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January 18, 2021

A new method to make a massive number of anti-cancer cells

The Shin Kaneko laboratory reports a new method that produces T cells at massive scale and clinical grade.

Cancer immunotherapies have quickly become the most potent medical attack against cancer. The patient's own cells, namely T cells, are removed, manipulated and transplanted back. Building on this effort are scientists like CiRA Professor Shin Kaneko, who is using iPS cell technologies to prepare T cells for an "off-the-shelf" cancer immunotherapy.

In its latest study, his lab reports a new method to prepare clinical-grade T cells at mass scale. The method was shown to work using the iPS cell stock manufactured at CiRA, which has been the source for many other cell products that have been transplanted into patients in clinical trials.

In cancer immunotherapies, T cells are harvested from the patient's blood and manipulated to enhance their antagonistic effects against cancer cells. Part of the manipulation includes proliferating the cells, akin to increasing the number of soldiers to a battle.

However, current methods can only proliferate T cells to a degree. Stem cells, iPS cells especially, on the other hand, can be proliferated almost without limit. Further, iPS cells can be then differentiated into just about any cell type including T cells. It is for this reason that the Kaneko lab is researching the use of iPS cells to prepare new cancer immunotherapies.

"The iPS cell stock provides us a clinical-grade starting source to produce T cells. However, there has been no effective method that differentiates the iPS cells under clinical standards," said Kaneko.

Many cell types including blood cells have been manufactured from iPS cells without animal materials. CiRA Professor Koji Eto's platelet products are one example. However, Kaneko's team claims its paper is the first to produce T cells from iPS cells in this condition at mass scale.

"Feeder-free and serum-free systems for pluripotent stem cell proliferation and hematopoietic differentiation are well established, but none are for T cells," said Dr. Shoichi Iriguchi, who managed the project.

Key to their new differentiation system was the effects of two molecules known to have a role in T cell development: the chemokine SDF1α, or stromal cell defined factor 1 alpha, and the p38 inhibitor SB203580.

"We found SDF1α and SB203580 upregulated BCL11B gene, a master regulator of T cell commitment, while suppressing genes for myeloid commitment," said Iriguchi.

With this new method, the researchers prepared T cells from the iPS cell stock.

"The stock is designed to serve as many patients as possible. Therefore, we anticipate that a successful immunotherapy using T cells generated from the iPS cell stock will be widely available," said Kaneko.

The iPS cells were modified to express a T-cell receptor that would cause the resulting T cells to react to a gene commonly expressed in many cancer cells, Wilms tumor 1 (WT1). Transplanting the resulting T cells into mice suffering from cancer extended the lifespans by about 50%. The same cells were also compatible with chimeric antigen receptor (CAR) technology, which allows scientists to modify T cells to target a specific type of cancer.

"The advantage of combining CAR T therapy and iPS cells is that we can make many T cells from the iPS cell stock to attack the any type of cancer," explained Kaneko.

Both CAR T and iPS cell therapies have made the news in recent years, but for different diseases. Iriguchi is optimistic that the combinatorial approach by the lab will make cancer immunotherapies available readily for anyone.

"The stock removes the need to take cells from the patient, which requires time. Instead, our goal is to make an 'off-the-shelf' T cell product from iPS cells that is no different than getting a blood transfusion in the hospital," he said.

Paper Details
  • Journal: Nature Communications
  • Title: A clinically applicable and scalable method to regenerate T-cells from iPSCs for off-the-shelf T-cell immunotherapy
  • Authors: Shoichi Iriguchi1,2, Yutaka Yasui1, Yohei Kawai1,2, Suguru Arima2,3, Mihoko Kunitomo2,3,
    Takayuki Sato2,3, Tatsuki Ueda1, Atsutaka Minagawa1,2, Yuta Mishima1,2, Nariaki Yanagawa1,2,
    Yuji Baba2,3, Yasuyuki Miyake1,2, Kazuhide Nakayama2,3, Maiko Takiguchi2,3, Tokuyuki Shinohara2,3,
    Tetsuya Nakatsura4, Masaki Yasukawa5, Yoshiaki Kassai2,3, Akira Hayashi2,3, and Shin Kaneko1,2
  • Author Affiliations:
    1. Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application,
      Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
    2. Takeda-CiRA Joint Program (T-CiRA), Fujisawa, Japan
    3. T-CiRA Discovery, Takeda Pharmaceutical Company, Fujisawa, Japan
    4. Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center,
      National Cancer Center, Kashiwa, Chiba, Japan
    5. Department of Hematology, Clinical Immunology and Infectious Disease,
      Ehime University Graduate School of Medicine, Toon, Japan
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