(Published in 2018)
A research team led by Professor Shin Kaneko at the Center for iPS Cell Research and Application (CiRA), Kyoto University, has succeeded in enhancing the anti-tumor effect of regenerative T-cells from human iPS cells (iPSCs) by genome editing.
In this study, regenerative T-cells’ ability to attack tumor cells has been confirmed in a mouse study, which is a giant step towards clinical application. Professor Kaneko’s team is an advanced team working under T-CiRA, a joint research program with Takeda Pharmaceutical Company.
Current T-cell immunotherapy
T-cells are a type of immune cell. T-cells proliferate and eliminate non-self cells such as virus-infected cells and tumor cells.
When genes encoding a tumor-reactive T-cell receptor (TCR) are introduced into a patient’s T-cells, the number of the T-cells that attack a certain tumor can be increased. It is expected that the T-cells will attack and heal a certain tumor by transplantation.
Since each T-cell expresses one type of TCR, it can recognize only one type of antigen and does not respond to other antigens (antigen specificity). Therefore, TCR-transduced T-cells can specifically attack tumor cells.
Limitations of current T-cell immunotherapy
TCR- transduced T-cells from a patient’s own cells are less proliferative, and the number of them is limited. Moreover, these cells’ aggressiveness against tumor cells is weakened.
Results of this study
Firstly, the research team produced T-iPSCs from tumor-reactive T-cells in a patient’s blood, and then regenerate T-cells from the T-iPSCs. They found that these regenerative T-cells lose antigen specificity due to additional TCR gene rearrangement in the DP cell stage, one of precursor stages between iPSCs and T-cells, and they cannot attack tumor cells.
To solve this problem, they knockout RAG2 gene in T-iPSCs by using a genome editing system (CRISPR/Cas9) and have succeeded in blocking the unwanted rearrangement. The genome-edited T-cells were injected into tumor-bearing mice. Recipients of the genome-edited T-cells showed delayed tumor growth and longer survival compared to non-treated mice.
Secondly, they regenerate T-cells from monocyte-derived iPSCs that were transduced with an antigen-specific TCR. These regenerative T-cells expressed the transduced TCR without RAG2 gene knockout.
The TCR-transduced T-cells were injected into tumor-bearing mice. Recipients of the TCR-transduced iPSC-derived T-cells showed delayed tumor growth and superior survival compared to a group treated by TCR-transduced primary T-cells and a non-treated group. Furthermore, the group treated by the TCR-transduced iPSC-derived T-cells showed lower incidence of tumor metastasis.
Their study could contribute to safe and effective regenerative T-cell immunotherapies.
Immunotherapy with T-cell-derived iPSCs
iPSCs can proliferate indefinitely. If we produce iPSCs from antigen-specific T-cells (T-iPSCs) and regenerate T-cells from T-iPSCs, we can get many proliferative T-cells. For safe and effective immunotherapy, it is important to regenerate T-cells which exhibit the same antigen specificity as the original T-cells. This therapy utilizes a patient’s own T-cells and can only be used for the patient.