Immunotherapies have given hope to a large number of cancer patients. These therapies involve processing the patient's own immune cells so that they have a far stronger curative effect against cancer cells with fewer side effects compared to radiotherapies and chemotherapies. CAR (chimeric antigen receptor) immunotherapies are the latest and most powerful iteration. A new study led by CiRA Associate Professor Shin Kaneko shows how adding iPS cell technology to CAR immunotherapies adds even more potency to the treatment. The new therapy can effectively kill human ovarian cancer cells in mice and is the last step before starting patient trials.

CAR immunotherapies involve genetically modifying immune cells so that the cells are more effective at homing cancer-specific antigens. They are now available for treating leukemias, but there are still many obstacles before they reach clinical effectiveness for solid tumors like ovary cancer.

"Solid tumors have a more hostile environment than leukemias. Their size makes it difficult to penetrate the inner layers, and they have stronger immunosuppressive effects," explains Kaneko.

In previous work, the Kaneko team has shown how iPS cell technology can mitigate this immunosuppression by what he calls "rejuvenating" the immune cells. The group has therefore investigated how incorporating iPS cell technology into CAR therapies could enhance treatments for solid tumors.

Among the type of immune cells that can be produced by iPS cells, Kaneko focused on NK cells because, he explains, "They have strong cytotoxicity to tumor cells and CAR can increase their antigen specificity."

Ovary cancer was chosen because ovary cancer cells express glypican-3 (GPC3), an antigen expressed by several types of cancer cells but hardly by normal cells. Indeed, an early stage clinical trial of a CAR immunotherapy for liver cancer targeting GPC3 has shown little side effects. Another reason for the choice is that current treatments for ovary cancer have limited effectiveness.

iCAR cells were made by modifying clinical-grade iPS cells from a healthy donor to express the GPC3 receptor. Normally in CAR immunotherapies, the immune cells used come from the patient. This approach minimizes the risk of an immune reaction by the patient to the transplanted cells but is not an option for iPS cell-based immunotherapies because of the added time needed to reprogram the cells to iPS cells and then differentiate them into the immune cells used for the immunotherapy.

"GVHD [graft-versus-host disease] is a major concern for any therapy using cells from donors. We did comprehensive tests to confirm that GVHD did not occur in our mouse models," explains Dr. Tatsuki Ueda, a scientist in the Kaneko lab and first author of the study.

The iCAR cells were then differentiated into natural kill cells (iCAR NK cells) and administered into mice in which ovarian cancer cells were injected days earlier, extending the lifespan of the animals by 50%. Other tests including the risk of tumorigenicity, which is always a concern when using stem cells in a therapy, further confirmed the safety of the iCAR NK cells.

Because the iCAR NK cells were made following Japanese regulations, Kaneko hopes to start his clinical trial within the next couple of years.

"There are more than 400 clinical trials using NK cells in immunotherapies, but the NK cells show short persistency, limited proliferation and poor tumor-targeting. We expect the combination of CAR and iPS cell technology will be a breakthrough for NK cell therapies," says Kaneko.

• doi: 10.1111/cas.14374