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A stem cell “kill switch” may make therapies safer, say Stanford researchers

3225255407_596aa5bdff_zStem cell biologist Hiromitsu Nakauchi, MD, PhD, and his colleagues published an interesting article today about how to use stem cell technology to boost our body's own immune cells to fight cancer or chronic viral infections like HIV or Epstein Barr virus. Because there's a possible cancer risk with the use of induced pluripotent stem cells, or iPS cells, in humans, he and his colleagues have devised an innovative way to specifically eliminate these cells within the body if they start to cause problems. Their research appears today in Stem Cell Reports.

As Nakauchi explained to me in an email:

The discovery of induced pluripotent stem cells created promising new avenues for therapies. However, the tumorigenic potential of undifferentiated iPSCs is a major safety concern that must be addressed before iPS cell-based therapies can be routinely used in the clinic.

The researchers studied a type of immune cell called a cytotoxic T cell. These cells recognize specific sequences, or antigens, on the surface of other cells. Some antigens indicate that the cell is infected with a virus; others are found on cells that have become cancerous. When a cytotoxic T cells sees these antigens, it moves in to kill the cell and remove the threat.

In order to ensure that our immune systems recognize the widest variety of antigens, developing T cells randomly shuffle their genes to create unique antigen receptors. Researchers have found that it's possible to identify, and isolate, T cell populations that specifically recognize cancer cells. By growing those cells in the laboratory, and then injecting them back into a patient, clinicians can give a boost to the immune response that can help kill tumor cells. The technique is known as adoptive immunotherapy, and it's shown promise in treating melanoma. However, these cytotoxic T cells can become exhausted as they fight the cancer and become less effective over time.

Recently researchers in Nakauchi's lab showed that it's possible to create induced pluripotent stem cells from cytotoxic T cells. These iPS cells are then induced to again become cytotoxic T cells. These rejuvenated T cells, or rejT cells, recognize the same antigen they did before their brief dip in the pluripotency pool, but they are far more sprightly than the cells from which they were derived - they can divide many more times and have longer telomeres (an indicator of youthfulness).

So far, so good. But, as Nakauchi mentioned above, iPS cells carry their own set of risks. Because they are by definition pluripotent (they can become any cell in the body), they can easily grow out of control. In fact, one way of proving a cell's pluripotency is to inject it into an animal and see if it forms a type of tumor called a teratoma, which is made up of multiple cell types.

Nakauchi and his colleagues hit upon a way to manipulate a naturally existing suicide pathway to control whether the cells lived or died in a mouse model. By introducing a gene encoding a protein called inducible caspase-9, or iC9, into the cytotoxic T cells, they found they could cause the cells to die throughout the body by activating iC9 with a specific chemical. These engineered T cells still recognized the same antigens, and were just as effective against cancer tumors as their unmodified peers. But they were quickly eliminated with a simple treatment.

This isn't the first time that researchers have explored the idea of a "kill switch" in iPS cells. But the iC9 approach efficiently and quickly kills cells whether or not are they dividing. (Previous approaches were effective only against rapidly dividing cells.) The research suggests that iC9 might be a viable way to increase the safety of iPS-cell-based therapies in humans.

As Nakauchi told me, "I think we are one step closer to a safe and efficient way to use adoptive immunotherapy against cancer."

Previously: “It’s not just science fiction anymore”: Childx speakers talk stem cell and gene therapy, Training the immune system to attack cancer throughout the body: A new clinical trial at Stanford and Researchers prime immune system’s T cells with foreign antibodies to target cancer cell
Photo by Tim Regan

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