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

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. _x000D_ _x000D_ 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._x000D_ _x000D_ 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.