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April 02, 2020

New ovarian cancer therapy using stem cells

The Shin Kaneko Laboratory reports the combination of CAR and iPS cell technologies to produce NK cells for cancer treatment

CiRA scientists show for the compatibility of CAR (chimeric antigen receptor) and iPS cell technologies for the manufacturing of natural killer (NK) cells in cancer immunotherapies. They use these NK cells to treat human ovarian cancer in mutant mice, with expectation of using these cells in patients. The study can be seen in Cancer Science.

Among CAR therapies, CAR-T therapy is the best known. CAR-T therapy is a new form a cancer therapy in which T cells from the patient are reprogrammed to express an antigen receptor that has a high affinity for cancer cells. T cells are harvested from the patient, undergo CAR modification, and are then proliferated. The expanded CAR-T cells are then infused back to the patient, where they kill cancer cells, and their success has revolutionized the cancer field.

"It seems every research group developing anti-cancer treatments is studying CAR-T," says CiRA Associate Professor Shin Kaneko.

Besides killing off foreign pathogens, the immune system is also designed to kill cancer cells before they spread. Cancers thrive when they evade the immune system, playing a game of hide-and-seek. By wisely selecting the antigen receptor, CAR-T therapies give the immune system Superman-like x-ray vision. The result is a remarkable effect against otherwise incurable cancers.

Or, more accurately, "some" otherwise incurable cancers. It turns out that the success of CAR-T therapies is mostly with leukemias, whereas solid tumors have proven more adept at resisting CAR-T.

The Shin Kaneko laboratory is an expert at producing immune cells from iPS cells. Considering that T cells are just one subset of the whole immune cell family, Dr. Tatsuki Ueda, M.D., a scientist in the lab, wondered if using CAR on other immune cells could prove effective for tumor cells.

"Very recently NK cell-based immunotherapies have demonstrated good clinical efficacy," he says, "but the NK cells show short persistency and insufficient tumor homing."

One of the challenges in all CAR therapies is the proliferation step. This step tends to compromise the function of the cells. As a solution, Kaneko has shown that iPS cells can be modified with CAR and then expanded. Expanding CAR-iPS cells is much easier than other cell types and maintains the integrity of the immune cell function.

By making the CAR one with a high affinity for glypican-3, a membrane protein specifically expressed on liver and ovarian cancer cells, his team could effectively and safely eliminate tumors in the mutant mice using NK cells derived from CAR-iPS cells.

"Chemotherapy for clear-cell carcinoma of the ovary is not effective in relapse or recurrent cases", Kaneko explains for why his team selected a CAR for glypican-3.

The resulting NK cells made from the CAR-iPS cells showed a good anti-tumor effect in mice.

In addition, one of the concerns about any cancer therapy is the killing of non-cancer cells. Here too, the manufactured NK cells passed grade.

Another important point of the study is that the iPS cells used came from the CiRA iPS Cell Stock and were approved for patient use. In fact, CiRA and National Cancer Center Hospital East are preparing a framework for a clinical study to treat disseminated ovarian cancer.

"The combination of CAR and iPS cells could also make all immune cells for a potent anti-cancer therapy," says Kaneko.

Paper Details
  • Journal: Cancer Science
  • Title: Non-clinical efficacy, safety, and stable clinical cell processing of iPSC-derived anti-GPC3 CAR-expressing NK/ILC cells
  • Authors: Tatsuki Ueda1, Ayako Kumagai1, Shoichi Iriguchi1, Yutaka Yasui1,2, Tadayo Miyasaka1, Kengo Nakagoshi1, Kazuki Nakane1, Keigo Saito3, Mari Takahashi3, Aki Sasaki4, Shinsuke Yoshida4, Naoko Takasu4, Hiroshi Seno5, Yasushi Uemura3, Koji Tamada6, Tetsuya Nakatsura3, Shin Kaneko1
  • Author Affiliations:
    1. Shin Kaneko Laboratory, Department of Cell growth and Differentiation, Center for iPS cell research and application (CiRA), Kyoto University, Japan
    2. Thyas Co. Ltd., Kyoto, Japan
    3. Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan
    4. Department of Life Science Frontiers, Center for iPS cell research and application (CiRA), Kyoto University, Kyoto, Japan
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