Frontline Cancer: Some cancers may be suitable targets of iPSC-derived NK cells

FRONTLINE CANCER:

In recent years, CAR-T cell-based immunotherapies have grabbed headlines, taking off like, well, a race car. Broadly speaking, these treatments are based on the idea that the body's own immune system is best-suited to fighting cancer — something it does every day to great effect in most people — but that sometimes it can use extra help.

Until recently, cancer treatments have been relatively blunt-force remedies that do not adequately differentiate between healthy and malignant cells. They often sacrificed normal tissues in the effort to kill cancerous cells, resulting in temporary but often harsh side effects and long-term unwanted consequences, including secondary malignancies. Moreover, many therapies do not account for the heterogeneity or differences in cancers between individual patients with the same diagnosis, or even within a single tumor in a single patient. No two cancers are alike, and no cancer looks exactly the same everywhere within an afflicted individual.

Our immune systems are generally up to the task of fighting back. The innate immune system rushes to the immediate attack of any perceived pathogen — invader or malignant cell — with an army of first responders: neutrophils, monocytes, macrophages, cytokines and acute phase proteins. The adaptive immune system responds with cells specifically armed to meet the enemy: B lymphocytes and T lymphocytes, both types of white blood cells.

Emerging CAR-T cell immunotherapies are based on the idea of extracting normal T-cells from cancer patients and basically upgrading them with genetically modified chimeric antigen receptors (the CAR in CAR-T) so that they bind with a certain protein on the patient's cancer cells, the first step to killing them. These modified CAR-T cells are grown in large numbers in a lab and then infused back into the patient.

There have been some striking success stories using immunotherapy, but progress is uneven and sometimes over-hyped. The approach demands a lot more study and testing. And it's time-consuming and costly. T-cells must be isolated from each patient. They work only in that patient. If it's not possible to harvest sufficient T-cells, there is no immunotherapy.

But there may soon be another option. Natural killer (NK) cells are another type of immune cell that also belongs to the innate immune system. They recognize and respond to abnormal cells, typically cells infected by a virus or that are in some way mutated. In a recent paper, published in Cell Stem Cell, Dan Kaufman, M.D., Ph.D., a professor of medicine in the division of regenerative medicine and director of cell therapy at UC San Diego School of Medicine, and colleagues reported that modified NK cells derived from human-induced pluripotent stem cells (iPSCs, the cells that can become almost any type of cell) also displayed heightened activity against a mouse model of ovarian cancer.

In short, Kaufman and colleagues created CAR-NK cells from iPSCs and tested them in mice carrying a human ovarian cancer xenograft. They compared that approach against other versions of NK cells and CAR-T cells. The former worked as well as the latter, but with less toxicity. And data showed that other solid tumors, such as breast, colon and brain cancers, plus blood cancers like leukemia, might also be suitable targets of iPSC-derived NK cells.

The news is significant. Unlike T-cells, NK cells don't have to be matched to a specific patient and they can be grown in the lab from multiple lines of iPSCs. "One batch of iPSC-derived NK cells can be potentially used to treat thousands of patients," said Kaufman, "which means we can develop standardized, 'off-the-shelf' treatments and use these in combination with other cancer drugs."

Also, previous research by Kaufman and others indicates that NK cells do not trigger the same kinds of toxicities as chemotherapy, radiation or even CAR-T cells. In their paper, the researchers found few adverse effects in mouse models. NK cells may just be safer to use.

"Because this innovative iPSC-derived NK therapy may overcome defects in the patient's own immune system, it may help to eradicate ovarian cancer relapse in its early stages and thus is a tremendous advance for the field of cancer research and regenerative medicine," said Catriona Jamieson, M.D., Ph.D., chief of the division of regenerative medicine and deputy director of the Moores Cancer Center at UC San Diego Health.

The war on cancer often seems like a slog, a hurry up and wait for the next remedy, which may or may not come. That's true, but occasionally, the news is more exciting than not. CAR-T immunotherapies have been in clinical trials for a while, a necessary step before they can become standard treatment.

Kaufman and colleagues are working with private industry to launch the first safety trials for their iPSC-derived NK cells. It can't happen a moment too soon.

— Scott M. Lippman, M.D., is director of UC San Diego Moores Cancer Center. His column on medical advances from the front lines of cancer research and care appears in this publication monthly. You can reach Dr. Lippman at mcc-dir-lippman@ucsd.edu

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