一期：用于新型 T 细胞免疫疗法的工程诱导胸腺上皮细胞

• 批准号: 2234041
• 负责人: Hui Gai
• 金额: $ 27.5万
• 依托单位: RATTAN LIFE SCIENCE INC.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2234041&HistoricalAwards=false
• 关键词: SBIR; Phase; Engineered; Induced; Thymic

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.

这个小型企业创新研究(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。采用细胞疗法(ACT)使癌症患者的医学发生了革命性的变化，CAR-T疗法在治疗晚期难治性白血病和淋巴瘤方面取得了显著的成功。尽管在血液恶性肿瘤方面取得了成功，但实体肿瘤，约占癌症的90%，仍然难以治愈。要根除较大的肿瘤并达到完全缓解，成功的ACT需要持续的体内抗肿瘤作用。研究强调了更好的ACT疗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，幼稚的T细胞来源的效应细胞表现出强大的增殖能力、强大的肿瘤杀伤力以及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瘤具有明显更高的效率。该项目可能使大规模和可再生的同质T细胞的生产具有最佳和持久的肿瘤杀伤性能。这一方法旨在解决T细胞耗尽这一尚未满足的挑战，提高可扩展性，减少重复采血，并为患者提供更广泛的途径。该项目旨在开发一种平台技术，以产生IPSC来源的NAÏve CD4+和CD8+T细胞，具有保真度、可重复性和可扩展性。该平台使用一种专有方法来产生IPSC来源的胸腺上皮细胞，作为实现天真T细胞产生的关键元素。其基本原理存在于胸腺的自然生物学中，在胸腺中，未成熟的CD_4~+CD_8~+双阳性T细胞向NAÏve CD_4~+或CD_8~+T细胞的转变需要通过一种称为正选择的过程与胸腺上皮细胞相互作用。目前基于Notch激活的IPSC来源的T细胞方法的治疗效果引起了关注，因为通过单一Notch激活产生的T细胞在表型和功能上都不同于NaÏve T细胞。通过提供生物学上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细胞免疫疗法的开发取得了重大进展，并具有临床上的细胞保真度。建议平台的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NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。