Kyoto University developed a scalable method to regenerate T-cells from iPSCs

A research team led by Professor Shin Kaneko at the Center for iPS Cell Research and Application (CiRA), Kyoto University, has succeeded in developing a clinically applicable and scalable method for T-cell generation from human iPSCs. The research was published in the scientific journal Nature Communications on January 18, 2021.

Current T-cell immunotherapy
In recent years, chimeric antigen receptor T-cell (CAR-T) therapy has come to be used in the treatment of tumor, and T-cell immunotherapy has been developed for a variety of diseases. T-cells are a type of immune cell. When T-cells recognize antigen proteins on the surface of non-self cells such as virus-infected cells and tumor cells, they proliferate and eliminate cells bearing those antigens. CAR-T therapy aims to induce immune reactivity against tumors by introducing genes encoding a tumor-reactive T-cell receptor (TCR) into patient T-cells. However, autologous CAR-T therapies are created from the blood of each individual patient, so they are slow and expensive. Furthermore, the obtained T-cells are less proliferative, and the number of them is limited.

iPSC-derived T-cell immunotherapy
If “off-the-shelf” and synthetic allogeneic T-cells can be produced from induced pluripotent stem cells (iPSCs) by using a clonal master iPSC bank, CAR-T therapy will be available to more patients.

Technical challenges of current methods
Even though it is possible to regenerate T-cells from iPSCs, low differentiation efficiency and poor scalability of current methods were challenges to be solved. T-cell differentiation from iPSCs required multiple murine stromal feeder cell layers to adjust the culture environment, which makes the control and reproducibility challenging. Moreover, all these cells would need to be free of virus contamination for clinical application, which may be extremely expensive or impossible in some cases.

Results of this study
In this study, the research team has established a feeder-free differentiation system, which is crucial to develop iPSC-based T-cell immunotherapy. They also identified SDF1α and a p38 inhibitor as the factors that facilitate T-cell differentiation. Adding these factors in culture medium enables to obtain large numbers of T-cells stably. Additionally, they confirmed that TCR-engineered iPSC-derived T-cells (iT cells) using the system shows anti-tumor activities both in vitro and in vivo tumor xenograft model. They generated CD19 chimeric antigen receptor-expressing iT cells (iCART cells) and injected them intravenously into leukemia-bearing mice. The analysis of bone marrow cells from iCART cell recipients revealed near complete elimination of tumor cells at day 10 and 15 after treatments. Recipients of iCART cells showed delayed relapse and longer overall survival compared to control groups. According to the results, iT cells can be used as a material for CAR-T therapies. This established system may provide a foundation to apply allogeneic iPSC-derived T-cell immunotherapy in a clinical setting as well as to study human T-cell biology.

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