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

Rattan Life Science Inc., Sunnyvale CA

Investigators

Abstract

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.